59 results on '"Airoldi C."'
Search Results
2. A community-built calibration system: The case study of quantification of metabolites in grape juice by qNMR spectroscopy
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Ales Čamra, John Warren, Taylor David, Dinesh Chalasani, Daniele Ragno, Jan Teipel, Tommaso Di Noia, Aurimas Bieliauskas, Elina Zailer-Hafer, Stefano Todisco, Domenico Acquotti, Lorraine M. Bateman, James Donarski, Piero Mastrorilli, Rosa Ragone, Cristina Airoldi, John S. Harwood, Michael Assfalg, Dolores Molero Vilchez, Francesco Longobardi, Magali Martin-Biran, Elisabetta Schievano, Domenico Mallamace, Elisabetta Torregiani, Biagia Musio, Stefania Pontrelli, Paolo Dambruoso, Marina Veronesi, Livio Stevanato, Augusta Caligiani, Erwann Hamon, Maurizio Triggiani, Davide Bertelli, Flaminia Cesare Marincola, Stefano Mammi, Bernd Diehl, Vito Gallo, Daniela Valensin, Bhavaraju Sitaram, Alessandro Barge, Claudia Di Napoli, Elena Sáez Barajas, Pasquale Scapicchio, Emanuela Callone, Antonino Rizzuti, Panteleimon G. Takis, Fabio Bertocchi, Anna Borioni, Cristiano Zuccaccia, Maria Cecilia Rossi, Mario Latronico, Andrea Kobrlová, Luca Goldoni, Nicola Intini, Freddy Thomas, Roberto Gobetto, Renzo Luisi, Ana M. Gil, Pierluigi Mazzei, Julien Wist, Roberto Consonni, Francesca Benevelli, Algirdas Šačkus, Antonio Randazzo, Salvatore Milone, Archimede Rotondo, Roger J. Mulder, Silvia Davalli, Andrea Mele, Musio, B, Ragone, R, Todisco, S, Rizzuti, A, Latronico, M, Mastrorilli, P, Pontrelli, S, Intini, N, Scapicchio, P, Triggiani, M, Di Noia, T, Acquotti, D, Airoldi, C, Assfalg, M, Barge, A, Bateman, L, Benevelli, F, Bertelli, D, Bertocchi, F, Bieliauskas, A, Borioni, A, Caligiani, A, Callone, E, Čamra, A, Cesare Marincola, F, Chalasani, D, Consonni, R, Dambruoso, P, Davalli, S, David, T, Diehl, B, Donarski, J, Gil, A, Gobetto, R, Goldoni, L, Hamon, E, Harwood, J, Kobrlová, A, Longobardi, F, Luisi, R, Mallamace, D, Mammi, S, Martin-Biran, M, Mazzei, P, Mele, A, Milone, S, Molero Vilchez, D, Mulder, R, Napoli, C, Ragno, D, Randazzo, A, Rossi, M, Rotondo, A, Šačkus, A, Sáez Barajas, E, Schievano, E, Sitaram, B, Stevanato, L, Takis, P, Teipel, J, Thomas, F, Torregiani, E, Valensin, D, Veronesi, M, Warren, J, Wist, J, Zailer-Hafer, E, Zuccaccia, C, Gallo, V, Musio, B., Ragone, R., Todisco, S., Rizzuti, A., Latronico, M., Mastrorilli, P., Pontrelli, S., Intini, N., Scapicchio, P., Triggiani, M., Di Noia, T., Acquotti, D., Airoldi, C., Assfalg, M., Barge, A., Bateman, L., Benevelli, F., Bertelli, D., Bertocchi, F., Bieliauskas, A., Borioni, A., Caligiani, A., Callone, E., Camra, A., Cesare Marincola, F., Chalasani, D., Consonni, R., Dambruoso, P., Davalli, S., David, T., Diehl, B., Donarski, J., Gil, A. M., Gobetto, R., Goldoni, L., Hamon, E., Harwood, J. S., Kobrlova, A., Longobardi, F., Luisi, R., Mallamace, D., Mammi, S., Martin-Biran, M., Mazzei, P., Mele, A., Milone, S., Molero Vilchez, D., Mulder, R. J., Napoli, C., Ragno, D., Randazzo, A., Rossi, M. C., Rotondo, A., Sackus, A., Saez Barajas, E., Schievano, E., Sitaram, B., Stevanato, L., Takis, P. G., Teipel, J., Thomas, F., Torregiani, E., Valensin, D., Veronesi, M., Warren, J., Wist, J., Zailer-Hafer, E., Zuccaccia, C., and Gallo, V.
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Analyte ,Magnetic Resonance Spectroscopy ,Traceability ,qNMR Interlaboratory comparison Calibration Multiple regression Validation Food quality control ,02 engineering and technology ,01 natural sciences ,Analytical Chemistry ,NO ,Food quality control ,Matrix (chemical analysis) ,Interlaboratory comparison ,Validation ,CHIM/06 - CHIMICA ORGANICA ,Calibration ,Calibration, Food quality control, Interlaboratory comparison, Multiple regression, qNMR, Validation ,Vitis ,qNMR ,Multiple regression ,qNMR, Interlaboratory comparison, Calibration, Multiple regression, Validation, Food quality control ,Spectroscopy ,Fruit and Vegetable Juices ,Reproducibility ,Spectrometer ,Chemistry ,010401 analytical chemistry ,Analytical technique ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,qNMR, interlaboratory comparison ,Fruit and Vegetable Juice ,0210 nano-technology ,Biological system - Abstract
Nuclear Magnetic Resonance (NMR) is an analytical technique extensively used in almost every chemical laboratory for structural identification. This technique provides statistically equivalent signals in spite of using spectrometer with different hardware features and is successfully used for the traceability and quantification of analytes in food samples. Nevertheless, to date only a few internationally agreed guidelines have been reported on the use of NMR for quantitative analysis. The main goal of the present study is to provide a methodological pipeline to assess the reproducibility of NMR data produced for a given matrix by spectrometers from different manufacturers, with different magnetic field strengths, age and hardware configurations. The results have been analyzed through a sequence of chemometric tests to generate a community-built calibration system which was used to verify the performance of the spectrometers and the reproducibility of the predicted sample concentrations.
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- 2020
3. Coffee variety, origin and extraction procedure: Implications for coffee beneficial effects on human health
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Cristina Airoldi, Carlotta Ciaramelli, Alessandro Palmioli, Ciaramelli, C, Palmioli, A, and Airoldi, C
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Coffee origin ,Magnetic Resonance Spectroscopy ,Antioxidant ,Polymers ,medicine.medical_treatment ,Coffea ,Raw material ,Coffee ,01 natural sciences ,Antioxidants ,Analytical Chemistry ,Arabica and Robusta coffee ,Sonication ,chemistry.chemical_compound ,Human health ,Roasted coffee bean ,Alkaloids ,0404 agricultural biotechnology ,Nutraceutical ,CHIM/01 - CHIMICA ANALITICA ,Trigonelline ,Caffeine ,CHIM/06 - CHIMICA ORGANICA ,medicine ,Humans ,Food science ,Beneficial effects ,Principal Component Analysis ,Green coffee bean ,010401 analytical chemistry ,Melanoidin ,04 agricultural and veterinary sciences ,General Medicine ,CHIM/10 - CHIMICA DEGLI ALIMENTI ,040401 food science ,NMR metabolic profiling ,Antioxidant capacity ,0104 chemical sciences ,chemistry ,Seeds ,Chlorogenic Acid ,Food Science - Abstract
We set up an efficient protocol for the rapid analysis of NMR spectra of green and roasted coffee extracts, enabling the automatic identification and quantification of metabolites in approximately two minutes per spectrum. This method allowed for the metabolic profiling and the subsequent evaluation of the content of bioactive compounds and antioxidant activity of coffee samples, depending on their species (Arabica and Robusta), geographical origin and extraction procedure (hydroalcoholic, espresso and moka). The hydroalcoholic extraction is the most efficient method in terms of yields of low molecular weight compounds (in particular chlorogenic acids), while moka extraction provides the highest amounts of melanoidins. Moreover, that the ratio between health-giving compounds (chlorogenic acids, trigonelline and choline) and caffeine is higher in Arabica coffees. The data collected provide useful insights for the selection of coffee raw material to be used in the preparation of coffee-based dietary supplements, nutraceuticals and functional beverages.
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- 2019
4. Methacycline displays a strong efficacy in reducing toxicity in a SCA3 Caenorhabditis elegans model
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Cristina Airoldi, Maria Elena Regonesi, Paolo Tortora, Luisa Diomede, Loredana Amigoni, Margherita Romeo, Antonino Natalello, Amigoni, L, Airoldi, C, Natalello, A, Romeo, M, Diomede, L, Tortora, P, and Regonesi, M
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Tetracycline ,Transgene ,Biophysics ,FIS/07 - FISICA APPLICATA (A BENI CULTURALI, AMBIENTALI, BIOLOGIA E MEDICINA) ,Motility ,Models, Biological ,Biochemistry ,Protein Structure, Secondary ,Protein Aggregates ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,CHIM/06 - CHIMICA ORGANICA ,medicine ,Animals ,Ataxin-3 ,Caenorhabditis elegans ,Mode of action ,Molecular Biology ,Methacycline ,030304 developmental biology ,Amyloid aggregation ataxin-3 tetracycline methacycline molecular recognition Caenorhabditis elegans ,0303 health sciences ,biology ,Chemistry ,biology.organism_classification ,BIO/10 - BIOCHIMICA ,Anti-Bacterial Agents ,Kinetics ,CHIM/08 - CHIMICA FARMACEUTICA ,Toxicity ,Thioflavin ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Background We have previously demonstrated the neuroprotective activity of tetracycline on a Spinocerebellar Ataxia 3 nematode model. Here, we present the screening of a small library of tetracycline congeners in order to identify the most effective compound in preventing ataxin-3 aggregation. Methods We performed the assays on the Josephin Domain as it is directly involved in the onset of fibrillation. We used thioflavin T and solubility assays to spot out the most effective tetracycline congeners; Fourier transform infrared and NMR spectroscopies to characterize their mode of action. We employed an ataxic Caenorhabditis elegans model to evaluate the pharmacological efficacy of tetracycline congeners. Results Methacycline was identified as the most effective compound. Like tetracycline, methacycline neither significantly affected the aggregation kinetics nor did it change the secondary structures of the final aggregates but increased the solubility of the aggregated species. Saturation transfer NMR experiments demonstrated methacycline capability to only bind the oligomeric species of Josephin Domain. Competition assays also showed that methacycline binds to the Josephin Domain more tightly than tetracycline. The treatment with methacycline induced a significant improvement in motility and locomotion of the transgenic C. elegans without changing its lifespan. The efficacy was distinctly stronger than that of tetracycline. Noteworthy, unlike tetracycline, methacycline was able to retard aging-related decline in motility of even the healthy worms used. Conclusions The apparent absence of toxic effects displayed by methacycline, along with its stronger efficacy in contrasting expanded ataxin-3 toxicity, makes it a possible candidate for a chronic treatment of the disease.
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- 2019
5. The Multi-Level Mechanism of Action of a Pan-Ras Inhibitor Explains its Antiproliferative Activity on Cetuximab-Resistant Cancer Cells
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Renata Tisi, Michela Spinelli, Alessandro Palmioli, Cristina Airoldi, Paolo Cazzaniga, Daniela Besozzi, Marco S. Nobile, Elisa Mazzoleni, Simone Arnhold, Luca De Gioia, Rita Grandori, Francesco Peri, Marco Vanoni, Elena Sacco, Information Systems IE&IS, Tisi, R, Spinelli, M, Palmioli, A, Airoldi, C, Cazzaniga, P, Besozzi, D, Nobile, M, Mazzoleni, E, Arnhold, S, De Gioia, L, Grandori, R, Peri, F, Vanoni, M, and Sacco, E
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anti-cancer agent ,mathematical modeling & ,RasG12V ,Mutant ,Settore BIO/11 - Biologia Molecolare ,medicine.disease_cause ,SDG 3 – Goede gezondheid en welzijn ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Biochemistry ,intrinsic nucleotide dissociation and exchange ,SDG 3 - Good Health and Well-being ,cetuximab ,medicine ,Molecular Biosciences ,HRAS ,RasG13D ,Molecular Biology ,lcsh:QH301-705.5 ,mathematical modeling & simulation ,Original Research ,Ras Inhibitor ,Cetuximab ,Settore INF/01 - Informatica ,Effector ,Chemistry ,Raf1 binding ,BIO/11 - BIOLOGIA MOLECOLARE ,simulation ,BIO/10 - BIOCHIMICA ,exchange factor ,Mechanism of action ,lcsh:Biology (General) ,Cancer cell ,Cancer research ,KRAS ,medicine.symptom ,medicine.drug - Abstract
Ras oncoproteins play a crucial role in the onset, maintenance, and progression of the most common and deadly human cancers. Despite extensive research efforts, only a few mutant-specific Ras inhibitors have been reported. We show that cmp4–previously identified as a water-soluble Ras inhibitor– targets multiple steps in the activation and downstream signaling of different Ras mutants and isoforms. Binding of this pan-Ras inhibitor to an extended Switch II pocket on HRas and KRas proteins induces a conformational change that down-regulates intrinsic and GEF-mediated nucleotide dissociation and exchange and effector binding. A mathematical model of the Ras activation cycle predicts that the inhibitor severely reduces the proliferation of different Ras-driven cancer cells, effectively cooperating with Cetuximab to reduce proliferation even of Cetuximab-resistant cancer cell lines. Experimental data confirm the model prediction, indicating that the pan-Ras inhibitor is an appropriate candidate for medicinal chemistry efforts tailored at improving its currently unsatisfactory affinity.
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- 2021
6. NMR-based Lavado cocoa chemical characterization and comparison with fermented cocoa varieties: insights on cocoa’s anti-amyloidogenic activity
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Alessandro Palmioli, Ada De Luigi, Cristina Airoldi, Gessica Sala, Laura Colombo, Carlotta Ciaramelli, Mario Salmona, Ciaramelli, C, Palmioli, A, De Luigi, A, Colombo, L, Sala, G, Salmona, M, and Airoldi, C
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Magnetic Resonance Spectroscopy ,Metabolite ,01 natural sciences ,Antioxidants ,Analytical Chemistry ,Anti-amyloidogenic compound ,chemistry.chemical_compound ,Protein Aggregates ,0404 agricultural biotechnology ,NMR spectroscopy ,CHIM/01 - CHIMICA ANALITICA ,Cell Line, Tumor ,Aβ peptide ,CHIM/06 - CHIMICA ORGANICA ,medicine ,Humans ,Food science ,Theobromine ,Chromatography, High Pressure Liquid ,Cacao ,Chromatography, Reverse-Phase ,Amyloid beta-Peptides ,Chemistry ,Atomic force microscopy ,Plant Extracts ,010401 analytical chemistry ,Significant difference ,food and beverages ,04 agricultural and veterinary sciences ,General Medicine ,Nuclear magnetic resonance spectroscopy ,Alzheimer's disease ,CHIM/10 - CHIMICA DEGLI ALIMENTI ,040401 food science ,Peptide Fragments ,0104 chemical sciences ,Flavanones ,Lavado cocoa ,Fermentation ,Flavanol ,Fermented Foods ,Metabolic profile ,Food Science ,medicine.drug - Abstract
The metabolic profile of Lavado cocoa was characterized for the first time by NMR spectroscopy, then compared with the profiles of fermented and processed varieties, Natural and commercial cocoa. The significant difference in the contents of theobromine and flavanols prompted us to examine the various cocoa varieties to seek correlations between these metabolite concentrations and the anti-amyloidogenic activity reported for cocoa in the literature. We combined NMR spectroscopy, preparative reversed-phase (RP) chromatography, atomic force microscopy, in vitro biochemical and cell assays, to investigate and compare the anti-amyloidogenic properties of extracts and fractions enriched in different metabolite classes. Lavado variety was the most active and the catechins and theobromine were the chemical components of cocoa hindering Aβ peptide on-pathway aggregation and toxicity in a human neuroblastoma SH-SY5Y cell line.
