64 results on '"Barile, E"'
Search Results
2. Crononutrizione: una tematica emergente nella gestione del diabete di tipo 2
- Author
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Cristiana Randazzo, Carola Buscemi, and Anna Maria Barile e Silvio Buscemi
- Subjects
General Earth and Planetary Sciences ,General Environmental Science - Abstract
Evidence has been accumulated that a different timing in the consumption of meals, namely the chrononutrition, is able to influence the daily metabolic biorhythms, influencing the onset and possibly the treatment of clinical conditions as obesity and diabetes, including the possibility of independently influencing the cardiovascular risk. Behaviors originating from new social customs are able to interfere with these physiological mechanisms activating of genes and proteins that make individuals more or less flexible, capable of adaptation. So, the inability to adapt could favor a higher risk to health. Therefore, chrononutrition is a characteristic of the diet that is important to address further to the amount of energy and macronutrient intake. Once again, even in this area, the Mediterranean dietary style proves to be a healthy reference approach.
- Published
- 2022
3. DECOMPOSITION OF MEDICAGO SATIVA RESIDUES AFFECTS PHYTOTOXICITY, FUNGAL GROWTH AND SOIL-BORNE PATHOGEN DISEASES
- Author
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Bonanomi, G., Antignani, V., Barile, E., Lanzotti, V., and Scala, F.
- Published
- 2011
4. Inhibition of melanoma development in the Nras(Q61K)::Ink4a-/- mouse model by the small molecule BI-69A11
- Author
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Feng, Y., Lau, E., Scortegagna, M., Ruller, C., De, S. K., Barile, E., Krajewski, S., Aza-Blanc, P., Williams, R., Pinkerton, A. B., Jackson, M., Chin, L., Pellecchia, M., Bosenberg, M., and Ronai, Z.
- Published
- 2012
- Full Text
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5. Applications
- Author
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Barile, E, primary, Davis, R, additional, Fante, R, additional, Guella, T, additional, Torres, J, additional, and Vaccaro, J, additional
- Published
- 2005
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6. Plant litter phytotoxicity: dynamical patterns, causal mechanisms and chemical characterization by 13C NMR spectroscopy
- Author
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BONANOMI, GIULIANO, LANZOTTI, VIRGINIA, MAZZOLENI, STEFANO, SCALA, FELICE, Antignani V., Barile E., Capodilupo M., Bonanomi, Giuliano, Antignani, V., Barile, E., Capodilupo, M., Lanzotti, Virginia, Mazzoleni, Stefano, and Scala, Felice
- Published
- 2009
7. Antifungal activity of five novel saponins from Allium minutiflorum
- Author
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Antignani V., Barile E., BONANOMI, GIULIANO, LANZOTTI, VIRGINIA, SCALA, FELICE, Antignani, V., Bonanomi, Giuliano, Barile, E., Lanzotti, Virginia, and Scala, Felice
- Published
- 2006
8. Decomposition of Medicago sativa residues affects plant growth and disease incidence
- Author
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BONANOMI, GIULIANO, LANZOTTI, VIRGINIA, SCALA, FELICE, Pane P., Antignani V., Barile E., Bonanomi, Giuliano, Pane, P., Antignani, V., Barile, E., Lanzotti, Virginia, and Scala, Felice
- Published
- 2006
9. Cyparissins A and B, jatrophane diterpenes from Euphorbia cyparissias as Pgp inhibitors and cytotoxic agents against ovarian cancer cell lines
- Author
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Lanzotti, V, Barile, E, Scambia, Giovanni, Ferlini, C., Scambia, Giovanni (ORCID:0000-0003-2758-1063), Lanzotti, V, Barile, E, Scambia, Giovanni, Ferlini, C., and Scambia, Giovanni (ORCID:0000-0003-2758-1063)
- Abstract
From the whole plant of Euphorbia cyparissias, two new diterpenes based on jatrophane skeleton, named cyparissins A and B (1 and 2) were isolated. Their chemical structures were established through a combination of nuclear magnetic resonance spectroscopy and mass spectrometric methods. The new cyparissins A and B were tested to evaluate their ability to inhibit P-glycoprotein-mediated multidrug resistance and their cytotoxic activity against A2780 human ovarian cancer cells, both WT and ADR. Compounds 1 and 2 showed moderate inhibitory effects on P-glycoprotein while showing a significant concentration-depending cytotoxic activity for both cancer cell lines. These isolated compounds are based on a new chemical structure that expands the knowledge base for this class of bioactive metabolites.
- Published
- 2015
10. Decomposition of Medicago Sativa Residues Affects Phytotoxicity, Fungal Growth and Soil-borne Pathogen Diseases
- Author
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Giuliano BONANOMI, Antignani, V., Barile, E., Lanzotti, V., Scala, F., Bonanomi, Giuliano, V., Antignani, E., Barile, Lanzotti, Virginia, and Scala, Felice
- Published
- 2011
11. NMR-based design and evaluation of novel bidentate inhibitors of the protein tyrosine phosphatase YopH
- Author
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Leone M, Barile E, Vazquez J, Mei A, Guiney D, Dahl R, and Pellecchia M
- Published
- 2010
12. BI-69A11 enhances susceptibility of colon cancer cells to mda-7/IL-24-induced growth inhibition by targeting Akt
- Author
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Pal, I, primary, Sarkar, S, additional, Rajput, S, additional, Dey, K K, additional, Chakraborty, S, additional, Dash, R, additional, Das, S K, additional, Sarkar, D, additional, Barile, E, additional, De, S K, additional, Pellecchia, M, additional, Fisher, P B, additional, and Mandal, M, additional
- Published
- 2014
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13. Saponins of Allium elburzense
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Barile, E., Zolfaghari, B., Sajjadi, S. E., and Lanzotti, V.
- Abstract
A phytochemical investigation of the bulbs of Allium elburzense has been undertaken, leading to the isolation of 13 furostanol and spirostanol saponins, eight of which are new, namely, elburzensosides A1/A2 (
1a /1b ), B1/B2 (2a /2b ), C1/C2 (3a /3b ), and D1/D2 (4a /4b ). On the basis of spectroscopic analysis, mainly 2D NMR and mass spectrometry, and chemical methods, the structures of the new compounds were determined as furost-2α,3β,5α,6β,22α-pentol 3-O-β-d -glucopyranosyl 26-O-β-d -glucopyranoside (1a ), furost-2α,3β,5α,6β,22α-pentol 3-O-[β-d -glucopyranosyl-(1→4)-O-β-d -glucopyranosyl] 26-O-β-d -glucopyranoside (2a ), furost-2α,3β,5α,22α-tetrol 3-O-β-d -glucopyranosyl 26-O-β-d -glucopyranoside (3a ), and furost-2α,3β,5α,22α-tetrol 3-O-[β-d -xylopyranosyl-(1→3)-O-β-d -glucopyranosyl-(1→4)-O-β-d -galactopyranosyl] 26-O-β-d -glucopyranoside (4a ), and the corresponding epimers at position 22 (1b −4b ). Along with these compounds we have isolated the corresponding 22-O-methyl derivatives that we consider extraction artifacts. All the new elburzensosides A1/A2−D1/D2 possess as a common structural feature an OH-5α that is rare among furostanol saponins. The reported compounds have been isolated in large amounts, and this makes A. elburzense a prolific producer of saponins of the furostanol and spirostanol types.- Published
- 2004
14. THE BAMBOO SPECIES USED IN THE PRODUCTION OF MUSICAL INSTRUMENTS BY FOUR FILIPINO TRIBES (KALINGA (LUBUAGAN SUBTRIBE), MAJUKAYONG, BAGOBO-TAGABAWA AND T'BOLI).
- Author
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Pitargue Jr. F. C., Conda J. M., Cortez Jr. R. E., Balmedina S. L., and Barile E. R.
- Subjects
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MUSICAL instruments , *INTRODUCED species , *MUSEUM exhibits , *ETHNOMUSICOLOGY , *FILIPINOS , *BAMBOO - Abstract
Bamboo Musical Instruments have been part of Filipino culture for centuries. While there are literature reports on the history and production of Philippine BMIs, only few recognised the bamboo species used in making them. Knowledge about these species will contribute to their conservation as well as in the proper care and protection of bamboo musical instruments in the market and those that are kept on display in museums such as the UP Center for Ethnomusicology. In this study, 31 instruments produced by four indigenous communities: Kalinga (Lubuagan subtribe), Majukayong, Bagobo-Tagabawa, and T'boli are documented and the bamboo species used in making them were identified. The instruments were classified into idiophones (21), aerophones (8), membranophones (1) and chordophones (1). They were made from nine bamboo species, namely: kauayan-tinik (Bambusa spinosa Roxb.), kauayan-kiling (B. vulgaris Schrad. ex Wendl.), giant bamboo (Dendrocalamus asper (Schultes f.) Backer ex Heyne), bayog (D. merillianus (Elmer) Elmer), kayali (Gigantochloa atter (Hassk.) Kurz), botong (G. levis (Blanco) Merr.), bentung (Schizotachyum brachycladum (Kurz) Kurz), anos (S. lima (Blanco) Merr.), and buho (S. lumampao (Blanco) Merr.). Commonly practiced among the tribes in the selection of the bamboo species to use is to consider the length of the bamboo internode, thickness of the culm, diametre of the pole, and availability of the species. The bamboo species that were found in the tribal areas include introduced species that have naturalised in the country. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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15. An Optically Pure Apogossypolone Derivative As Potent Pan-active Inhibitor of Anti-apoptotic Bcl-2 Family Proteins
- Author
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John C. Reed, Dayong Zhai, Rupesh Dash, Shinichi Kitada, William J. Placzek, Li Yang, John L. Stebbins, Bainan Wu, Paul B. Fisher, Michele F. Rega, Jun Wei, Maurizio Pellecchia, Russell Dahl, Elisa Barile, Ziming Zhang, Wei, J, Stebbins, Jl, Kitada, S, Dash, R, Zhai, D, Placzek, Wj, Wu, B, Rega, MICHELE FORTUNATO, Zhang, Z, Barile, E, Yang, L, Dahl, R, Fisher, Pb, Reed, Jc, and Pellecchia, M.