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- 2021
7. Phytotoxicity, nematicidal activity and chemical constituents of Peucedanum ostruthium (L.) W.D.J.Koch (Apiaceae)
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Cristina Airoldi, Sara Vitalini, Francesca Orlando, Giorgio Scarì, Marcello Iriti, Stefano Bocchi, Alessandro Palmioli, Ivano De Noni, Vitalini, S, Palmioli, A, Orlando, F, Scarì, G, Airoldi, C, De Noni, I, Bocchi, S, and Iriti, M
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0106 biological sciences ,Peucedanum ostruthium ,Phytochemical potential ,01 natural sciences ,Furanocoumarin ,CHIM/01 - CHIMICA ANALITICA ,CHIM/06 - CHIMICA ORGANICA ,Metabolic profiling ,Nematode ,chemistry.chemical_classification ,Echinochloa oryzoides ,Apiaceae ,biology ,Traditional medicine ,010405 organic chemistry ,Chemistry ,Glycoside ,Biocontrol ,Lolium multiflorum ,biology.organism_classification ,Weed ,0104 chemical sciences ,Rhizome ,Masterwort ,Phytotoxicity ,Agronomy and Crop Science ,010606 plant biology & botany - Abstract
Peucedanum ostruthium (L.) W.D.J.Koch (Apiaceae) is an alpine medicinal plant traditionally used as a panacea to treat various ailments. For the first time, its phytotoxic and nematotoxic properties were investigated. The inhibitory activity toward germination and seedling growth of the weeds Echinochloa oryzoides (Ard.) Fritsch and Lolium multiflorum Lam. was evaluated by two in vitro assays, carried out on filter paper and soil, using different aqueous extract concentrations (1, 10, and 20 %) and 0.25 g of powder of P. ostruthium leaves, inflorescences, and rhizomes. The study showed that all samples were more effective on L. multiflorum than E. oryzoides with p-values = 0.000 on both substrate types. Nevertheless, in all cases, the soil mitigated the P. ostruthium effects. Regarding nematicidal activity, the leaf extract was the most active against larvae and adults of the nematode Panagrolaimus rigidus. According to the motility test, their death was 85.6 ± 2.7 % and 90.5 ± 3.1 % 24 h after treatment. Lastly, NMR and UPLC-HR-MS analyses led to the identification of several compounds in the aqueous extracts, including mono- and di-substituted chlorogenic acids, flavonol glycosides, coumarins, and furanocoumarin glycosides. 5-Caffeoylquinic acid was the most abundant phenolic component in all plant organs.
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- 2021
8. Tubulin binding potentially clears up Bortezomib and Carfilzomib differential neurotoxic effect
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L. Broggi, Gabriella Nicolini, Guido Cavaletti, Alessandro Palmioli, Cristina Airoldi, A. Di Domizio, Cristina Meregalli, Alessio Malacrida, S. Semperboni, Malacrida, A, Semperboni, S, Di Domizio, A, Palmioli, A, Broggi, L, Airoldi, C, Meregalli, C, Cavaletti, G, and Nicolini, G
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Cancer therapy ,Science ,Antineoplastic Agents ,Guanosine Diphosphate ,Article ,Tubulin binding ,Cell Line ,Bortezomib ,chemistry.chemical_compound ,Mice ,Biopolymers ,Microtubule ,Tubulin ,medicine ,Neurotoxicity ,Animals ,Humans ,Computer Simulation ,Cytoskeleton ,Neurons ,Multidisciplinary ,biology ,Peripheral Nervous System Diseases ,Carfilzomib ,medicine.disease ,NMR ,Cell biology ,Mechanisms of disease ,chemistry ,Proteasome ,DRG ,biology.protein ,Medicine ,Guanosine Triphosphate ,Oligopeptides ,Proteasome Inhibitors ,medicine.drug ,Protein Binding - Abstract
Proteasome inhibitors (PIs) represent the gold standard in the treatment of multiple myeloma. Among PIs, Bortezomib (BTZ) is frequently used as first line therapy, but peripheral neuropathy (PN), occurring approximately in 50% of patients, impairs their life, representing a dose-limiting toxicity. Carfilzomib (CFZ), a second-generation PI, induces a significantly less severe PN. We investigated possible BTZ and CFZ off-targets able to explain their different neurotoxicity profiles. In order to identify the possible PIs off-targets we used the SPILLO-PBSS software that performs a structure-based in silico screening on a proteome-wide scale. Among the top-ranked off-targets of BTZ identified by SPILLO-PBSS we focused on tubulin which, by contrast, did not turn out to be an off-target of CFZ. We tested the hypothesis that the direct interaction between BTZ and microtubules would inhibit the tubulin alfa GTPase activity, thus reducing the microtubule catastrophe and consequently furthering the microtubules polymerization. This hypothesis was validated in a cell-free model, since BTZ (but not CFZ) reduces the concentration of the free phosphate released during GTP hydrolysis. Moreover, NMR binding studies clearly demonstrated that BTZ, unlike CFZ, is able to interact with both tubulin dimers and polymerized form. Our data suggest that different BTZ and CFZ neurotoxicity profiles are independent from their proteasome inhibition, as demonstrated in adult mice dorsal root ganglia primary sensory neurons, and, first, we demonstrate, in a cell free model, that BTZ is able to directly bind and perturb microtubules.
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- 2021
9. Targeting GRP receptor: Design, synthesis and preliminary biological characterization of new non-peptide antagonists of bombesin
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Cristina Airoldi, Martina Arici, Alexandre Orsato, Alessandro Palmioli, Cecilia Ceresa, Paola Coccetti, Barbara La Ferla, Gabriella Nicolini, Marcella Rocchetti, Elisabetta Donzelli, Farida Tripodi, Palmioli, A, Nicolini, G, Tripodi, F, Orsato, A, Ceresa, C, Donzelli, E, Arici, M, Coccetti, P, Rocchetti, M, La Ferla, B, and Airoldi, C
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GRP-R antagonist ,Antineoplastic Agents ,Circular dichroism ,01 natural sciences ,Biochemistry ,Epitope ,Gastrin Releasing Peptide (GRP) ,NMR-based structural and conformational analysi ,chemistry.chemical_compound ,Structure-Activity Relationship ,GRP-R ligand ,GRP receptors (GRP-R) ,CHIM/06 - CHIMICA ORGANICA ,Drug Discovery ,Gastrin-releasing peptide receptor ,Tumor Cells, Cultured ,Humans ,Receptor ,Bombesin (BN) ,Molecular Biology ,Cell Proliferation ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,MM and MD conformational studie ,Rational design ,Bombesin ,Biological activity ,Transmembrane protein ,0104 chemical sciences ,Receptors, Bombesin ,010404 medicinal & biomolecular chemistry ,CHIM/08 - CHIMICA FARMACEUTICA ,chemistry ,Drug Design ,Biophysics ,Pharmacophore ,Drug Screening Assays, Antitumor ,hormones, hormone substitutes, and hormone antagonists - Abstract
We report the rational design, synthesis, and in vitro preliminary evaluation of a new small library of non-peptide ligands of Gastrin Releasing Peptide Receptor (GRP-R), able to antagonize its natural ligand bombesin (BN) in the nanomolar range of concentration. GRP-R is a transmembrane G-protein coupled receptor promoting the stimulation of cancer cell proliferation. Being overexpressed on the surface of different human cancer cell lines, GRP-R is ideal for the selective delivery to tumor cells of both anticancer drug and diagnostic devices. What makes very challenging the design of non-peptide BN analogues is that the 3D structure of the GRP-R is not available, which is the case for many membrane-bound receptors. Thus, the design of GRP-R ligands has to be based on the structure of its natural ligands, BN and GRP. We recently mapped the BN binding epitope by NMR and here we exploited the same spectroscopy, combined with MD, to define BN conformation in proximity of biological membranes, where the interaction with GRP-R takes place. The gained structural information was used to identify a rigid C-galactosidic scaffold able to support pharmacophore groups mimicking the BN key residues’ side chains in a suitable manner for binding to GRP-R. Our BN antagonists represent hit compounds for the rational design and synthesis of new ligands and modulators of GRP-R. The further optimization of the pharmacophore groups will allow to increase the biological activity. Due to their favorable chemical properties and stability, they could be employed for the active receptor-mediated targeting of GRP-R positive tumors.
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- 2020
10. Structural Basis of Inhibition of the Pioneer Transcription Factor NF-Y by Suramin
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Andrea Bernardini, Carlo Camilloni, Andrea Saponaro, Marco Nardini, Michela Lapi, Valentina Nardone, Diletta Dolfini, Sebastiano Pasqualato, Nerina Gnesutta, Cristina Airoldi, Antonio Chaves-Sanjuan, Roberto Mantovani, Nardone, V, Chaves-Sanjuan, A, Lapi, M, Airoldi, C, Saponaro, A, Pasqualato, S, Dolfini, D, Camilloni, C, Bernardini, A, Gnesutta, N, Mantovani, R, and Nardini, M
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histone fold ,Magnetic Resonance Spectroscopy ,Suramin ,CAAT box ,Molecular Dynamics Simulation ,CCAAT box ,Biophysical Phenomena ,Article ,Structure-Activity Relationship ,medicine ,Humans ,Amino Acid Sequence ,Transcription factor ,lcsh:QH301-705.5 ,transcription factor ,suramin ,Chemistry ,Rational design ,Isothermal titration calorimetry ,Promoter ,General Medicine ,DNA ,inhibition ,Cell biology ,lcsh:Biology (General) ,CCAAT-Binding Factor ,Docking (molecular) ,Histone fold ,Protein Multimerization ,NF-Y ,medicine.drug ,Transcription Factors - Abstract
NF-Y is a transcription factor (TF) comprising three subunits (NF-YA, NF-YB, NF-YC) that binds with high specificity to the CCAAT sequence, a widespread regulatory element in gene promoters of prosurvival, cell-cycle-promoting, and metabolic genes. Tumor cells undergo &ldquo, metabolic rewiring&rdquo, through overexpression of genes involved in such pathways, many of which are under NF-Y control. In addition, NF-YA appears to be overexpressed in many tumor types. Thus, limiting NF-Y activity may represent a desirable anti-cancer strategy, which is an ongoing field of research. With virtual-screening docking simulations on a library of pharmacologically active compounds, we identified suramin as a potential NF-Y inhibitor. We focused on suramin given its high water-solubility that is an important factor for in vitro testing, since NF-Y is sensitive to DMSO. By electrophoretic mobility shift assays (EMSA), isothermal titration calorimetry (ITC), STD NMR, X-ray crystallography, and molecular dynamics (MD) simulations, we showed that suramin binds to the histone fold domains (HFDs) of NF-Y, preventing DNA-binding. Our analyses, provide atomic-level detail on the interaction between suramin and NF-Y and reveal a region of the protein, nearby the suramin-binding site and poorly conserved in other HFD-containing TFs, that may represent a promising starting point for rational design of more specific and potent inhibitors with potential therapeutic applications.
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- 2020
11. Effectiveness of Vigna unguiculata seed extracts in preventing colorectal cancer
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Gabriella Tedeschi, Grazia Sacco, Lorenzo Guzzetti, Paola Fusi, Cristina Airoldi, Massimo Labra, Davide Panzeri, Matilde Forcella, Simona Nonnis, Maria Elena Regonesi, Panzeri, D, Guzzetti, L, Sacco, G, Tedeschi, G, Nonnis, S, Airoldi, C, Labra, M, Fusi, P, Forcella, M, and Regonesi, M
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0301 basic medicine ,Colorectal cancer ,Cell Survival ,Metabolite ,Cetuximab ,Pharmacology ,Vigna ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Humans ,Protease Inhibitors ,Epidermal growth factor receptor ,Colorectal cancer, Vigna unguiculata, cetuximab, food ,Phosphorylation ,EC50 ,Plant Proteins ,biology ,Plant Extracts ,Cancer ,General Medicine ,biology.organism_classification ,medicine.disease ,Antineoplastic Agents, Phytogenic ,digestive system diseases ,ErbB Receptors ,030104 developmental biology ,chemistry ,Cell culture ,030220 oncology & carcinogenesis ,Seeds ,biology.protein ,Caco-2 Cells ,Colorectal Neoplasms ,Food Science ,medicine.drug ,Phytotherapy - Abstract
Colorectal cancer (CRC) is one of the most common types of cancer, especially in Western countries, and its incidence rate is increasing every year. In this study, for the first time Vigna unguiculata L. Walp. (cowpea) water boiled seed extracts were found to reduce the viability of different colorectal cancer (CRC) cell lines, such as E705, DiFi and SW480 and the proliferation of Caco-2 line too, without affecting CCD841 healthy cell line. Furthermore, the extracts showed the ability to reduce the level of Epidermal Growth Factor Receptor (EGFR) phosphorylation in E705, DiFi and SW480 cell lines and to lower the EC50 of a CRC common drug, cetuximab, on E705 and DiFi lines from 161.7 ng mL-1 to 0.06 ng mL-1 and from 49.5 ng mL-1 to 0.2 ng mL-1 respectively. The extract was characterized in its protein and metabolite profiles by tandem mass spectrometry and 1H-NMR analyses. A Bowman-Birk protease inhibitor was identified within the protein fraction and was supposed to be the main active component. These findings confirm the importance of a legume-based diet to prevent the outbreak of many CRC and to reduce the amount of drug administered during a therapeutic cycle.