- Subjects
Genetically modified mouse ,Cancer Research ,Anti-apoptotic Bcl-2 ,Apoptosis ,Pharmacology ,lcsh:RC254-282 ,Apogossypolone ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Medicine ,Cytotoxicity ,Original Research ,030304 developmental biology ,Cancer ,0303 health sciences ,5′ apogossypolone derivatives ,Cell growth ,business.industry ,Bcl-2 family ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Molecular biology ,3. Good health ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,5’ Apogossypolone derivatives ,business - Abstract
Our focus in the past several years has been on the identification of novel and effective pan-Bcl-2 antagonists. We have recently reported a series of Apogossypolone (ApoG2) derivatives, resulting in the chiral compound (+/-) BI97D6. We report here the synthesis and evaluation on its optically pure (-) and (+) atropisomers. Compound (-) BI97D6 potently inhibits the binding of BH3 peptides to Bcl-XL, Bcl-2, Mcl-1 and Bfl-1 with IC50 values of 76 ± 5, 31 ± 2, 25 ± 8 and 122 ± 28 nM, respectively. In a cellular assay, compound (-) BI97D6 effectively inhibits cell growth in the PC-3 human prostate cancer and H23 human lung cancer cell lines with EC50 values of 0.22 ± 0.08 and 0.14 ± 0.02 µM, respectively. Similarly, compound (-) BI97D6 effectively induces apoptosis in the BP3 human lymphoma cell line in a dose-dependent manner. The compound also shows little cytotoxicity against bax-/-/bak-/- cells, suggesting that it kills cancers cells predominantly via a Bcl-2 pathway. Moreover, compound (-) BI97D6 displays in vivo efficacy in both a Bcl-2 transgenic mouse model and in a prostate cancer xenograft model in mice. Therefore, compound (-) BI97D6 represents a promising drug lead for the development of novel apoptosis-based therapies for cancer.
- Published
- 2011
16. Potential Therapeutic Targeting of Coronavirus Spike Glycoprotein Priming.
- Author
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Barile E, Baggio C, Gambini L, Shiryaev SA, Strongin AY, and Pellecchia M
- Subjects
- Animals, Antigens, Bacterial toxicity, Antiviral Agents therapeutic use, Bacterial Toxins toxicity, Betacoronavirus pathogenicity, Binding Sites, COVID-19, Drug Delivery Systems, Female, Furin pharmacology, Humans, Mice, Mice, Inbred BALB C, Models, Molecular, Pandemics, RAW 264.7 Cells, SARS-CoV-2, Serine Proteinase Inhibitors therapeutic use, Spike Glycoprotein, Coronavirus chemistry, Antiviral Agents pharmacology, Coronavirus Infections drug therapy, Pneumonia, Viral drug therapy, Serine Proteases metabolism, Serine Proteinase Inhibitors pharmacology, Spike Glycoprotein, Coronavirus metabolism
- Abstract
Processing of certain viral proteins and bacterial toxins by host serine proteases is a frequent and critical step in virulence. The coronavirus spike glycoprotein contains three (S1, S2, and S2') cleavage sites that are processed by human host proteases. The exact nature of these cleavage sites, and their respective processing proteases, can determine whether the virus can cross species and the level of pathogenicity. Recent comparisons of the genomes of the highly pathogenic SARS-CoV2 and MERS-CoV, with less pathogenic strains (e.g., Bat-RaTG13, the bat homologue of SARS-CoV2) identified possible mutations in the receptor binding domain and in the S1 and S2' cleavage sites of their spike glycoprotein. However, there remains some confusion on the relative roles of the possible serine proteases involved for priming. Using anthrax toxin as a model system, we show that in vivo inhibition of priming by pan-active serine protease inhibitors can be effective at suppressing toxicity. Hence, our studies should encourage further efforts in developing either pan-serine protease inhibitors or inhibitor cocktails to target SARS-CoV2 and potentially ward off future pandemics that could develop because of additional mutations in the S-protein priming sequence in coronaviruses.
- Published
- 2020
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17. Enthalpy-Based Screening of Focused Combinatorial Libraries for the Identification of Potent and Selective Ligands.
- Author
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Baggio C, Udompholkul P, Barile E, and Pellecchia M
- Subjects
- Escherichia coli metabolism, Ligands, Protein Conformation, Protein Domains, Structure-Activity Relationship, X-Linked Inhibitor of Apoptosis Protein metabolism, Combinatorial Chemistry Techniques, Drug Discovery methods, Thermodynamics, X-Linked Inhibitor of Apoptosis Protein chemistry
- Abstract
In modern drug discovery, the ability of biophysical methods, including nuclear magnetic resonance spectroscopy or surface plasmon resonance, to detect and characterize ligand-protein interactions accurately and unambiguously makes these approaches preferred versus conventional biochemical high-throughput screening of large collections of compounds. Nonetheless, ligand screening strategies that address simultaneously potency and selectivity have not yet been fully developed. In this work, we propose a novel method for screening large collections of combinatorial libraries using enthalpy measurements as a primary screening technique. We demonstrate that selecting binders that are driven by enthalpy (ΔH) results in agents that are not only potent but also more selective for a given target. This general and novel approach, we termed ΔH screening of fPOS (enthalpy screening of focused positional scanning library), combines the principles of focused combinatorial chemistry with rapid calorimetry measurements to efficiently identify potent and selective inhibitors.
- Published
- 2017
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18. Potent and Selective EphA4 Agonists for the Treatment of ALS.
- Author
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Wu B, De SK, Kulinich A, Salem AF, Koeppen J, Wang R, Barile E, Wang S, Zhang D, Ethell I, and Pellecchia M
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- Amyotrophic Lateral Sclerosis metabolism, Amyotrophic Lateral Sclerosis pathology, Animals, Binding Sites, Cells, Cultured, Disease Models, Animal, Drug Design, Half-Life, Humans, Ligands, Mice, Mice, Inbred BALB C, Mice, Transgenic, Molecular Docking Simulation, Protein Binding, Protein Isoforms metabolism, Protein Structure, Tertiary, Receptor, EphA4 chemistry, Receptor, EphA4 metabolism, Small Molecule Libraries chemistry, Small Molecule Libraries metabolism, Small Molecule Libraries pharmacokinetics, Small Molecule Libraries therapeutic use, Structure-Activity Relationship, Superoxide Dismutase genetics, Superoxide Dismutase metabolism, Amyotrophic Lateral Sclerosis drug therapy, Receptor, EphA4 agonists
- Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease that affects motor neurons. Recent studies identified the receptor tyrosine kinase EphA4 as a disease-modifying gene that is critical for the progression of motor neuron degeneration. We report on the design and characterization of a family of EphA4 targeting agents that bind to its ligand binding domain with nanomolar affinity. The molecules exhibit excellent selectivity and display efficacy in a SOD1 mutant mouse model of ALS. Interestingly, the molecules appear to act as agonists for the receptor in certain surrogate cellular assays. While the exact mechanisms responsible for the therapeutic effect of the new agonists remain to be elucidated, we believe that the described agent represents both an invaluable pharmacological tool to further decipher the role of the EphA4 in ALS and potentially other human diseases, and a significant stepping stone for the development of novel treatments., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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19. hBfl-1/hNOXA Interaction Studies Provide New Insights on the Role of Bfl-1 in Cancer Cell Resistance and for the Design of Novel Anticancer Agents.
- Author
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Barile E, Marconi GD, De SK, Baggio C, Gambini L, Salem AF, Kashyap MK, Castro JE, Kipps TJ, and Pellecchia M
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- Amino Acid Sequence, Apoptosis, Cell Line, Tumor, Humans, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Drug Resistance, Neoplasm, Minor Histocompatibility Antigens metabolism, Neoplasms metabolism, Proto-Oncogene Proteins c-bcl-2 metabolism
- Abstract
Upregulation of antiapoptotic Bcl-2 proteins in certain tumors confers cancer cell resistance to chemotherapy or radiations. Members of the antiapoptotic Bcl-2 proteins, including Bcl-2, Mcl-1, Bcl-xL, Bcl-w, and Bfl-1, inhibit apoptosis by selectively binding to conserved α-helical regions, named BH3 domains, of pro-apoptotic proteins such as Bim, tBid, Bad, or NOXA. Five antiapoptotic proteins have been identified that interact with various selectivity with BH3 containing pro-apoptotic counterparts. Cancer cells present various and variable levels of these proteins, making the design of effective apoptosis based therapeutics challenging. Recently, BH3 profiling was introduced as a method to classify cancer cells based on their ability to resist apoptosis following exposure to selected BH3 peptides. However, these studies were based on binding affinities measured with model BH3 peptides and Bcl-2-proteins taken from mouse sequences. While the majority of these interactions are conserved between mice and humans, we found surprisingly that human NOXA binds to human Bfl-1 potently and covalently via conserved Cys residues, with over 2 orders of magnitude increased affinity over hMcl-1. Our data suggest that some assumptions of the original BH3 profiling need to be revisited and that perhaps further targeting efforts should be redirected toward Bfl-1, for which no suitable specific inhibitors or pharmacological tools have been reported. In this regard, we also describe the initial design and characterizations of novel covalent BH3-based agents that potently target Bfl-1. These molecules could provide a novel platform on which to design effective Bfl-1 targeting therapeutics.
- Published
- 2017
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20. The Cell Surface Receptor CD44: NMR-Based Characterization of Putative Ligands.