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- 2020
12. Synthesis, Molecular Modeling and Biological Evaluation of Metabolically Stable Analogues of the Endogenous Fatty Acid Amide Palmitoylethanolamide
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Valentina Artusa, Alessandro Palmioli, Alessia D’Aloia, Laura Cipolla, Cristina Airoldi, Federica Arrigoni, Barbara Costa, Giuseppe Zampella, Michela Ceriani, Renata Tisi, D'Aloia, A, Arrigoni, F, Tisi, R, Palmioli, A, Ceriani, M, Artusa, V, Airoldi, C, Zampella, G, Costa, B, and Cipolla, L
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Models, Molecular ,PEA analogues ,THP-1 Cells ,Proton Magnetic Resonance Spectroscopy ,Interleukin-1beta ,Ligands ,Substrate Specificity ,lcsh:Chemistry ,Mice ,chemistry.chemical_compound ,Fatty acid amide hydrolase ,fatty acid amide hydrolase ,lcsh:QH301-705.5 ,Integral membrane protein ,Spectroscopy ,Fatty acid amide ,PEA analogue ,Hydrolysis ,Fatty Acids ,NF-kappa B ,food and beverages ,General Medicine ,Computer Science Applications ,Biochemistry ,Ethanolamines ,Thermodynamics ,lipids (amino acids, peptides, and proteins) ,Microglia ,PPAR- receptor ,Cell Survival ,Palmitic Acids ,Article ,Catalysis ,Inorganic Chemistry ,Animals ,Humans ,PPAR-α receptor ,PPAR alpha ,Physical and Theoretical Chemistry ,Cell Shape ,Molecular Biology ,palmitoylethanolamide ,Palmitoylethanolamide ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Organic Chemistry ,Metabolism ,Amides ,lcsh:Biology (General) ,lcsh:QD1-999 ,chemistry ,inflammation ,metabolism ,Drug metabolism ,Ex vivo - Abstract
Palmitoylethanolamide (PEA) belongs to the class of N-acylethanolamine and is an endogenous lipid potentially useful in a wide range of therapeutic areas, products containing PEA are licensed for use in humans as a nutraceutical, a food supplement, or food for medical purposes for its analgesic and anti-inflammatory properties demonstrating efficacy and tolerability. However, the exogenously administered PEA is rapidly inactivated, in this process, fatty acid amide hydrolase (FAAH) plays a key role both in hepatic metabolism and in intracellular degradation. So, the aim of the present study was the design and synthesis of PEA analogues that are more resistant to FAAH-mediated hydrolysis. A small library of PEA analogues was designed and tested by molecular docking and density functional theory calculations to find the more stable analogue. The computational investigation identified RePEA as the best candidate in terms of both synthetic accessibility and metabolic stability to FAAH-mediated hydrolysis. The selected compound was synthesized and assayed ex vivo to monitor FAAH-mediated hydrolysis and to confirm its anti-inflammatory properties. 1H-NMR spectroscopy performed on membrane samples containing FAAH in integral membrane protein demonstrated that RePEA is not processed by FAAH, in contrast with PEA. Moreover, RePEA retains PEA&rsquo, s ability to inhibit LPS-induced cytokine release in both murine N9 microglial cells and human PMA-THP-1 cells.
- Published
- 2020
13. On-cell saturation transfer difference NMR for the identification of FimH ligands and inhibitors
- Author
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Alessandro Palmioli, Cristina Airoldi, Paola Sperandeo, Alessandra Polissi, Sara Bertuzzi, Palmioli, A, Sperandeo, P, Bertuzzi, S, Polissi, A, and Airoldi, C
- Subjects
Dendrimers ,Magnetic Resonance Spectroscopy ,Multivalent ligand ,Ligands ,01 natural sciences ,Biochemistry ,Virulence factor ,Pilus ,Epitope ,On-cell STD NMR ,Structure-Activity Relationship ,CHIM/06 - CHIMICA ORGANICA ,Drug Discovery ,FimH adhesin ,FimH ligand screening ,Molecular Biology ,Pathogen ,Adhesins, Escherichia coli ,Ligand-receptor interaction studie ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Anti-adhesive therapie ,Anti-virulence ,Organic Chemistry ,Lectin-mediated adhesion inhibitor ,Yeast ,0104 chemical sciences ,Bacterial adhesin ,010404 medicinal & biomolecular chemistry ,Agglutination (biology) ,Epitope mapping ,Carbohydrate-lectin interaction ,Fimbriae Proteins ,Mannose - Abstract
We describe the development of an on-cell NMR method for the rapid screening of FimH ligands and the structural identification of ligand binding epitopes. FimH is a mannose-binding bacterial adhesin expressed at the apical end of type 1 pili of uropathogenic bacterial strains and responsible for their D-mannose sensitive adhesion to host mammalian epithelial cells. Because of these properties, FimH is a key virulence factor and an attractive therapeutic target for urinary tract infection. We prepared synthetic D-mannose decorated dendrimers, we tested their ability to prevent the FimH-mediated yeast agglutination, and thus we used the compounds showing the best inhibitory activity as models of FimH multivalent ligands to set up our NMR methodology. Our experimental protocol, based on on-cell STD NMR techniques, is a suitable tool for the screening and the epitope mapping of FimH ligands aimed at the development of new antiadhesive and diagnostic tools against urinary tract infection pathogens. Notably, the study is carried out in a physiological environment, i.e. at the surface of living pathogen cells expressing FimH.
- Published
- 2021
14. Green coffee extract enhances oxidative stress resistance and delays aging in Caenorhabditis elegans
- Author
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Carlotta Ciaramelli, Cristina Airoldi, Ivano De Noni, Milda Stuknytė, Loredana Amigoni, Maria Elena Regonesi, Alessandro Palmioli, Ilaria Bruni, Chiara Magoni, Amigoni, L, Stuknytė, M, Ciaramelli, C, Magoni, C, Bruni, I, De Noni, I, Airoldi, C, Regonesi, M, and Palmioli, A
- Subjects
0301 basic medicine ,Antioxidant ,medicine.medical_treatment ,media_common.quotation_subject ,Medicine (miscellaneous) ,Green coffee extract ,medicine.disease_cause ,01 natural sciences ,High resolution mass spectrometry ,03 medical and health sciences ,NMR spectroscopy ,Antioxidant activity ,CHIM/06 - CHIMICA ORGANICA ,medicine ,TX341-641 ,Healthy aging ,Caenorhabditis elegans ,Caenorhabditis elegan ,media_common ,Nutrition and Dietetics ,biology ,Chemistry ,Nutrition. Foods and food supply ,010401 analytical chemistry ,Longevity ,Chlorogenic acid ,Stress resistance ,biology.organism_classification ,BIO/10 - BIOCHIMICA ,0104 chemical sciences ,030104 developmental biology ,Biochemistry ,Polyphenol ,Chlorogenic acids ,Oxidative stress ,Food Science - Abstract
Nutritional factors play a pivotal role for healthy aging and longevity. This is related to the antioxidant properties of the molecules present in some foods. Due to the high content of polyphenols, Green Coffee Extract (GCE) is a powerful antioxidant. Nevertheless, little is known about its effect on aging. We demonstrated the benefic effects of GCE on stress resistance, fertility and adult mean lifespan using Caenorhabditis elegans as a model. The mean and maximum lifespan of worms treated with GCE increased significantly in a dose-dependent manner, and animals pre-treated were more resistant to oxidative stress. NMR and UPLC/ESI-HRMS analyses of GCE confirmed a significant content of chlorogenic acids, being 5-O-caffeoylquinic acid (5-CQA) the most abundant isomer. The major activity demonstrated by GCE in comparison to the pure 5-CQA on C. elegans phenotypes clearly demonstrated the importance of the employment of a natural extract to develop functional foods and supplements.
- Published
- 2017
15. Targeting Bacterial Biofilm: A New LecA Multivalent Ligand with Inhibitory Activity
- Author
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Alessandro Palmioli, Cristina Airoldi, Alessandra Polissi, Paola Sperandeo, Palmioli, A, Sperandeo, P, Polissi, A, and Airoldi, C
- Subjects
Dendrimers ,Multidrug tolerance ,medicine.drug_class ,Antibiotics ,Virulence ,010402 general chemistry ,medicine.disease_cause ,Ligands ,01 natural sciences ,Biochemistry ,Microbiology ,CHIM/06 - CHIMICA ORGANICA ,medicine ,Adhesins, Bacterial ,Molecular Biology ,biofilm inhibitors, functionalized dendrimers, LecA, multivalency, NMR spectroscopy ,biology ,010405 organic chemistry ,Chemistry ,Pseudomonas aeruginosa ,Organic Chemistry ,Biofilm ,Galactosides ,biochemical phenomena, metabolism, and nutrition ,BIO/19 - MICROBIOLOGIA GENERALE ,Ligand (biochemistry) ,biology.organism_classification ,In vitro ,0104 chemical sciences ,Anti-Bacterial Agents ,Biofilms ,Molecular Medicine ,Bacteria - Abstract
Biofilm formation by bacterial pathogens is a hallmark of chronic infections and is associated to increased antibiotic tolerance that makes pathogens difficult to eradicate with conventional antibiotic therapies. Infections caused by Pseudomonas aeruginosa are of great concern, especially for immunocompromised and cystic fibrosis patients. P. aeruginosa lectins LecA and LecB are virulence factors and play a key role in establishing biofilm; therefore, inhibition of the function of these proteins has potential in dismantling the bacterium from the protective biofilm environment and in restoring the activity of antibiotics. Here, we report the NMR characterization of the binding of a galactose-based dendrimer (Gal18) to LecA. Moreover, we demonstrate the activity of the Gal18 molecule in inhibiting P. aeruginosa biofilm formation in vitro.
- Published
- 2019
16. bioNMR-based identification of natural anti-Aβ compounds in Peucedanum ostruthium
- Author
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Cristina Airoldi, Laura Colombo, Mario Salmona, Ivano De Noni, Alessandro Palmioli, Barbara La Ferla, Ada De Luigi, Sara Bertuzzi, Palmioli, A, Bertuzzi, S, De Luigi, A, Colombo, L, La Ferla, B, Salmona, M, De Noni, I, and Airoldi, C
- Subjects
Peucedanum ostruthium ,Peptide ,Human cell line ,01 natural sciences ,Biochemistry ,Structure-Activity Relationship ,Nutraceutical ,CHIM/01 - CHIMICA ANALITICA ,Drug Discovery ,Alzheimer’s disease, anti-amyloidogenic compounds, chlorogenic acids, furanocoumarins, NMR spectroscopy, Peucedanum ostruthium, UPLC-HR-MS ,CHIM/06 - CHIMICA ORGANICA ,Structure–activity relationship ,Medicinal plants ,Molecular Biology ,Nuclear Magnetic Resonance, Biomolecular ,chemistry.chemical_classification ,Biological Products ,Amyloid beta-Peptides ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Plant Extracts ,Organic Chemistry ,Biological activity ,CHIM/10 - CHIMICA DEGLI ALIMENTI ,biology.organism_classification ,0104 chemical sciences ,Plant Leaves ,010404 medicinal & biomolecular chemistry ,CHIM/08 - CHIMICA FARMACEUTICA ,Polyphenol ,Apiaceae - Abstract
The growing interest in medicinal plants for the identification of new bioactive compounds and the formulation of new nutraceuticals and drugs prompted us to develop a powerful experimental approach allowing the detailed metabolic profiling of complex plant extracts, the identification of ligands of macromolecular targets of biomedical relevance and a preliminary characterization of their biological activity. To this end, we selected Peucedanum ostruthium, a plant traditionally employed in Austria and Italy for its several potential therapeutic applications, as case study. We combined the use of NMR and UPLC-HR-MS for the identification of the metabolites present in its leaves and rhizome extracts. Due to the significant content of polyphenols, particularly chlorogenic acids, recently identified as anti-amyloidogenic compounds, polyphenols-enriched fractions were prepared and tested for their ability to prevent Aβ1-42 peptide aggregation and neurotoxicity in a neuronal human cell line. STD-NMR experiments allowed the detailed identification of Aβ oligomers’ ligands responsible for the anti-amyloidogenic activity. These data provide experimental protocols and structural information suitable for the development of innovative molecular tools for prevention, therapy and diagnosis of Alzheimer’s disease.
- Published
- 2018
17. Structure-Activity Relationship in Monosaccharide-Based Toll-Like Receptor 4 (TLR4) Antagonists
- Author
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Sonsoles Martín-Santamaría, Rudi Beyaert, Andra B Schromm, Lenny Zaffaroni, Cristina Airoldi, Fabio A. Facchini, Silvia Rapisarda, Grisha Pirianov, Carlotta Ciaramelli, Matilde Forcella, Paola Fusi, Roman Jerala, Alberto Minotti, Jean-Marc Billod, Valentina Calabrese, Charys Palmer, Fabio Lapenta, Francesco Peri, Harald Braun, Facchini, F, Zaffaroni, L, Minotti, A, Rapisarda, S, Calabrese, V, Forcella, M, Fusi, P, Airoldi, C, Ciaramelli, C, Billod, J, Schromm, A, Braun, H, Palmer, C, Beyaert, R, Lapenta, F, Jerala, R, Pirianov, G, Martin-Santamaria, S, and Peri, F
- Subjects
0301 basic medicine ,Lipopolysaccharides ,Models, Molecular ,Molecular model ,LIPOPOLYSACCHARIDE RECOGNITION ,Molecular Conformation ,PROTEIN ,Ligands ,ACTIVATION ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Glucosamine ,CHIM/06 - CHIMICA ORGANICA ,Drug Discovery ,Medicine and Health Sciences ,N-LINKED GLYCOSYLATIONS ,chemistry.chemical_classification ,TLR4, MD-2, glycolipids, SAR ,BIOACTIVITY ,Fatty Acids ,Monosaccharides ,Biological activity ,Recombinant Proteins ,3. Good health ,Molecular Docking Simulation ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Signal Transduction ,Stereochemistry ,Molecular Dynamics Simulation ,Binding, Competitive ,Cell Line ,03 medical and health sciences ,Structure-Activity Relationship ,Molecule ,Monosaccharide ,Structure–activity relationship ,Animals ,Humans ,ddc:610 ,CELL ,Interleukin-8 ,Antagonist ,Fatty acid ,Biology and Life Sciences ,SEVERE SEPSIS ,Toll-Like Receptor 4 ,030104 developmental biology ,HEK293 Cells ,CHIM/08 - CHIMICA FARMACEUTICA ,chemistry ,MD-2 ,ENDOTOXIN ,LIPID-A ANALOGS ,BIOLOGICAL-ACTIVITY ,030215 immunology - Abstract
The structure-activity relationship was investigated in a series of synthetic TLR4 antagonists formed by a glucosamine core linked to two phosphate esters and two linear carbon chains. Molecular modeling showed that the compounds with 10, 12, and 14 carbons chains are associated with higher stabilization of the MD-2/TLR4 antagonist conformation than in the case of the C16 variant. Binding experiments with human MD-2 showed that the C12 and C14 variants have higher affinity than C10, while the C16 variant did not interact with the protein. The molecules, with the exception of the C16 variant, inhibited the LPS-stimulated TLR4 signal in human and murine cells, and the antagonist potency mirrored the MD-2 affinity calculated from in vitro binding experiments. Fourier-transform infrared, nuclear magnetic resonance, and small angle X-ray scattering measurements suggested that the aggregation state in aqueous solution depends on fatty acid chain lengths and that this property can influence TLR4 activity in this series of compounds.