- Author
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Baggio C, Barile E, Di Sorbo G, Kipps TJ, and Pellecchia M
- Subjects
- Amino Acid Sequence, Binding Sites, Calorimetry, Humans, Hyaluronan Receptors chemistry, Hyaluronan Receptors genetics, Nuclear Magnetic Resonance, Biomolecular, Peptides chemistry, Protein Binding, Recombinant Proteins biosynthesis, Recombinant Proteins chemistry, Recombinant Proteins isolation & purification, Hyaluronan Receptors metabolism, Ligands, Peptides metabolism
- Abstract
The cell surface receptor CD44 is a glycoprotein belonging to the hyaluronan-binding proteins, termed hyaladherins. CD44 is expressed in a wide variety of isoforms in many cells and, in particular, is present on the surface of malignant cells where it is involved in the onset and progression of cancer. In a first attempt to identify novel CD44-binding agents, we first characterized, with NMR spectroscopic techniques, several agents that were reported to bind to human CD44 (hCD44). To our surprise, however, none of these putative CD44-binding agents, including a peptide that is in phase 2 clinical trials (A6 peptide) and a recently reported fragment hit, were found to interact significantly with recombinant hCD44(21-178). Nonetheless, we further report that a fragment-screening campaign, with solution NMR spectroscopy as the detection method, identified a viable fragment hit that bound in a potentially functional pocket on the surface of CD44, opposite to the hyaluronic acid binding site. We hypothesize that this pocket could be indirectly associated with the cellular and in vivo activity of the A6 peptide, which would provide a novel framework for the possible development of therapeutically viable CD44 antagonists., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2016
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21. High-Throughput Screening (HTS) by NMR Guided Identification of Novel Agents Targeting the Protein Docking Domain of YopH.
- Author
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Bottini A, Wu B, Barile E, De SK, Leone M, and Pellecchia M
- Subjects
- Anti-Bacterial Agents chemical synthesis, Anti-Bacterial Agents chemistry, Dose-Response Relationship, Drug, Magnetic Resonance Spectroscopy, Microbial Sensitivity Tests, Nuclear Magnetic Resonance, Biomolecular, Peptoids chemical synthesis, Peptoids chemistry, Plague drug therapy, Protein Binding drug effects, Protein Domains drug effects, Structure-Activity Relationship, Yersinia pestis drug effects, Anti-Bacterial Agents pharmacology, Bacterial Outer Membrane Proteins chemistry, Bacterial Outer Membrane Proteins metabolism, High-Throughput Screening Assays, Peptoids pharmacology, Protein Tyrosine Phosphatases chemistry, Protein Tyrosine Phosphatases metabolism
- Abstract
Recently we described a novel approach, named high-throughput screening (HTS) by NMR that allows the identification, from large combinatorial peptide libraries, of potent and selective peptide mimetics against a given target. Here, we deployed the "HTS by NMR" approach for the design of novel peptoid sequences targeting the N-terminal domain of Yersinia outer protein H (YopH-NT), a bacterial toxin essential for the virulence of Yersinia pestis. We aimed at disrupting the protein-protein interactions between YopH-NT and its cellular substrates, with the goal of inhibiting indirectly YopH enzymatic function. These studies resulted in a novel agent of sequence Ac-F-pY-cPG-d-P-NH2 (pY=phosphotyrosine; cPG=cyclopentyl glycine) with a Kd value against YopH-NT of 310 nm. We demonstrated that such a pharmacological inhibitor of YopH-NT results in the inhibition of the dephosphorylation by full-length YopH of a cellular substrate. Hence, potentially this agent represents a valuable stepping stone for the development of novel therapeutics against Yersinia infections. The data reported further demonstrate the utility of the HTS by NMR approach in deriving novel peptide mimetics targeting protein-protein interactions., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2016
- Full Text
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22. Therapy of pancreatic cancer via an EphA2 receptor-targeted delivery of gemcitabine.
- Author
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Quinn BA, Wang S, Barile E, Das SK, Emdad L, Sarkar D, De SK, Morvaridi SK, Stebbins JL, Pandol SJ, Fisher PB, and Pellecchia M
- Subjects
- Animals, Cell Line, Tumor, Deoxycytidine administration & dosage, Humans, Mice, Mice, Nude, Xenograft Model Antitumor Assays, Gemcitabine, Antimetabolites, Antineoplastic administration & dosage, Deoxycytidine analogs & derivatives, Molecular Targeted Therapy methods, Pancreatic Neoplasms drug therapy, Receptor, EphA2 metabolism
- Abstract
First line treatment for pancreatic cancer consists of surgical resection, if possible, and a subsequent course of chemotherapy using the nucleoside analogue gemcitabine. In some patients, an active transport mechanism allows gemcitabine to enter efficiently into the tumor cells, resulting in a significant clinical benefit. However, in most patients, low expression of gemcitabine transporters limits the efficacy of the drug to marginal levels, and patients need frequent administration of the drug at high doses, significantly increasing systemic drug toxicity. In this article we focus on a novel targeted delivery approach for gemcitabine consisting of conjugating the drug with an EphA2 targeting agent. We show that the EphA2 receptor is highly expressed in pancreatic cancers, and accordingly, the drug-conjugate is more effective than gemcitabine alone in targeting pancreatic tumors. Our preliminary observations suggest that this approach may provide a general benefit to pancreatic cancer patients and offers a comprehensive strategy for enhancing delivery of diverse therapeutic agents to a wide range of cancers overexpressing EphA2, thereby potentially reducing toxicity while enhancing therapeutic efficacy.
- Published
- 2016
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23. SBI-0640756 Attenuates the Growth of Clinically Unresponsive Melanomas by Disrupting the eIF4F Translation Initiation Complex.
- Author
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Feng Y, Pinkerton AB, Hulea L, Zhang T, Davies MA, Grotegut S, Cheli Y, Yin H, Lau E, Kim H, De SK, Barile E, Pellecchia M, Bosenberg M, Li JL, James B, Hassig CA, Brown KM, Topisirovic I, and Ronai ZA
- Subjects
- Animals, Blotting, Western, Cell Line, Tumor, Disease Models, Animal, Gene Knockout Techniques, Humans, Melanoma metabolism, Mice, Antineoplastic Agents pharmacology, Cell Proliferation drug effects, Eukaryotic Initiation Factor-4F metabolism, Lactams pharmacology, Melanoma pathology, Quinolones pharmacology
- Abstract
Disrupting the eukaryotic translation initiation factor 4F (eIF4F) complex offers an appealing strategy to potentiate the effectiveness of existing cancer therapies and to overcome resistance to drugs such as BRAF inhibitors (BRAFi). Here, we identified and characterized the small molecule SBI-0640756 (SBI-756), a first-in-class inhibitor that targets eIF4G1 and disrupts the eIF4F complex. SBI-756 impaired the eIF4F complex assembly independently of mTOR and attenuated growth of BRAF-resistant and BRAF-independent melanomas. SBI-756 also suppressed AKT and NF-κB signaling, but small-molecule derivatives were identified that only marginally affected these pathways while still inhibiting eIF4F complex formation and melanoma growth, illustrating the potential for further structural and functional manipulation of SBI-756 as a drug lead. In the gene expression signature patterns elicited by SBI-756, DNA damage, and cell-cycle regulatory factors were prominent, with mutations in melanoma cells affecting these pathways conferring drug resistance. SBI-756 inhibited the growth of NRAS, BRAF, and NF1-mutant melanomas in vitro and delayed the onset and reduced the incidence of Nras/Ink4a melanomas in vivo. Furthermore, combining SBI-756 and a BRAFi attenuated the formation of BRAFi-resistant human tumors. Taken together, our findings show how SBI-756 abrogates the growth of BRAF-independent and BRAFi-resistant melanomas, offering a preclinical rationale to evaluate its antitumor effects in other cancers., (©2015 American Association for Cancer Research.)
- Published
- 2015
- Full Text
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24. Design and Characterization of Novel EphA2 Agonists for Targeted Delivery of Chemotherapy to Cancer Cells.
- Author
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Wu B, Wang S, De SK, Barile E, Quinn BA, Zharkikh I, Purves A, Stebbins JL, Oshima RG, Fisher PB, and Pellecchia M
- Subjects
- Amino Acid Sequence, Animals, Antineoplastic Agents chemical synthesis, Cell Line, Tumor, Cell Survival drug effects, Drug Delivery Systems methods, Female, Humans, Male, Melanoma, Experimental drug therapy, Melanoma, Experimental metabolism, Mice, Mice, Nude, Models, Animal, Molecular Targeted Therapy, Paclitaxel chemistry, Paclitaxel pharmacology, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms metabolism, Rats, Receptor, EphA2 chemistry, Xenograft Model Antitumor Assays, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Paclitaxel analogs & derivatives, Receptor, EphA2 agonists
- Abstract
The development of novel, targeted delivery agents for anti-cancer therapies requires the design and optimization of potent and selective tumor-targeting agents that are stable and amenable to conjugation with chemotherapeutic drugs. While short peptides represent potentially an excellent platform for these purposes, they often get degraded and are eliminated too rapidly in vivo. In this study, we used a combination of nuclear magnetic resonance-guided structure-activity relationships along with biochemical and cellular studies to derive a novel tumor-homing agent, named 123B9, targeting the EphA2 tyrosine kinase receptor ligand-binding domain. Conjugating 123B9 to the chemotherapeutic drug paclitaxel (PTX) via a stable linker results in an agent that is significantly more effective than the unconjugated drug in both a pancreatic cancer xenograft model and a melanoma lung colonization and metastases model. Hence, 123B9 could represent a promising strategy for the development of novel targeted therapies for cancer., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
- Full Text
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25. Cyparissins A and B, jatrophane diterpenes from Euphorbia cyparissias as Pgp inhibitors and cytotoxic agents against ovarian cancer cell lines.