- Published
- 2018
18. NMR-driven identification of anti-amyloidogenic compounds in green and roasted coffee extracts
- Author
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Chiara Zoia, Laura Colombo, Gessica Sala, Carlotta Ciaramelli, Cristina Airoldi, Alessandro Palmioli, Chiara Riva, Ada De Luigi, Mario Salmona, Ciaramelli, C, Palmioli, A, De Luigi, A, Colombo, L, Sala, G, Riva, C, Zoia, C, Salmona, M, and Airoldi, C
- Subjects
Magnetic Resonance Spectroscopy ,Food Handling ,Coffee, 5-CQA ,Cell ,Color ,Food chemistry ,010402 general chemistry ,01 natural sciences ,Coffee ,Analytical Chemistry ,Anti-amyloidogenic compound ,chemistry.chemical_compound ,NMR spectroscopy ,Cell Line, Tumor ,Aβ peptide ,CHIM/06 - CHIMICA ORGANICA ,medicine ,Humans ,Cytotoxicity ,Hydrogen peroxide ,Amyloid beta-Peptides ,010405 organic chemistry ,Chemistry ,Atomic force microscopy ,Plant Extracts ,Melanoidin ,General Medicine ,Nuclear magnetic resonance spectroscopy ,In vitro ,0104 chemical sciences ,medicine.anatomical_structure ,Biochemistry ,Cell culture ,Protein Multimerization ,Alzheimer’s disease ,Food Science - Abstract
To identify food and beverages that provide the regular intake of natural compounds capable of interfering with toxic amyloidogenic aggregates, we developed an experimental protocol that combines NMR spectroscopy and atomic force microscopy, in vitro biochemical and cell assays to detect anti-Aβ molecules in natural edible matrices. We applied this approach to investigate the potential anti-amyloidogenic properties of coffee and its molecular constituents. Our data showed that green and roasted coffee extracts and their main components, 5-O-caffeoylquinic acid and melanoidins, can hinder Aβ on-pathway aggregation and toxicity in a human neuroblastoma SH-SY5Y cell line. Coffee extracts and melanoidins also counteract hydrogen peroxide- and rotenone-induced cytotoxicity and modulate some autophagic pathways in the same cell line.
- Published
- 2018
19. Epigallocatechin-3-gallate and related phenol compounds redirect the amyloidogenic aggregation pathway of ataxin-3 towards non-toxic aggregates and prevent toxicity in neural cells and Caenorhabditis elegans animal model
- Author
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Annalisa Relini, Amanda Penco, Elena Gatta, Jacopo Vertemara, Antonino Natalello, Paolo Tortora, Cristina Airoldi, Marcella Bonanomi, Cristina Visentin, Luca De Gioia, Maria Elena Regonesi, Francesca Pellistri, Visentin, C, Pellistri, F, Natalello, A, Vertemara, J, Bonanomi, M, Gatta, E, Penco, A, Relini, A, DE GIOIA, L, Airoldi, C, Regonesi, M, and Tortora, P
- Subjects
0301 basic medicine ,Amyloid ,amyloid aggregation ,FIS/07 - FISICA APPLICATA (A BENI CULTURALI, AMBIENTALI, BIOLOGIA E MEDICINA) ,Amyloidogenic Proteins ,Nerve Tissue Proteins ,Catechin ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Phenols ,antiamyloid compound ,polyphenols ,EGCG ,ataxin-3 ,amyloid toxicity ,cerebellar granule cells ,Caenorhabditis elegans ,CHIM/06 - CHIMICA ORGANICA ,Genetics ,amyloid, caenorhabditis elegans, neurons, phenols, spectroscopy, fourier transform infrared, gastric cancer, early toxic effect ,Animals ,Humans ,Gallic acid ,Cytotoxicity ,Molecular Biology ,Genetics (clinical) ,Neurons ,biology ,Nuclear Proteins ,Hydrogen Bonding ,Neurodegenerative Diseases ,General Medicine ,Gallate ,biology.organism_classification ,BIO/10 - BIOCHIMICA ,Molecular Docking Simulation ,Disease Models, Animal ,030104 developmental biology ,Biochemistry ,chemistry ,Polyphenol ,Ataxin ,Peptides ,030217 neurology & neurosurgery - Abstract
The protein ataxin-3 (ATX3) triggers an amyloid-related neurodegenerative disease when its polyglutamine stretch is expanded beyond a critical threshold. We formerly demonstrated that the polyphenol epigallocatechin-3-gallate (EGCG) could redirect amyloid aggregation of a full-length, expanded ATX3 (ATX3-Q55) towards non-toxic, soluble, SDS-resistant aggregates. Here, we have characterized other related phenol compounds, although smaller in size, i.e. (-)-epigallocatechin gallate (EGC), and gallic acid (GA). We analysed the aggregation pattern of ATX3-Q55 and of the N-terminal globular Josephin domain (JD) by assessing the time course of the soluble protein, as well its structural features by FTIR and AFM, in the presence and the absence of the mentioned compounds. All of them redirected the aggregation pattern towards soluble, SDS-resistant aggregates. They also prevented the appearance of ordered side-chain hydrogen bonding in ATX3-Q55, which is the hallmark of polyQ-related amyloids. Molecular docking analyses on the JD highlighted three interacting regions, including the central, aggregation-prone one. All three compounds bound to each of them, although with different patterns. This might account for their capability to prevent amyloidogenesis. Saturation transfer difference NMR experiments also confirmed EGCG and EGC binding to monomeric JD. ATX3-Q55 pre-incubation with any of the three compounds prevented its calcium-influx-mediated cytotoxicity towards neural cells. Finally, all the phenols significantly reduced toxicity in a transgenic Caenorhabditis elegans strain expressing an expanded ATX3. Overall, our results show that the three polyphenols act in a substantially similar manner. GA, however, might be more suitable for antiamyloid treatments due to its simpler structure and higher chemical stability.
- Published
- 2017
20. Natural Compounds against Neurodegenerative Diseases: Molecular Characterization of the Interaction of Catechins from Green Tea with Aβ1–42, PrP106–126, and Ataxin‐3 Oligomers
- Author
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Erika Sironi, Cristina Airoldi, Maria Elena Regonesi, Mario Salmona, Massimo Messa, Marcella Bonanomi, Angela Lompo, Laura Colombo, Sironi, E, Colombo, L, Lompo, A, Messa, M, Bonanomi, M, Regonesi, M, Salmona, M, and Airoldi, C
- Subjects
Circular dichroism ,structure–activity relationship ,Amyloid ,Prions ,Molecular Sequence Data ,Nerve Tissue Proteins ,Protein Aggregation, Pathological ,Catechin ,Catalysis ,NMR spectroscopy ,Molecular recognition ,CHIM/06 - CHIMICA ORGANICA ,medicine ,Humans ,Moiety ,Structure–activity relationship ,Amino Acid Sequence ,Ataxin-3 ,Nuclear Magnetic Resonance, Biomolecular ,Flavonoids ,Biological Products ,Amyloid beta-Peptides ,Tea ,Chemistry ,Organic Chemistry ,Rational design ,Nuclear Proteins ,Neurodegenerative Diseases ,General Chemistry ,Peptide Fragments ,circular dichroism ,Repressor Proteins ,amyloid peptide ,Biochemistry ,Mechanism of action ,Ataxin ,molecular recognition ,medicine.symptom - Abstract
By combining NMR spectroscopy, transmission electron microscopy, and circular dichroism we have identified the structural determinants involved in the interaction of green tea catechins with Aβ1-42, PrP106-126, and ataxin-3 oligomers. The data allow the elucidation of their mechanism of action, showing that the flavan-3-ol unit of catechins is essential for interaction. At the same time, the gallate moiety, when present, seems to increase the affinity for the target proteins. These results provide important information for the rational design of new compounds with anti-amyloidogenic activity and/or molecular tools for the specific targeting of amyloid aggregates in vivo.
- Published
- 2014
21. Synthesis and biological evaluation of arabinose 5-phosphate mimics modified at position five
- Author
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Cristina Airoldi, Luca Gabrielli, Laura Cipolla, Alessandra Polissi, Francesco Nicotra, Paola Sperandeo, Serena Gianera, Cipolla, L, Airoldi, C, Sperandeo, P, Gianera, S, Polissi, A, Nicotra, F, and Gabrielli, L
- Subjects
Arabinose ,Chemistry Techniques, Synthetic ,Isomerase ,Bacterial growth ,medicine.disease_cause ,Biochemistry ,Analytical Chemistry ,chemistry.chemical_compound ,Biomimetic Materials ,In vivo ,CHIM/06 - CHIMICA ORGANICA ,Arabinose 5-phosphate ,NMR interaction studies ,Phosphate analogues ,Pseudomonas aeruginosa ,Sugar isomerase ,Aldose-Ketose Isomerases ,Escherichia coli ,Mutation ,Pentosephosphates ,medicine ,Synthetic ,Organic Chemistry ,Chemistry Techniques ,General Medicine ,Phosphate ,chemistry ,Arabinose 5-phosphate, sugar isomerase, NMR interaction studies, phosphate analogues, Pseudomonas aeruginosa - Abstract
A set of new metabolically stable arabinose 5-phosphate analogues possessing phosphate mimetic groups at position 5 was synthesised. Their ability to interact with arabinose 5-phosphate isomerase from Pseudomonas aeruginosa was evaluated by STD-NMR studies. The synthesised compounds were also characterised for their activity in vivo on P. aeruginosa and Escherichia coli strains. Unfortunately, none of the synthesised compounds was able neither to bind API nor to inhibit bacterial growth.
- Published
- 2014
22. H-1 NMR To Explore the Metabolome of Exhaled Breath Condensate in alpha(1)-Antitrypsin Deficient Patients: A Pilot Study
- Author
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Marco Fumagalli, Valeria Mazzoni, Carlotta Ciaramelli, Rita Bussei, Simona Viglio, Paolo Iadarola, Cristina Airoldi, Jan Stolk, Airoldi, C, Ciaramelli, C, Fumagalli, M, Bussei, R, Mazzoni, V, Viglio, S, Iadarola, P, and Stolk, J
- Subjects
0301 basic medicine ,exhaled breath condensate ,medicine.medical_specialty ,Metabolite ,α1-antitrypsin COPD ,Biochemistry ,Gastroenterology ,alpha 1-antitrypsin COPD ,03 medical and health sciences ,chemistry.chemical_compound ,Metabolomics ,Internal medicine ,CHIM/06 - CHIMICA ORGANICA ,medicine ,Metabolome ,Exhaled breath condensate ,Alpha 1-antitrypsin deficiency ,NMR-based metabolomic ,Case-control study ,Exhalation ,General Chemistry ,Nuclear magnetic resonance spectroscopy ,medicine.disease ,030104 developmental biology ,chemistry ,NMR-based metabolomics - Abstract
The metabolomic analysis of exhaled breath condensate (EBC) may provide insights on both the pathology of pulmonary disorders and the response to therapy. This pilot study describes the ability of nuclear magnetic resonance (NMR)-based metabolomics to discriminate α1-antitrypsin deficient (AATD)-patients, who were diagnosed with moderate to severe emphysema, from healthy individuals. Comparative analysis of samples from these two homogeneous cohorts of individuals resulted in the generation of NMR profiles that were different from both a qualitative and a quantitative point-of-view. Among the identified metabolites that separated patients from controls, acetoin, propionate, acetate, and propane-1,2 diol were those presenting the biggest difference. Unambiguous confirmation that the two groups could be completely differentiated on the basis of their metabolite content came from the application of univariate and multivariate statistical analysis (principal component analysis, partial least squares discriminant analysis (PLS-DA), and orthogonal PLS-DA). MetaboAnalyst 3.0 platform, used to define a relationship among metabolites, allowed us to observe that pyruvate metabolism is the most-involved pathway, most of metabolites being originated from pyruvate. These preliminary data suggest that NMR, with its ability to differentiate the metabolic fingerprint of EBC of AATD patients from that of healthy controls, has a potential "clinical applicability" in this area.
- Published
- 2016
23. Fluorescent amyloid β-peptide ligand derivatives as potential diagnostic tools for Alzheimer’s disease
- Author
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Cristina Airoldi, Francesco Nicotra, Barbara La Ferla, F Ornaghi, Francisco Cardona, Laura Colombo, Giulio Sancini, Erika Sironi, Ilaria Cambianica, Mario Salmona, Airoldi, C, Cardona, F, Sironi, E, Colombo, L, Salmona, M, Cambianica, I, Ornaghi, F, Sancini, G, Nicotra, F, and LA FERLA, B
- Subjects
fluorescent derivative ,Chemistry ,Ligand ,General Chemical Engineering ,General Chemistry ,Diagnostic tools ,Stain ,Fluorescence ,Amyloid β peptide ,In vitro model ,Benzopyran ,chemistry.chemical_compound ,Binding ability ,Biochemistry ,BIO/09 - FISIOLOGIA ,CHIM/06 - CHIMICA ORGANICA ,Aβ-peptide ligand ,glycofused compounds ,Alzheimer’s disease - Abstract
Aβ-peptide ligands based on a cis-glycofused benzopyran structure have been fluorescently labeled using coumarine derivatives. Among the synthesized compounds, two conserved their binding ability to β-amyloid peptides, as shown by NMR experiments. Moreover, exploiting its fluorescent property, it was demonstrated that one of such compounds was able to cross an in vitro model of blood–brain barrier (BBB) and to stain Aβ‑deposits.
- Published
- 2013
24. Natural Compounds against Alzheimer’s Disease: Molecular Recognition of Aβ1-42 Peptide bySalvia sclareoidesExtract and its Major Component, Rosmarinic Acid, as Investigated by NMR
- Author
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Jesús Jiménez-Barbero, Alice Martins, Catarina Dias, Erika Sironi, Amélia P. Rauter, Filipa Marcelo, Francesco Nicotra, Cristina Airoldi, Airoldi, C, Sironi, E, Dias, C, Marcelo, F, Martins, A, Rauter, A, Nicotra, F, and Jimenez Barbero, J
- Subjects
Magnetic Resonance Spectroscopy ,Amyloid ,Peptide ,Depsides ,Biochemistry ,chemistry.chemical_compound ,Molecular recognition ,Alzheimer Disease ,CHIM/06 - CHIMICA ORGANICA ,Methyl caffeate ,medicine ,Humans ,Salvia ,chemistry.chemical_classification ,Amyloid beta-Peptides ,Plant Extracts ,Chemistry ,Rosmarinic acid ,Organic Chemistry ,Rational design ,P3 peptide ,General Chemistry ,Peptide Fragments ,Mechanism of action ,Cinnamates ,medicine.symptom ,NMR spectroscopy, Alzheimer’s disease, Aβ peptide, rosmarinic acid, molecular recognition, NMR binding studies - Abstract
Amyloid peptides, Aβ1-40 and Aβ1-42, represent major molecular targets to develop potential drugs and diagnostic tools for Alzheimer's Disease (AD). In fact, oligomeric and fibrillar aggregates generated by these peptides are amongst the principal components of amyloid plaques found post mortem in patients suffering from AD. Rosmarinic acid has been demonstrated to be effective in preventing the aggregation of amyloid peptides in vitro and to delay the progression of the disease in animal models. Nevertheless, no information is available about its molecular mechanism of action. Herein, we report the NMR characterization of the interaction of Salvia sclareoides extract and that of its major component, rosmarinic acid, with Aβ1-42 peptide, whose oligomers have been described as the most toxic Aβ species in vivo. Our data shed light on the structural determinants of rosmarinic acid-Aβ1-42 oligomers interaction, thus allowing the elucidation of its mechanism of action. They also provide important information for the rational design of new compounds with higher affinity for Aβ peptides to generate new anti-amyloidogenic molecules and/or molecular tools for the specific targeting of amyloid aggregates in vivo. In addition, we identified methyl caffeate, another natural compound present in different plants and human diet, as a good ligand of Aβ1-42 oligomers, which also shows anti-amyloidogenic activity. Finally, we demonstrated the possibility to exploit STD-NMR and trNOESY experiments to screen extracts from natural sources for the presence of Aβ peptide ligands.