- Author
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Lanzotti V, Barile E, Scambia G, and Ferlini C
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Cell Line, Tumor drug effects, Female, Humans, Molecular Structure, Ovarian Neoplasms pathology, Antineoplastic Agents, Phytogenic pharmacology, Diterpenes pharmacology, Drug Resistance, Multiple drug effects, Drug Resistance, Neoplasm drug effects, Euphorbia chemistry
- Abstract
From the whole plant of Euphorbia cyparissias, two new diterpenes based on jatrophane skeleton, named cyparissins A and B (1 and 2) were isolated. Their chemical structures were established through a combination of nuclear magnetic resonance spectroscopy and mass spectrometric methods. The new cyparissins A and B were tested to evaluate their ability to inhibit P-glycoprotein-mediated multidrug resistance and their cytotoxic activity against A2780 human ovarian cancer cells, both WT and ADR. Compounds 1 and 2 showed moderate inhibitory effects on P-glycoprotein while showing a significant concentration-depending cytotoxic activity for both cancer cell lines. These isolated compounds are based on a new chemical structure that expands the knowledge base for this class of bioactive metabolites., (Copyright © 2015. Published by Elsevier B.V.)
- Published
- 2015
- Full Text
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26. A Potent Anti-influenza Compound Blocks Fusion through Stabilization of the Prefusion Conformation of the Hemagglutinin Protein.
- Author
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White KM, De Jesus P, Chen Z, Abreu P Jr, Barile E, Mak PA, Anderson P, Nguyen QT, Inoue A, Stertz S, Koenig R, Pellecchia M, Palese P, Kuhen K, García-Sastre A, Chanda SK, and Shaw ML
- Abstract
An ultrahigh-throughput screen was performed to identify novel small molecule inhibitors of influenza virus replication. The screen employed a recombinant influenza A/WSN/33 virus expressing Renilla luciferase and yielded a hit rate of 0.5%, of which the vast majority showed little cytotoxicity at the inhibitory concentration. One of the top hits from this screen, designated S20, inhibits HA-mediated membrane fusion. S20 shows potent antiviral activity (IC
50 = 80 nM) and low toxicity (CC50 = 40 μM), yielding a selectivity index of 500 and functionality against all of the group 1 influenza A viruses tested in this study, including the pandemic H1N1 and avian H5N1 viruses. Mechanism of action studies proved a direct S20-HA interaction and showed that S20 inhibits fusion by stabilizing the prefusion conformation of HA. In silico docking studies were performed, and the predicted binding site in HA2 corresponds with the area where resistance mutations occurred and correlates with the known role of this region in fusion. This high-throughput screen has yielded many promising new lead compounds, including S20, which will potentially shed light on the molecular mechanisms of viral infection and serve as research tools or be developed for clinical use as antivirals.- Published
- 2015
- Full Text
- View/download PDF
27. High-Throughput Screening by Nuclear Magnetic Resonance (HTS by NMR) for the Identification of PPIs Antagonists.
- Author
-
Wu B, Barile E, De SK, Wei J, Purves A, and Pellecchia M
- Subjects
- Combinatorial Chemistry Techniques, Crystallography, X-Ray, Ephrin-A5 chemistry, High-Throughput Screening Assays, Humans, Ligands, Magnetic Resonance Spectroscopy, Models, Molecular, Myeloid Cell Leukemia Sequence 1 Protein antagonists & inhibitors, Peptides chemistry, Protein Binding, Protein Interaction Domains and Motifs, Protein Interaction Mapping, Receptor, EphA4 antagonists & inhibitors, X-Linked Inhibitor of Apoptosis Protein antagonists & inhibitors, Drug Discovery, Myeloid Cell Leukemia Sequence 1 Protein chemistry, Receptor, EphA4 chemistry, Small Molecule Libraries chemistry, X-Linked Inhibitor of Apoptosis Protein chemistry
- Abstract
In recent years the ever so complex field of drug discovery has embraced novel design strategies based on biophysical fragment screening (fragment-based drug design; FBDD) using nuclear magnetic resonance spectroscopy (NMR) and/or structure-guided approaches, most often using X-ray crystallography and computer modeling. Experience from recent years unveiled that these methods are more effective and less prone to artifacts compared to biochemical high-throughput screening (HTS) of large collection of compounds in designing protein inhibitors. Hence these strategies are increasingly becoming the most utilized in the modern pharmaceutical industry. Nonetheless, there is still an impending need to develop innovative and effective strategies to tackle other more challenging targets such as those involving protein-protein interactions (PPIs). While HTS strategies notoriously fail to identify viable hits against such targets, few successful examples of PPIs antagonists derived by FBDD strategies exist. Recently, we reported on a new strategy that combines some of the basic principles of fragment-based screening with combinatorial chemistry and NMR-based screening. The approach, termed HTS by NMR, combines the advantages of combinatorial chemistry and NMR-based screening to rapidly and unambiguously identify bona fide inhibitors of PPIs. This review will reiterate the critical aspects of the approach with examples of possible applications.