- Published
- 2013
25. Protein Kinase A Activation Promotes Cancer Cell Resistance to Glucose Starvation and Anoikis
- Author
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Michele Vasso, Karsten Hiller, Francesco Nicotra, Sara De Palma, Raffaella Rizzi, Roberta Palorini, Lilia Alberghina, Claudia Cirulli, Pietro Paolo Lombardi, Giuseppina Votta, Ferdinando Chiaradonna, Francesca Ricciardiello, Humberto De Vitto, Cecilia Gelfi, Yuri Pirola, Cristina Airoldi, Luxembourg Centre for Systems Biomedicine (LCSB): Metabolomics (Hiller Group) [research center], Palorini, R, Votta, G, Pirola, Y, De Vitto, H, De Palma, S, Airoldi, C, Vasso, M, Ricciardiello, F, Lombardi, P, Cirulli, C, Rizzi, R, Nicotra, F, Hiller, K, Gelfi, C, Alberghina, L, and Chiaradonna, F
- Subjects
0301 basic medicine ,Cancer Research ,Glutamine ,Cell ,Cancer Treatment ,Biochemistry, biophysics & molecular biology [F05] [Life sciences] ,Biochemistry ,Mice ,0302 clinical medicine ,Glucose Metabolism ,Neoplasms ,Medicine and Health Sciences ,Cyclic AMP ,Anoikis ,Amino Acids ,Biochimie, biophysique & biologie moléculaire [F05] [Sciences du vivant] ,Genetics (clinical) ,Glucose metabolism, Autophagic cell death, Cell metabolism, Glutamine, Glucose, Metabolic pathways, Amino acid metabolism,Cancer treatment ,Cell Death ,Organic Compounds ,Kinase ,Acidic Amino Acids ,Monosaccharides ,Endoplasmic Reticulum Stress ,BREAST-CANCER ,EXTRACELLULAR-MATRIX ,TUMOR PROGRESSION ,GLUTAMINE UPTAKE ,ENZYME-ACTIVITY ,SRC ACTIVATION ,ER STRESS ,METABOLISM ,DEPRIVATION ,PATHWAY ,BIO/10 - BIOCHIMICA ,Cell biology ,Chemistry ,medicine.anatomical_structure ,Oncology ,Cell Processes ,030220 oncology & carcinogenesis ,Physical Sciences ,Carbohydrate Metabolism ,Metabolic Pathways ,Signal transduction ,Glycolysis ,Research Article ,Cell Physiology ,Programmed cell death ,lcsh:QH426-470 ,Cell Survival ,Autophagic Cell Death ,Carbohydrates ,Biology ,03 medical and health sciences ,Cell Line, Tumor ,Autophagy ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Organic Chemistry ,Chemical Compounds ,Biology and Life Sciences ,Proteins ,Cancer ,Cell Biology ,medicine.disease ,Cyclic AMP-Dependent Protein Kinases ,Cell Metabolism ,Amino Acid Metabolism ,lcsh:Genetics ,Metabolism ,Glucose ,030104 developmental biology ,Starvation ,Cancer cell ,Transcriptome - Abstract
Cancer cells often rely on glycolysis to obtain energy and support anabolic growth. Several studies showed that glycolytic cells are susceptible to cell death when subjected to low glucose availability or to lack of glucose. However, some cancer cells, including glycolytic ones, can efficiently acquire higher tolerance to glucose depletion, leading to their survival and aggressiveness. Although increased resistance to glucose starvation has been shown to be a consequence of signaling pathways and compensatory metabolic routes activation, the full repertoire of the underlying molecular alterations remain elusive. Using omics and computational analyses, we found that cyclic adenosine monophosphate-Protein Kinase A (cAMP-PKA) axis activation is fundamental for cancer cell resistance to glucose starvation and anoikis. Notably, here we show that such a PKA-dependent survival is mediated by parallel activation of autophagy and glutamine utilization that in concert concur to attenuate the endoplasmic reticulum (ER) stress and to sustain cell anabolism. Indeed, the inhibition of PKA-mediated autophagy or glutamine metabolism increased the level of cell death, suggesting that the induction of autophagy and metabolic rewiring by PKA is important for cancer cellular survival under glucose starvation. Importantly, both processes actively participate to cancer cell survival mediated by suspension-activated PKA as well. In addition we identify also a PKA/Src mechanism capable to protect cancer cells from anoikis. Our results reveal for the first time the role of the versatile PKA in cancer cells survival under chronic glucose starvation and anoikis and may be a novel potential target for cancer treatment., Author Summary Tumor heterogeneity exists in many human cancers, and it has been shown that it can play a role in tumor progression. Indeed, cell diversity may be critically important when tumors experience selective pressures, like nutrient deprivation, hypoxia, chemotherapy. PKA, through incompletely understood mechanisms, controls several cellular processes like cell growth, cell differentiation, cell metabolism, cell migration and, as more recently observed, also cancer progression. In this work, we show that activation of PKA induces the ability of a cancer cell sub-population to survive under strong stress conditions namely nutrient deprivation and cell detachment. Indeed, PKA activation in these cells results in autophagy induction, and at the same time, in activation of glutamine metabolism and Src kinase. Importantly, blocking directly the PKA pathway, as well as the autophagy, the glutamine metabolism or the Src pathway by inhibitory drugs, almost completely prevents cell growth of this sub-population of resistant cancer cells. These results suggest that drugs, targeting especially PKA pathway as well as downstream processes like autophagy, glutamine metabolism and Src signaling, may specifically inhibit cancer cells ability to survive under selective pressure favoring cancer resistance.
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- 2016
26. Curcumin derivatives as new ligands of Aβ peptides
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Cristiano Zona, Dario Aurilia, Erika Sironi, Francesco Nicotra, Mario Salmona, Cristina Airoldi, Massimo Masserini, Barbara La Ferla, Laura Colombo, Maria Gregori, Massimo Messa, Airoldi, C, Zona, C, Sironi, E, Colombo, L, Messa, M, Aurilia, D, Gregori, M, Masserini, M, Salmona, M, Nicotra, F, and LA FERLA, B
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Curcumin ,Stereochemistry ,Alzheimer’s disease, Abeta peptides, Abeta ligands, Curcumin derivatives, NMR interaction studies, Conformational analysis, Brain amyloid plaque staining ,Mice, Transgenic ,Bioengineering ,Molecular Dynamics Simulation ,010402 general chemistry ,01 natural sciences ,Applied Microbiology and Biotechnology ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Alzheimer Disease ,Animals ,Humans ,Nuclear Magnetic Resonance, Biomolecular ,Brain Chemistry ,Amyloid beta-Peptides ,Improved solubility ,Histocytochemistry ,Chemistry ,Aβ peptide ,General Medicine ,Peptide Fragments ,0104 chemical sciences ,3. Good health ,Solubility ,Chemical stability ,030217 neurology & neurosurgery ,Protein Binding ,Biotechnology - Abstract
Curcumin derivatives with high chemical stability, improved solubility and carrying a functionalized appendage for the linkage to other entities, have been synthesized in a straightforward manner. All compounds retained Curcumin ability to bind Aβ peptide oligomers without inducing their aggregation. Moreover all Curcumin derivatives were able to stain very efficiently Aβ deposits. © 2011 Elsevier B.V..
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- 2011
27. Sugar-Based Enantiomeric and Conformationally Constrained Pyrrolo[2,1-c][1,4]-Benzodiazepines as Potential GABAA Ligands
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Cristina Airoldi, Amélia P. Rauter, Ana Catarina Araújo, Barbara Costa, Laura Cipolla, Francesco Nicotra, Araújo, A, Rauter, A, Nicotra, F, Airoldi, C, Costa, B, and Cipolla, L
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Models, Molecular ,Molecular model ,Stereochemistry ,Molecular Conformation ,Substituent ,Fructose ,In Vitro Techniques ,Ligands ,Ring (chemistry) ,Binding, Competitive ,Benzodiazepines ,Radioligand Assay ,Structure-Activity Relationship ,chemistry.chemical_compound ,CHIM/06 - CHIMICA ORGANICA ,Drug Discovery ,Animals ,Moiety ,Pyrroles ,Spiro Compounds ,Sugar alcohol ,BIO/14 - FARMACOLOGIA ,Cerebral Cortex ,chemistry.chemical_classification ,Bicyclic molecule ,Chemistry ,Stereoisomerism ,Receptors, GABA-A ,Pyrrolobenzodiazepine, L-Fructose derivative, Proline analogues, GABAA receptor, Binding Assay, Conformational Analysis ,Rats ,Anti-Anxiety Agents ,Nitro ,Molecular Medicine ,Enantiomer - Abstract
Synthesis of a library of pyrrolo[2,1-c][1,4]-benzodiazepines derived from spiro bicyclic d- or l-proline analogues containing a d- or l-fructose moiety was developed. The l-fructose moiety was obtained by using a new synthetic pathway starting from l-arabinose through a six steps synthesis in 18% overall yield. Molecular modeling calculations and DNMR studies showed that d- and l-fructose-based pyrrolobenzodiazepines exhibit a rigid (P)- and (M)-helical conformation, respectively, in which the C-11a substituent was always pseudoequatorial. Additionally, pyrrolobenzodiazepines functionalized with a chloride, bromide, nitro, or amino group in the benzene ring, with or without N-methylation and with or without protection of sugar alcohol groups, allowed a relationship between the molecular structure and biological activity to be established. The conformation of the diazepam ring was not the sole key player influencing binding affinities, and the sugar moiety can in some cases increase the binding activity, possibly by participating in the binding event. Finally, these compounds have increased the understanding of the differential recognition of (M)-/(P)-helical benzodiazepines on GABAA receptor. © 2011 American Chemical Society.
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- 2011
28. Tetracycline prevents Aβ oligomer toxicity through an atypical supramolecular interaction
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Fabrizio Tagliavini, Francesco Nicotra, Cristina Airoldi, Antonino Natalello, Claudia Manzoni, Erika Sironi, Silvia Maria Doglia, Elena Del Favero, Mario Salmona, Laura Colombo, Laura Cantù, Gianluigi Forloni, Airoldi, C, Colombo, L, Manzoni, C, Sironi, E, Natalello, A, Doglia, S, Forloni, G, Tagliavini, F, Del Favero, E, Cantù, L, Nicotra, F, and Salmona, M
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Cell Survival ,Stereochemistry ,Tetracycline ,Supramolecular chemistry ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Oligomer ,Cell Line ,Alzheimer’s disease, amyloid beta-oligomers, amyloid beta-peptides, NMR spectroscopy, tetracycline ,03 medical and health sciences ,chemistry.chemical_compound ,CHIM/06 - CHIMICA ORGANICA ,medicine ,Animals ,Physical and Theoretical Chemistry ,Binding site ,030304 developmental biology ,0303 health sciences ,Amyloid beta-Peptides ,Organic Chemistry ,Nuclear magnetic resonance spectroscopy ,Rats ,0104 chemical sciences ,Solutions ,Monomer ,chemistry ,Thioflavin ,Two-dimensional nuclear magnetic resonance spectroscopy ,medicine.drug - Abstract
The antibiotic tetracycline was reported to possess an anti-amyloidogenic activity on a variety of amyloidogenic proteins both in in vitro and in vivo models. To unveil the mechanism of action of tetracycline on Aβ1-40 and Aβ1-42 at both molecular and supramolecular levels, we carried out a series of experiments using NMR spectroscopy, FTIR spectroscopy, dynamic laser light-scattering (DLS) and atomic force microscopy (AFM). Firstly we showed that the co-incubation of Aβ1-42 oligomers with tetracycline hinders the toxicity towards N2a cell lines in a dose-dependent manner. Therefore, the nature of the interaction between the drug and Aβ oligomers was investigated. To carry out NMR and FTIR studies we have prepared Aβ peptide solutions containing assemblies ranging from monomers to large oligomers. Saturation transfer difference (STD) NMR experiments have shown that tetracycline did not interact with monomers at variance with oligomers. Noteworthy, in this latter case we observed that this interaction was very peculiar since the transfer of magnetization from Aβ oligomers to tetracycline involved all drug protons. In addition, intermolecular cross-peaks between tetracycline and Aβ were not observed in NOESY spectra, indicating the absence of a specific binding site and suggesting the occurrence of a supramolecular interaction. DLS and AFM studies supported this hypothesis since the co-dissolution of Aβ peptides and tetracycline triggered the immediate formation of new aggregates that improved the solubility of Aβ peptides, preventing in this way the progression of the amyloid cascade. Moreover, competitive NMR binding experiments showed for the first time that tetracycline competes with thioflavin T (ThT) in the binding to Aβ peptides. Our data shed light on a novel mechanism of anti-amyloidogenic activity displayed by tetracycline, governed by hydrophobic and charge multiparticle interactions. © 2011 The Royal Society of Chemistry.
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- 2011
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29. Fructose-Based Proline Analogues: Exploring the Prolyl trans/cis-Amide Rotamer Population in Model Peptides
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Laura Cipolla, Cristina Airoldi, Filipa Marcelo, Maria Gregori, Francesco Nicotra, Jesús Jiménez-Barbero, Davide Bini, Cipolla, L, Airoldi, C, Bini, D, Gregori, M, Marcelo, F, Jiménez Barbero, J, and Nicotra, F
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education.field_of_study ,Molecular model ,Bicyclic molecule ,Peptidomimetic ,Stereochemistry ,Organic Chemistry ,Population ,Carbohydrates ,Molecular modeling ,Molecular dynamics ,chemistry.chemical_compound ,chemistry ,proline mimetics, carbohydrate scaffolds, peptidomimetics, NMR, Molecular Modelling ,Amide ,Moiety ,Peptidomimetics ,Proline ,Physical and Theoretical Chemistry ,Peptides ,education ,Cis–trans isomerism - Abstract
9 páginas, 4 figuras, 2 tablas, 2 esquemas -- PAGS nros. 128-136, A D-fructose moiety in which a D-proline ring has been engineered with a spiranic junction in the glycidic scaffold has been used as a proline mimetic. The bicyclic structure, which possesses high structural rigidity, was then included in model peptides to explore their prolyl cis/trans amide rotamer populations. Model peptide conformations were studied by molecular dynamics and NMR experiments, We gratefully acknowledge financial support by Regione Lombardia (Programma Operativo Regione Lombardia Ob. 3 Fondo Sociale Europeo 2000–2006), Sovvenzione Globale Progetto Ingenio A0001127/2007, Consorzio Interuniversitario Nazionale “Metodologie e Processi Innovativi di Sintesi” (C.I.N.M.P.I.S.) and the Fondo di Ateneo per la Ricerca FAR 2008. The Fundação para Ciência e Tecnologia (FCT) Portugal is also thanked for post-doctoral research (grant SFRH/BDP/65462/2009)
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- 2010
30. Structure-Activity Studies on Arylamides and Arysulfonamides Ras Inhibitors
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Renata Tisi, Sandro Olivieri, Alessandro Palmioli, Sonia Fantinato, Cristina Airoldi, Enzo Martegani, L De Gioia, Francesco Peri, Sonia Colombo, Colombo, S, Palmioli, A, Airoldi, C, Tisi, R, Fantinato, S, Olivieri, S, DE GIOIA, L, Martegani, E, and Peri, F
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Cyclin-Dependent Kinase Inhibitor p21 ,Computational chemistry ,Cancer Research ,Stereochemistry ,Hydroxylamines ,Guanosine Diphosphate ,Inhibitory Concentration 50 ,Mice ,chemistry.chemical_compound ,Hydroxylamine ,Two-Hybrid System Techniques ,Amide ,Drug Discovery ,Animals ,Humans ,Structure–activity relationship ,Nucleotide ,Ra ,Cell Proliferation ,Pharmacology ,chemistry.chemical_classification ,Sulfonamides ,Molecular Structure ,ras-GRF1 ,Biological activity ,Structure-activity relationship ,Small molecule ,Sulfonamide ,Cell Transformation, Neoplastic ,Anticancer agent ,Oncology ,chemistry ,Biochemistry ,Drug Design ,Mutation ,NIH 3T3 Cells ,ras Proteins ,Guanosine Triphosphate ,Pharmacophore - Abstract
This paper reports the synthesis of a panel of small molecules with arylamides and arylsulfonamides groups and their biological activity in inhibiting nucleotide exchange on human Ras. The design of these molecules was guided by experimental and molecular modelling data previously collected on similar compounds. Aim of this work is the validation of the hypothesis that a phenyl hydroxylamine group linked to a second aromatic moiety generates a pharmacophore capable to interact with Ras and to inhibit its activation. In vitro experiments on purified human Ras clearly show that the presence of an aromatic hydroxylamine and a sulfonamide group in the same molecule is a necessary condition for Ras binding and nucleotide exchange inhibition. The inhibitor potency is lower in molecules in which either the hydroxylamine has been replaced by other functional groups or the sulfonamide has been replaced by an amide. In the case both these moieties, the hydroxylamine and sulfonamide are absent, inactive compounds are obtained.
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- 2010
31. Re LPS Biogenetic Pathway: Enzyme Characterisation and Synthetic Efforts Towards Inhibitors
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Francesco Nicotra, Cristina Airoldi, Alessandra Polissi, Laura Cipolla, Paolo Galliani, Cipolla, L, Airoldi, C, Galliani, P, Polissi, A, and Nicotra, F
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chemistry.chemical_classification ,Enzyme ,Biochemistry ,Chemistry ,Stereochemistry ,CHIM/06 - CHIMICA ORGANICA ,Organic Chemistry ,LPS, inhibitors, enzyme characterisation ,BIO/19 - MICROBIOLOGIA GENERALE - Abstract
Lipopolysaccharides (LPSs) constitute the lipid portion of the outer leaflet of Gram-negative bacteria; they are essential for growth, and are also responsible for the variety of biological effects associated with Gram-negative sepsis. Recent advances have elucidated the exact chemical structure of this highly complex macromolecule and part of the enzymology involved in its biosynthesis. Enzymes involved in LPS biogenesis are optimal targets for the development of novel therapeutics since they are sufficiently conserved among diverse, clinically-relevant bacteria and no analogue counterpart is present in humans. During the last thirty years a number of inhibitors to LPS biosynthesis have been developed: some of these compounds have antibacterial properties, while others show excellent in vitro activity and are undergoing further investigation. This review will focus on the biology of LPS in bacteria summarizing the knowledge about structure and enzymatic catalysis, as well as chemical efforts towards the synthesis of inhibitors of the key enzymes involved in the biosynthesis of the minimal conserved structure Kdo2-LipA, also referred to as Re LPS. Only a short overview will be given on lipid A biosynthesis and inhibitors, while main focus will be Kdo biosynthesis towards Re LPS. Future directions and perspectives will also be outlined. © 2008 Bentham Science Publishers Ltd.
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- 2008
32. Glucose-Derived Ras Pathway Inhibitors: Evidence of Ras–Ligand Binding and Ras–GEF (Cdc25) Interaction Inhibition
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Sonia Colombo, Marco Vanoni, Annalisa D'Urzo, Alessandro Palmioli, Cristina Airoldi, Enzo Martegani, Francesco Peri, Airoldi, C, Palmioli, A, D'Urzo, A, Colombo, S, Vanoni, M, Martegani, E, and Peri, F
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Cdc25 ,Saccharomyces cerevisiae ,Cell Cycle Proteins ,Carbohydrate metabolism ,Biochemistry ,Fungal Proteins ,Ras-GRF1 ,CHIM/06 - CHIMICA ORGANICA ,Ras, sugar, Gef ,Humans ,Molecular Biology ,Fungal protein ,biology ,ras-GRF1 ,Chemistry ,Organic Chemistry ,Ras Guanine Nucleotide Exchange Factors ,biology.organism_classification ,BIO/10 - BIOCHIMICA ,Ras pathway ,Glucose ,ras Proteins ,biology.protein ,Molecular Medicine ,ras Guanine Nucleotide Exchange Factors - Abstract
In this communication the ability of new compound to inhibit nucleotide exchange on human Ras through STD NMR experiments is presented. Interestingly, the Surface Plasmon Resonance (SPR) studies reported here demonstrate for the first time that both glucose-derived and arabinose-derived compounds inhibit the interaction between Ras and the Guanine nucleotide Exchange Factor protein (C-Cdc25). This experimental evidence contributes to explain at a molecular level the mode of action of our inhibitors. Too complex to change. New glucose-derived phenylhydroxylamines inhibit nucleotide exchange on human Ras. NMR and SPR experiments indicated that the Ras-GEF interaction is inhibited when the Ras-ligand complex is formed. (Chemical Equation Presented). © 2007 Wiley-VCH Verlag GmbH & Co. KGaA.
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- 2007
33. Performance Assessment in Fingerprinting and Multi Component Quantitative NMR Analyses
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Piero Mastrorilli, Michael Assfalg, Leonardo Tenori, Pierluigi Mazzei, Elisabetta Schievano, Anatoly P. Sobolev, Antonino Rizzuti, Davide Bertelli, Raffaele Lamanna, Cristina Airoldi, Fabio Arnesano, Domenico Mallamace, Cesare Cosentino, Nicola Intini, Roberto Consonni, Ileana Menegazzo, Fabio Sciubba, Salvatore Milone, Roberto Gobetto, Francesca Liguori, Virginia D'Aiuto, Sandra Angelica De Pascali, Mariacristina Valerio, Francesca Benevelli, Maurizio Triggiani, Domenico Acquotti, Silvia Davalli, Luca Rocchigiani, Laura Ruth Cagliani, Vitoantonio Bevilacqua, Adele Mucci, Thelma A. Pertinhez, Luca Casadei, Claudia Di Napoli, Andrea Faccini, Francesco Longobardi, Pasquale Scapicchio, Paolo Fanizzi, Flaminia Cesare Marincola, Mario Latronico, Giuseppe Colafemmina, Vito Gallo, Gallo, V, Intini, N, Mastrorilli, P, Latronico, M, Scapicchio, P, Triggiani, M, Bevilacqua, V, Fanizzi, P, Acquotti, D, Airoldi, C, Arnesano, F, Assfalg, M, Benevelli, F, Bertelli, D, Cagliani, L, Casadei, L, Cesare Marincola, F, Colafemmina, G, Consonni, R, Cosentino, C, Davalli, S, De Pascali, S, D'Aiuto, V, Faccini, A, Gobetto, R, Lamanna, R, Liguori, F, Longobardi, F, Mallamace, D, Mazzei, P, Menegazzo, I, Milone, S, Mucci, A, Napoli, C, Pertinhez, T, Rizzuti, A, Rocchigiani, L, Schievano, E, Sciubba, F, Sobolev, A, Tenori, L, and Valerio, M
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Calibration (statistics) ,Analytical chemistry ,Analytical Chemistry ,Quality (physics) ,CHIM/06 - CHIMICA ORGANICA ,Range (statistics) ,nuclear magnetic resonance, inter-laboratory comparison, quantitative analysis, NMR ,Spectroscopy ,Quantitative NMR ,Analytical Chemistry, NMR ,fingerprinting ,quantitative analysis ,Spectrometer ,Chemistry ,Relaxation (NMR) ,METABOLIC PROFILE ,SPECTROSCOPY ,H-1-NMR ,QUANTIFICATION ,DISCRIMINATION ,IDENTIFICATION ,STRESS ,ACID ,NMR ,NMR spectra database ,nuclear magnetic resonance ,multivariate analysis ,Line (geometry) ,Analytical Chemistry, NMR spectroscopy, Quantitative NMR analysis, fingerprint ,NMR, fingerprinting, multivariate analysis ,inter-laboratory comparison - Abstract
An interlaboratory comparison (ILC) was organized with the aim to set up quality control indicators suitable for multicomponent quantitative analysis by nuclear magnetic resonance (NMR) spectroscopy. A total of 36 NMR data sets (corresponding to 1260 NMR spectra) were produced by 30 participants using 34 NMR spectrometers. The calibration line method was chosen for the quantification of a five-component model mixture. Results show that quantitative NMR is a robust quantification tool and that 26 out of 36 data sets resulted in statistically equivalent calibration lines for all considered NMR signals. The performance of each laboratory was assessed by means of a new performance index (named Qp-score) which is related to the difference between the experimental and the consensus values of the slope of the calibration lines. Laboratories endowed with a Qp-score falling within the suitable acceptability range are qualified to produce NMR spectra that can be considered statistically equivalent in terms of relative intensities of the signals. In addition, the specific response of nuclei to the experimental excitation/relaxation conditions was addressed by means of the parameter named NR. NR is related to the difference between the theoretical and the consensus slopes of the calibration lines and is specific for each signal produced by a well-defined set of acquisition parameters. (Graph Presented).
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- 2015
34. How Epigallocatechin-3-gallate and Tetracycline Interact with the Josephin Domain of Ataxin-3 and Alter Its Aggregation Mode
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Cristina Airoldi, Maria Elena Regonesi, Marcella Bonanomi, Cristina Visentin, Antonino Natalello, Paolo Tortora, Marco Vanoni, Michela Spinelli, Bonanomi, M, Visentin, C, Natalello, A, Spinelli, M, Vanoni, M, Airoldi, C, Regonesi, M, and Tortora, P
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Amyloid ,Tetracycline ,Repressor ,Nerve Tissue Proteins ,aggregation inhibitor ,Josephin domain ,Catechin ,Catalysis ,Molecular recognition ,Spectroscopy, Fourier Transform Infrared ,CHIM/06 - CHIMICA ORGANICA ,medicine ,Humans ,Surface plasmon resonance ,Ataxin-3 ,Chemistry ,Organic Chemistry ,food and beverages ,General Chemistry ,tetracyclines ,medicine.disease ,Repressor Proteins ,Neuroprotective Agents ,Biochemistry ,Mechanism of action ,Ataxin ,Spinocerebellar ataxia ,epigallocatechin-3-gallate ,molecular recognition ,medicine.symptom ,Peptides ,medicine.drug - Abstract
Epigallocatechin-3-gallate (EGCG) and tetracycline are two known inhibitors of amyloid aggregation able to counteract the fibrillation of most of the proteins involved in neurodegenerative diseases. We have recently investigated their effect on ataxin-3 (AT3), the polyglutamine-containing protein responsible for spinocerebellar ataxia type 3. We previously showed that EGCG and tetracycline can contrast the aggregation process and toxicity of expanded AT3, although by different mechanisms. Here, we have performed further experiments by using the sole Josephin domain (JD) to further elucidate the mechanism of action of the two compounds. By protein solubility assays and FTIR spectroscopy we have first observed that EGCG and tetracycline affect the JD aggregation essentially in the same way displayed when acting on the full-length expanded AT3. Then, by saturation transfer difference (STD) NMR experiments, we have shown that EGCG binds both the monomeric and the oligomeric JD form, whereas tetracycline can only interact with the oligomeric one. Surface plasmon resonance (SPR) analysis has confirmed the capability of the sole EGCG to bind monomeric JD, although with a KD value suggestive for a non-specific interaction. Our investigations provide new details on the JD interaction with EGCG and tetracycline, which could explain the different mechanisms by which the two compounds reduce the toxicity of AT3.
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- 2015
35. Sugar-Derived Ras Inhibitors: Group Epitope Mapping by NMR Spectroscopy and Biological Evaluation
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Francesco Peri, Cristina Airoldi, Jesús Jiménez-Barbero, Silvia Mari, Sonia Colombo, Francesco Nicotra, Enzo Martegani, Peri, F, Airoldi, C, Colombo, S, Mari, S, Jiménez Barbero, J, Martegani, E, and Nicotra, F
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Bicyclic molecule ,Stereochemistry ,Chemistry ,Organic Chemistry ,Biological activity ,Plasma protein binding ,Nuclear magnetic resonance spectroscopy ,In vitro ,chemistry.chemical_compound ,Epitope mapping ,Biochemistry ,NMR spectroscopy, inhibitors, medicinal chemistry, drug design, epitope mapping ,CHIM/06 - CHIMICA ORGANICA ,Physical and Theoretical Chemistry ,Pharmacophore ,Phenylhydroxylamine - Abstract
Novel inhibitors of Ras protein activation have been found, containing a bicyclic core derived from D-arabinose and benzyl and phenylhydroxylamine moieties. NMR studies (trNOE, saturation-transfer difference, STD) of the binding between these molecules and human p21 h-Ras are reported. A pharmacophore mapping indicates that both the benzyl and the phenylhydroxylamine moieties are essential for protein binding. Molecules lacking one of these groups were synthesized and tested to confirm this hypothesis, and no interaction with Ras in vitro, nor biological activity in mammalian cells was observed. Our studies led to the development of molecules that selectively inhibit Ras-dependent cellular growth in mammalian cells. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
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- 2006
36. Arabinose 5-phosphate isomerase as a target for antibacterial design: studies with substrate analogues and inhibitors
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Paola Sperandeo, Serena Gianera, Cristina Airoldi, Ronald W. Woodard, Alessandra Polissi, Silvia Merlo, Laura Cipolla, Tod P. Holler, Francesco Nicotra, Luca Gabrielli, Gabrielli, L, Merlo, S, Airoldi, C, Sperandeo, P, Gianera, S, Polissi, A, Nicotra, F, Holler, T, Woodard, R, and Cipolla, L
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Arabinose ,D-Arabinose 5-phosphate isomerase ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Isomerase ,Microbial Sensitivity Tests ,medicine.disease_cause ,Biochemistry ,Substrate Specificity ,chemistry.chemical_compound ,Molecular recognition ,Bacterial Proteins ,Isomerism ,Drug Discovery ,CHIM/06 - CHIMICA ORGANICA ,medicine ,Escherichia coli ,Enzyme Inhibitors ,Molecular Biology ,Aldose-Ketose Isomerases ,chemistry.chemical_classification ,NMR binding studie ,Organic Chemistry ,Substrate (chemistry) ,Enzyme inhibitor ,Furanose ,Recombinant Proteins ,Anti-Bacterial Agents ,Epitope mapping ,Enzyme ,chemistry ,Drug Design ,Pseudomonas aeruginosa ,Molecular Medicine ,Protein Binding - Abstract
Structural requirements of d -arabinose 5-phosphate isomerase (KdsD, E.C. 5.3.1.13) from Pseudomonas aeruginosa were analysed in detail using advanced NMR techniques. We performed epitope mapping studies of the binding between the enzyme and the most potent KdsD inhibitors found to date, together with studies of a set of newly synthesised arabinose 5-phosphate (A5P) mimetics. We report here the first experimental evidence that KdsD may bind the furanose form of A5P, suggesting that catalysis of ring opening may be an important part of KdsD catalysis.
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- 2014
37. Nanoliposomes presenting on surface a cis-glycofused benzopyran compound display binding affinity and aggregation inhibition ability towards Amyloid b1-42 peptide
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Spyridon Mourtas, Francesco Nicotra, Cristina Airoldi, Barbara La Ferla, Eleni Markoutsa, Sophia G. Antimisiaris, Francisco Cardona, Giuseppe D'Orazio, Erika Sironi, Cristiano Zona, Airoldi, C, Mourtas, S, RIBEIRO CARDONA, F, Zona, C, Sironi, E, D'Orazio, G, Markoutsa, E, Nicotra, F, Antimisiaris, S, and LA FERLA, B
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Protein Structure ,Secondary ,Glycosylation ,Surface Properties ,Stereochemistry ,Peptide ,Stereoisomerism ,Plasma protein binding ,Ligands ,Protein Structure, Secondary ,chemistry.chemical_compound ,Drug Discovery ,CHIM/06 - CHIMICA ORGANICA ,Alzheimer disease (AD) ,Amyloid β (Aβ) ,Copper-free click chemistry ,Glycoderivatives ,Liposomes ,NMR interaction studies ,Amyloid beta-Peptides ,Benzopyrans ,Click Chemistry ,Peptide Fragments ,Protein Binding ,Protein Multimerization ,Nanoparticles ,Pharmacology ,chemistry.chemical_classification ,Liposome ,Alzheimer disease (AD), Amyloid b (Ab), Glycoderivatives, NMR interaction studies, Liposomes, Copper-free click chemistry ,Organic Chemistry ,General Medicine ,Ligand (biochemistry) ,Benzopyran ,chemistry ,Click chemistry ,Biophysics - Abstract
Nanoliposomes decorated on their surface with ligands for Aβ-peptides, the key morphological features of Alzheimer's disease (AD), have been synthesized and characterized for their ability to target Aβ-peptide aggregates. A tricyclic benzopyrane-glycofused structure has been exploited as Aβ-peptide ligand, which was linked to liposomes via a copper-free, chemoselective, biocompatible click chemistry reaction. The tricyclic-decorated liposomes presented a mean diameter in the nanomolar range (150–200 nm), a negative z-potential and a good stability, at least up to one month. Integrity studies performed in the presence of serum proteins indicated that these decorated nanoliposomes fulfill the requirements for in vivo applications. NMR experiments carried out with Aβ 1-42 oligomers using both surface functionalized and plain (control) liposomes, revealed that the binding ability of the nanoliposomes was mediated by the presence of the tricyclic ligand on their surface. Finally ThT assay carried out with tricyclic-decorated liposomes showed significant decrease in thioflavine T fluorescence after 24 h, suggesting a significant inhibition/delay of Aβ 1-42 aggregation.
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- 2014
38. Cis-Glyco-Fused Benzopyran Derivatives as Hit Compounds for the Development of Therapeutic and Diagnostic Tools against Neurodegenerative Diseases
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Cristina Airoldi, Francisco Cardona, Erika Sironi, Mario Salmona, Barbara La Ferla, Alessandra M. Martorana, Laura Colombo, Silvia Merlo, Merlo, S, Sironi, E, Colombo, L, RIBEIRO CARDONA, F, Martorana, A, Salmona, M, LA FERLA, B, and Airoldi, C
- Subjects
amyloid beta-peptide ,Amyloid ,Chemistry ,Structural similarity ,P3 peptide ,General Chemistry ,Diagnostic tools ,Fibril ,Benzopyran ,chemistry.chemical_compound ,Molecular recognition ,neurodegenerative disease ,NMR spectroscopy ,Biochemistry ,prion protein ,CHIM/06 - CHIMICA ORGANICA ,molecular recognition ,Prion protein - Abstract
Oligomeric and fibrillar aggregates generated by amyloid-β (Aβ) and prion protein (PrP) peptides are amongst the principal components of amyloid plaques found post mortem in patients suffering from Alzheimer’s disease and mammalian prion diseases. Hence these amyloid peptides represent major molecular targets to develop potential drugs and diagnostic tools for the above-mentioned neurodegenerative diseases. Recently, a small library of cis-glyco-fused benzopyran compounds has been synthesized by us, and their ability to recognize and bind Aβ peptide oligomers and stain Aβ deposits was demonstrated. By exploiting the structural similarity between Aβ and PrP aggregates, herein the interaction of these benzopyran molecules with PrP oligomers and their inhibition of the PrP aggregation process that leads to amyloid fibril formation are investigated. Finally, the in vitro staining of PrP fibrils is achieved with a fluorescently labeled cis-glyco-fused benzopyran derivative able to cross a model of the blood–brain barrier.
- Published
- 2014
39. Exploiting the Therapeutic Potential of 8-β-d-Glucopyranosylgenistein: Synthesis, Antidiabetic Activity, and Molecular Interaction with Islet Amyloid Polypeptide and Amyloid β-Peptide (1-42)
- Author
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Catarina Dias, Eurico J. Cabrita, Amélia P. Rauter, Ana S. Viana, Rodrigo F.M. de Almeida, Cristina Airoldi, Filipa Marcelo, Maria Paula Macedo, Francesco Nicotra, Ana M. Matos, Alice Martins, Ana R. Jesus, Rogério T. Ribeiro, Jesús Jiménez-Barbero, Jesus, A, Dias, C, Matos, A, de Almeida, R, Viana, A, Marcelo, F, Ribeiro, R, Macedo, M, Airoldi, C, Nicotra, F, Martins, A, Cabrita, E, Jiménez Barbero, J, and Rauter, A
- Subjects
medicine.medical_specialty ,Magnetic Resonance Spectroscopy ,Protein Conformation ,medicine.medical_treatment ,Microscopy, Atomic Force ,Flavonoids, Alzheimer's, diabete, NMR spectroscopy, AFM, carbohydrates ,Streptozocin ,Epitope ,Diabetes Mellitus, Experimental ,Epitopes ,chemistry.chemical_compound ,Protein structure ,Glucosides ,Alzheimer Disease ,Internal medicine ,Drug Discovery ,CHIM/06 - CHIMICA ORGANICA ,medicine ,Animals ,Humans ,Hypoglycemic Agents ,Insulin ,Benzothiazoles ,Genista ,Rats, Wistar ,Protein Kinase Inhibitors ,geography ,Amyloid beta-Peptides ,geography.geographical_feature_category ,Chemistry ,medicine.disease ,Islet ,Genistein ,In vitro ,Islet Amyloid Polypeptide ,Rats ,Oxygen ,Thiazoles ,Endocrinology ,Postprandial ,Microscopy, Fluorescence ,Biochemistry ,Drug Design ,Hyperglycemia ,Molecular Medicine ,Thioflavin ,Alzheimer's disease ,Protein Binding - Abstract
8-β-d-Glucopyranosylgenistein (1), the major component of Genista tenera, was synthesized and showed an extensive therapeutical impact in the treatment of STZ-induced diabetic rats, producing normalization of fasting hyperglycemia and amelioration of excessive postprandial glucose excursions and and increasing β-cell sensitivity, insulin secretion, and circulating insulin within 7 days at a dose of 4 (mg/kg bw)/day. Suppression of islet amyloid polypeptide (IAPP) fibril formation by compound 1 was demonstrated by thioflavin T fluorescence and atomic force microscopy. Molecular recognition studies with IAPP and Aβ1-42 employing saturation transfer difference (STD) confirmed the same binding mode for both amyloid peptides as suggested by their deduced epitope. Insights into the preferred conformation in the bound state and conformers' geometry resulting from interaction with Aβ1-42 were also given by STD, trNOESY, and MM calculations. These studies strongly support 8-β-d-glucopyranosylgenistein as a promising molecular entity for intervention in amyloid events of both diabetes and the frequently associated Alzheimer's disease.
- Published
- 2014
40. Carbohydrate mimetics and scaffolds: sweet spots in medicinal chemistry
- Author
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Barbara La Ferla, Laura Russo, C. Zona, Nasrin Shaikh, Alexandre Orsato, Laura Cipolla, Cristina Airoldi, Francesco Nicotra, Cipolla, L, LA FERLA, B, Airoldi, C, Zona, C, Orsato, A, Shaikh, N, Russo, L, and Nicotra, F
- Subjects
Drug ,Nitrogen ,media_common.quotation_subject ,Chemistry, Pharmaceutical ,Molecular Sequence Data ,Human immunodeficiency virus (HIV) ,Carbohydrates ,medicine.disease_cause ,Drug Discovery ,CHIM/06 - CHIMICA ORGANICA ,medicine ,Carbohydrate Conformation ,Combinatorial Chemistry Techniques ,Humans ,Glycomimetics, Carbohydrate Scaffolds ,media_common ,Pharmacology ,chemistry.chemical_classification ,biology ,Molecular Structure ,Molecular Mimicry ,Carbohydrate ,Oxygen ,Enzyme ,chemistry ,Biochemistry ,Carbohydrate Sequence ,Drug Design ,biology.protein ,Molecular Medicine ,Target protein ,Pharmacophore ,Neuraminidase - Abstract
Several glycoprocessing enzymes and glycoreceptors have been recognized as important targets for therapeutic intervention. This concept has inspired the development of important classes of therapeutics, such as anti-influenza drugs inhibiting influenza virus neuraminidase, anti-inflammatory drugs targeting lectin-sialyl-Lewis X interaction and glycosidase inhibitors against HIV, Gaucher’s disease, hepatitis and cancer. These therapeutics are mainly carbohydrate mimics in which proper modifications permit stronger interactions with the target protein, higher stability, better pharmacokinetic properties and easier synthesis. Furthermore, the conformational rigidity and polyfunctionality of carbohydrates stimulate their use as scaffolds for the generation of libraries by combinatorial decoration with different pharmacophores. This mini-review will present examples of how to exploit carbohydrates mimics and scaffolds in drug research.
- Published
- 2011
41. Cis-glyco-fused benzopyran compounds as new amyloid β peptide ligands
- Author
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Cristina Airoldi, Laura Colombo, Francisco Cardona, Mario Salmona, Francesco Nicotra, Erika Sironi, Barbara La Ferla, Artur M. S. Silva, Airoldi, C, Cardona, F, Sironi, E, Colombo, L, Salmona, M, Silva, A, Nicotra, F, and LA FERLA, B
- Subjects
Stereochemistry ,Ligands ,010402 general chemistry ,01 natural sciences ,Molecular mechanics ,Catalysis ,Beta amyloid peptides, glycofused compounds, Abeta ligands ,chemistry.chemical_compound ,Molecular dynamics ,CHIM/06 - CHIMICA ORGANICA ,Materials Chemistry ,Benzopyrans ,Amyloid beta-Peptides ,010405 organic chemistry ,Metals and Alloys ,Stereoisomerism ,General Chemistry ,Combinatorial chemistry ,Amyloid β peptide ,0104 chemical sciences ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Benzopyran ,chemistry ,Ceramics and Composites ,Protein Binding - Abstract
A small library of glyco-fused benzopyran compounds has been synthesised. Their interaction features with Aβ peptides have been characterised by using STD-NMR and trNOESY experiments. The conformational analysis of the compounds has also been carried out through molecular mechanics (MM) and molecular dynamics (MD) simulations.
- Published
- 2011
42. Saturation transfer difference NMR experiments of membrane proteins in living cells under HR-MAS conditions: the interaction of the SGLT1 co-transporter with its ligands
- Author
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Cristina Airoldi, Francesco Nicotra, Stefano Giovannardi, Barbara La Ferla, Jesús Jiménez-Barbero, Airoldi, C, Giovannardi, S, LA FERLA, B, Jiménez Barbero, J, and Nicotra, F
- Subjects
Magnetic Resonance Spectroscopy ,SGLT1 co-transporter ,ligand–receptor interaction ,Analytical chemistry ,HR-MAS ,membrane proteins ,Ligands ,Catalysis ,Saturation Transfer Difference (STD)-NMR ,hSGLT1 cotransporter ,ligand-cotransporter interaction ,NMR spectroscopy ,Molecular recognition ,CHIM/06 - CHIMICA ORGANICA ,Magic angle spinning ,Humans ,ligand–receptor interactions ,membrane protein ,Glucose Transporter Type 1 ,Symporters ,Ligand ,Chemistry ,Organic Chemistry ,HEK 293 cells ,NMR tube ,General Chemistry ,Nuclear magnetic resonance spectroscopy ,Folding (chemistry) ,Membrane ,Biophysics - Abstract
5 páginas, 2 figuras -- PAGS nros. 13335-13339, With the magic roundabout: A new methodology that combines high-resolution magic angle spinning (HR-MAS) techniques with saturation transfer difference (STD) NMR spectroscopy is described. This approach significantly improves the versatility of the STD experiment, and expands its use for samples containing living cells derived from solid tissues (see figure), The research leading to these results has received funding from the CARIPLO foundation (CARIPLO 2008-3175 “Development of NMR techniques for tissue engineering studies”). J.J.-B. also thanks MICINN for funding (CTQ2009-08546). This work was also supported by FAR (to S.G.). The authors acknowledge Dr. Marco Palazzo and Prof. Cristiano Rumio who provided the total cDNA [oligo(dT)16] from the HT29 human colon adenocarcinoma cell line, and Ivan Raimondo and Maria Daniela Renna
- Published
- 2011
43. New targets for antibacterial design: Kdo biosynthesis and LPS machinery transport to the cell surface
- Author
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Silvia Merlo, Laura Cipolla, F Nicotra, Cristina Airoldi, Luca Gabrielli, Alessandra Polissi, Cipolla, L, Polissi, A, Airoldi, C, Gabrielli, L, Merlo, S, and Nicotra, F
- Subjects
Lipopolysaccharides ,Gram-negative bacteria ,LPS, OM biogenesis, enzyme inhibitors, Kdo, Lipid A, Gram-negative bacteria, antibiotics, enzyme structure, pathogenic microorganisms, Kdo2-LipA, antibacterials ,Biochemistry ,Lipid A ,chemistry.chemical_compound ,Biosynthesis ,Drug Discovery ,CHIM/06 - CHIMICA ORGANICA ,Animals ,Humans ,Antibacterial agent ,Pharmacology ,chemistry.chemical_classification ,Bacteria ,biology ,Organic Chemistry ,Sugar Acids ,Biological Transport ,biology.organism_classification ,BIO/19 - MICROBIOLOGIA GENERALE ,Enzyme structure ,Anti-Bacterial Agents ,Enzyme ,chemistry ,Drug Design ,Molecular Medicine ,Biogenesis - Abstract
Lipopolysaccharide (LPS), which constitutes the lipid portion of the outer leaflet of Gram-negative bacteria, is essential for growth. It is also responsible for the variety of biological effects associated with Gram-negative sepsis. Recent advances have elucidated the exact chemical structure of this highly complex macromolecule and much of the enzymology involved in its biosynthesis. Enzymes involved in LPS biogenesis are optimal targets for the development of novel therapeutics since they are sufficiently conserved among diverse, clinically-relevant bacteria and no analogue counterpart is present in humans. During the last thirty years a number of inhibitors of LPS biosynthesis have been developed: some of these compounds have antibacterial properties, while others show excellent in vitro activity and are undergoing further investigation. The main focus of this review will be the biology of LPS in bacteria summarizing the knowledge about structure and enzymatic catalysis, as well as chemical efforts towards the synthesis of inhibitors of the key enzymes involved in the biosynthesis of Kdo, toward the minimal conserve structure Kdo2-LipA. In addition, very recent advances in deciphering the molecular mechanisms of LPS transport to the cell surface, as a new target to develop novel antibacterials, will be reported. Future directions and perspectives will also be outlined. © 2011 Bentham Science Publishers Ltd.
- Published
- 2011
44. Natural glycoconjugates with antitumor activity
- Author
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Cristina Airoldi, Francesco Nicotra, Francisco Cardona, Alexandre Orsato, Barbara La Ferla, Silvia Merlo, Cristiano Zona, Erika Sironi, Giuseppe D'Orazio, LA FERLA, B, Airoldi, C, Zona, C, Orsato, A, Cardona, F, Merlo, S, Sironi, E, D'Orazio, G, and Nicotra, F
- Subjects
chemistry.chemical_classification ,Biological Products ,Glycosylation ,Molecular Structure ,Glycoconjugate ,Organic Chemistry ,Glycoside ,Glycosidic bond ,Antineoplastic Agents ,Biochemistry ,Glycopeptide ,chemistry.chemical_compound ,Structure-Activity Relationship ,Aglycone ,chemistry ,Drug Discovery ,CHIM/06 - CHIMICA ORGANICA ,Enediyne ,Structure–activity relationship ,biological product ,Glycoconjugates ,antineoplastic agent ,glycoconjugate - Abstract
Cancer is one of the major causes of death worldwide. As a consequence, many different therapeutic approaches, including the use of glycosides as anticancer agents, have been developed. Various glycosylated natural products exhibit high activity against a variety of microbes and human tumors. In this review we classify glycosides according to the nature of their aglycone (non-saccharidic) part. Among them, we describe anthracyclines, aureolic acids, enediyne antibiotics, macrolide and glycopeptides presenting different strengths and mechanisms of action against human cancers. In some cases, the glycosidic residue is crucial for their activity, such as in anthracycline, aureolic acid and enediyne antibiotics; in other cases, Nature has exploited glycosylation to improve solubility or pharmacokinetic properties, as in the glycopeptides. In this review we focus our attention on natural glycoconjugates with anticancer properties. The structure of several of the carbohydrate moieties found in these conjugates and their role are described. The structure-activity relationship of some of these compounds, together with the structural features of their interaction with the biological targets, are also reported. Taken together, all this information is useful for the design of new potential anti-tumor drugs. © The Royal Society of Chemistry 2011.
- Published
- 2011
45. Targeting Bacterial Membranes: Identification of Pseudomonas aeruginosaD-Arabinose-5P Isomerase and NMR Characterisation of its Substrate Recognition and Binding Properties
- Author
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Cristina Airoldi, Francesco Nicotra, Silvia Sommaruga, Silvia Merlo, Laura Cipolla, Alessandra Polissi, Paola Sperandeo, Airoldi, C, Sommaruga, S, Merlo, S, Sperandeo, P, Cipolla, L, Polissi, A, and Nicotra, F
- Subjects
Arabinose ,Stereochemistry ,Isomerase ,Biology ,medicine.disease_cause ,Biochemistry ,Substrate Specificity ,NMR, LPS, bacteria, API ,chemistry.chemical_compound ,Biosynthesis ,CHIM/06 - CHIMICA ORGANICA ,medicine ,Nuclear Magnetic Resonance, Biomolecular ,Molecular Biology ,Aldose-Ketose Isomerases ,chemistry.chemical_classification ,Pseudomonas aeruginosa ,Organic Chemistry ,Rational design ,Nuclear magnetic resonance spectroscopy ,BIO/19 - MICROBIOLOGIA GENERALE ,Enzyme ,Membrane ,chemistry ,Genes, Bacterial ,Mutation ,Molecular Medicine ,Protein Binding - Abstract
The identification and characterisation of Pseudomonas aeruginosa KdsD (Pa-KdsD), a D-arabinose-5P isomerase involved in the biosynthesis of 3-deoxy-D-manno-oct-2-ulosonic acid and thus of lipopolysaccharide (LPS), are reported. We have demonstrated that KdsD is essential for P. aeruginosa survival and thus represents a key target for the development of novel antibacterial drugs. The key amino acid residues for protein activity have been identified. The structural requirements for substrate recognition and binding have been characterised for the wild-type protein, and the effect of mutations of the key residues on catalytic activity and binding have been evaluated by saturation transfer difference (STD) NMR spectroscopy. Our data provide important structural information for the rational design of new KdsD inhibitors as potential antibacterial drugs. Rational design of antibacterial drugs: The identification and characterisation of P. aeruginosa API, which is involved in the biosynthesis of lipopolysaccharides, are reported. Structural requirements for substrate recognition and binding and the effects of mutations of the key residues have been evaluated by STD NMR spectroscopy. This information is essential for the rational design of new potential antibacterial drugs. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
- Published
- 2011
46. Beta amyloid aggregation inhibitors: small molecules as candidate drugs for therapy of Alzheimer's disease
- Author
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Francesco Nicotra, C. Zona, B. La Ferla, Francesca Re, N. Quattrocchi, Cristina Airoldi, Massimo Masserini, Re, F, Airoldi, C, Zona, C, Quattrocchi, N, LA FERLA, B, Nicotra, F, and Masserini, M
- Subjects
Models, Molecular ,Pathology ,medicine.medical_specialty ,Amyloid ,Molecular Sequence Data ,Aggregation inhibitor ,Fibril ,Biochemistry ,Small Molecule Libraries ,Amyloid beta-Protein Precursor ,Alzheimer Disease ,Drug Discovery ,Amyloid precursor protein ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Pharmacology ,biology ,β-amyloid ,Chemistry ,Organic Chemistry ,Neurodegeneration ,P3 peptide ,Alzheimer's disease ,medicine.disease ,Small molecule ,Cell biology ,Biochemistry of Alzheimer's disease ,biology.protein ,Molecular Medicine - Abstract
The progressive production and subsequent accumulation of β-amyloid (Aβ), a proteolytic fragment of the membrane-associated amyloid precursor protein (APP), plays a central role in Alzheimer's Disease (AD). Aβ is released in a soluble form that may be responsible for cognitive dysfunction in the early stages of the disease, then progressively forms oligomeric, multimeric and fibrillar aggregates, triggering neurodegeneration. Eventually, the aggregation and accumulation of Aβ culminates with the formation of extracellular plaques, one of the morphological hallmarks of the disease, detectable post-mortem in AD brains. In this review we report the known structural features of amyloid peptides and fibrils, and we give an overview of all small molecules that have been found to interact with Aβ aggregation. Deeper knowledge of the mechanism leading to amyloid fibrils along with their molecular structure and the molecular interactions responsible for activity of small molecules could supply useful information for the design of new AD therapeutic agents.
- Published
- 2010
47. Synthesis of 3-Deoxy-D-threopentofuranose 5-Phosphate, a Substrate of Arabinose 5-Phosphate Isomerase
- Author
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Cristina Airoldi, Francesco Nicotra, Silvia Merlo, Airoldi, C, Merlo, S, and Nicotra, F
- Subjects
Arabinose ,Deoxysugar ,LPS biosynthesi ,Stereochemistry ,Organic Chemistry ,Substrate (chemistry) ,Isomerase ,Phosphate ,Biochemistry ,Arabinose 5-phosphate ,Thiocarbamate ,chemistry.chemical_compound ,chemistry ,API ,CHIM/06 - CHIMICA ORGANICA ,Organic chemistry ,Phosphorylation ,Deoxygenation - Abstract
3-Deoxy-d-threopentofuranose 5-phosphate, a substrate of arabinose 5-phosphate isomerase, has been synthesised starting from d-arabinose. Selective protection of the hydroxyl groups at C-1, C-2, and C-5 allowed deoxygenation of position 3 by conversion into a thiocarbamate and radical reduction. Deprotection and phosphorylation of the primary hydroxyl group and final deprotection of the other hydroxyl groups afforded the desired compound.
- Published
- 2010
48. Selective cytotoxicity of a bicyclic Ras inhibitor in cancer cells expressing K-Ras(G13D)
- Author
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Takehiko Sasazuki, Luca De Gioia, Federica Di Nicolantonio, Elena Sacco, Alessandro Di Domizio, Alberto Bardelli, Alessandro Palmioli, Francesco Peri, Annalisa D'Urzo, Senji Shirasawa, Marco Vanoni, Cristina Airoldi, Enzo Martegani, Palmioli, A, Sacco, E, Airoldi, C, Di Nicolantonio, F, D'Urzo, A, Shirasawa, S, Sasazuki, T, DI DOMIZIO, A, DE GIOIA, L, Martegani, E, Bardelli, A, Peri, F, and Vanoni, M
- Subjects
Magnetic Resonance Spectroscopy ,Biophysics ,Antineoplastic Agents ,Biology ,HCT-116 cells, NMR, Nucleotide dissociation/exchange, Ras mutant, Ras inhibitor ,Biochemistry ,RAS mutation ,Proto-Oncogene Proteins p21(ras) ,Bridged Bicyclo Compounds ,In vivo ,Cell Line, Tumor ,CHIM/06 - CHIMICA ORGANICA ,KRAS ,Humans ,Nucleotide ,Molecular Biology ,chemistry.chemical_classification ,Ras Inhibitor ,Bicyclic molecule ,Molecular Structure ,ras-GRF1 ,Cell Biology ,BIO/11 - BIOLOGIA MOLECOLARE ,Molecular biology ,BIO/10 - BIOCHIMICA ,In vitro ,chemistry ,Docking (molecular) ,Cancer cell ,Mutation ,Intracellular - Abstract
Mutation of RAS genes is a critical event in the pathogenesis of different human tumors and in some developmental disorders. Here we present an arabinose-derived bicyclic compound displaying selective cytotoxicity in human colorectal cancer cells expressing K-Ras G13D , that shows high intrinsic nucleotide exchange rate. We characterize binding of bicyclic compounds by docking and NMR experiments and their inhibitory activity on GEF-mediated nucleotide exchange on wild-type and mutant Ras proteins. We demonstrate that the in vitro inhibition of Ras nucleotide exchange depends on the molar ratio between Ras and its GEF activator, suggesting that the observed in vivo selective effect may depend on biochemical parameters and actual intracellular concentration of the Ras protein and its regulators.
- Published
- 2009
49. Pyrrolo[2,1-c][1,4]benzodiazepine as a scaffold for the design and synthesis of anti-tumour drugs
- Author
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Davide Bini, Cristina Airoldi, Laura Cipolla, Ana Cristina Araújo, Cipolla, L, Araújo, A, Airoldi, C, and Bini, D
- Subjects
Cancer Research ,Stereochemistry ,Guanine ,Anti- Tumour Drug ,Antineoplastic Agents ,Biology ,chemistry.chemical_compound ,Benzodiazepines ,Structure-Activity Relationship ,CHIM/06 - CHIMICA ORGANICA ,medicine ,Structure–activity relationship ,Humans ,Pyrroles ,Binding site ,Cytotoxicity ,Transcription factor ,Gene ,transcription factor ,Pharmacology ,Binding Sites ,Synthesi ,PBD dimer ,Cancer ,DNA ,medicine.disease ,pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) ,chemistry ,Drug Design ,cytotoxicity ,Molecular Medicine ,anticancer therapeutics - Abstract
Compounds that bind in the minor groove of DNA have found use in the experimental treatment of cancer and certain infectious diseases. Furthermore, agents which target and can recognize discrete sequences of DNA have the potential to offer selective therapies by modulating the activity of specific transcription factors or genes. For this reason, a number of sequence-selective DNA binding agents have been evaluated with a range of affinities and recognition fidelities. In this respect, the pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are of interest as they bind to guanine residues in the minor groove with a preference for Pu-G-Pu sequences. A dramatic increase in cytotoxicity and sequence selectivity has been achieved by linking two PBD units to form PBD dimers as cross-linking agents on opposite DNA strands (e.g., interstrand cross-links). SJG-136 is currently undergoing Phase I evaluation in both the United States (through the NCI) and United Kingdom (through Cancer Research United Kingdom). This review will focus on design, synthesis and structure activity relationship studies of pyrrolobenzodiazepines as anticancer therapeutics reported since 2003.
- Published
- 2009
50. Design, Synthesis and Biological Evaluation of Levoglucosenone-derived Ras Activation Inhibitors
- Author
-
Anske Stephanie van Neuren, Cristina Airoldi, Jörg Weiser, Enzo Martegani, Maria Antonia Gomez-Zurita Frau, Francesco Peri, Carlo Battistini, Sonia Colombo, Dario Ballinari, Christian Müller, Alessandro Bitto, Matthias Stein, Müeller, C, Gomez Zurita Frau, M, Ballinari, D, Colombo, S, Bitto, A, Martegani, E, Airoldi, C, van Neuren, A, Stein, M, Weiser, J, Battistini, C, and Peri, F
- Subjects
Magnetic Resonance Spectroscopy ,Molecular model ,Stereochemistry ,Biochemistry ,Cell Line ,Drug Discovery ,CHIM/06 - CHIMICA ORGANICA ,Animals ,Humans ,Nucleotide ,Enzyme Inhibitors ,General Pharmacology, Toxicology and Pharmaceutics ,Cell Proliferation ,Biological evaluation ,Pharmacology ,chemistry.chemical_classification ,Ras, antitumor drugs, levoglucosenone ,Molecular Structure ,Organic Chemistry ,Bridged Bicyclo Compounds, Heterocyclic ,In vitro ,Glucose ,chemistry ,Design synthesis ,Cell culture ,Drug Design ,ras Proteins ,Molecular Medicine ,Signal transduction ,Tricyclic - Abstract
A panel of new potential Ras ligands was generated by decorating a tricyclic levoglucosenone-derived scaffold with aromatic moieties. Some members of the panel show in vitro inhibitory activity toward the nucleotide exchange process on Ras and are toxic to some human cancer cell lines.
- Published
- 2009
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