- Published
- 2015
- Full Text
- View/download PDF
28. Design, synthesis and bioevaluation of an EphA2 receptor-based targeted delivery system.
- Author
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Barile E, Wang S, Das SK, Noberini R, Dahl R, Stebbins JL, Pasquale EB, Fisher PB, and Pellecchia M
- Subjects
- Amino Acid Sequence, Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Cell Line, Tumor, Cell Survival drug effects, Drug Carriers chemistry, Female, Humans, Male, Mice, Mice, Inbred BALB C, Paclitaxel chemistry, Paclitaxel pharmacology, Paclitaxel therapeutic use, Peptides chemical synthesis, Peptides chemistry, Prostatic Neoplasms drug therapy, Receptor, EphA2 chemistry, Transplantation, Heterologous, Drug Carriers chemical synthesis, Drug Design, Receptor, EphA2 metabolism
- Abstract
Because of its overexpression in a range of solid tumors, the EphA2 receptor is a validated target for cancer therapeutics. We recently described a new targeted delivery system based on specific EphA2-targeting peptides conjugated with the chemotherapeutic agent paclitaxel. Here, we investigate the chemical determinants responsible for the stability and degradation of these agents in plasma. Introducing modifications in both the peptide and the linker between the peptide and paclitaxel resulted in drug conjugates that are both long-lived in rat plasma and that markedly decrease tumor size in a prostate cancer xenograft model compared with paclitaxel alone treatment. These studies identify critical rate-limiting degradation sites on the peptide-drug conjugates, enabling the design of agents with increased stability and efficacy. These results provide support for our central hypothesis that peptide-drug conjugates targeting EphA2 represent an innovative and potentially effective strategy to selectively deliver cytotoxic drugs to cancer cells., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2014
- Full Text
- View/download PDF
29. NMR-based approaches for the identification and optimization of inhibitors of protein-protein interactions.
- Author
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Barile E and Pellecchia M
- Subjects
- Biophysics, Drug Design, Ligands, Protein Binding drug effects, Magnetic Resonance Spectroscopy methods, Proteins antagonists & inhibitors, Proteins chemistry
- Published
- 2014
- Full Text
- View/download PDF
30. Synthesis and SAR studies of dual AKT/NF-κB inhibitors against melanoma.
- Author
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Barile E, De SK, Feng Y, Chen V, Yang L, Ronai Z, and Pellecchia M
- Subjects
- Animals, Benzimidazoles chemistry, Benzimidazoles pharmacology, Benzimidazoles toxicity, Cell Line, Tumor, Cell Survival drug effects, Enzyme Activation drug effects, Female, Humans, Melanoma drug therapy, Melanoma metabolism, Melanoma pathology, Mice, Mice, Nude, NF-kappa B metabolism, Phosphorylation drug effects, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors toxicity, Proto-Oncogene Proteins c-akt metabolism, Quinolones chemistry, Quinolones pharmacology, Quinolones toxicity, Structure-Activity Relationship, Transplantation, Heterologous, NF-kappa B antagonists & inhibitors, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-akt antagonists & inhibitors
- Abstract
The protein Kinase B alpha (AKT) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways are central regulators of cellular signaling events at the basis of tumor development and progression. Both pathways are often up-regulated in different tumor types including melanoma. We recently reported the identification of compound 1 (BI-69A11) as inhibitor of the AKT and the NF-κB pathways. Here, we describe SAR studies that led to novel fluorinated derivatives with increased cellular potency, reflected in efficient inhibition of AKT and IKKs. Selected compounds demonstrated effective toxicity on melanoma, breast, and prostate cell lines. Finally, a representative derivative showed promising efficacy in an in vivo melanoma xenograft model., (© 2013 John Wiley & Sons A/S.)
- Published
- 2013
- Full Text
- View/download PDF
31. HTS by NMR of combinatorial libraries: a fragment-based approach to ligand discovery.
- Author
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Wu B, Zhang Z, Noberini R, Barile E, Giulianotti M, Pinilla C, Houghten RA, Pasquale EB, and Pellecchia M
- Subjects
- High-Throughput Screening Assays methods, Humans, Ligands, Models, Molecular, Protein Structure, Tertiary, Receptor, EphA4 chemistry, Structure-Activity Relationship, X-Linked Inhibitor of Apoptosis Protein chemistry, X-Linked Inhibitor of Apoptosis Protein metabolism, Combinatorial Chemistry Techniques methods, Drug Design, Magnetic Resonance Spectroscopy methods, Receptor, EphA4 metabolism, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology
- Abstract
Fragment-based ligand design (FBLD) approaches have become more widely used in drug discovery projects from both academia and industry, and are even often preferred to traditional high-throughput screening (HTS) of large collection of compounds (>10(5)). A key advantage of FBLD approaches is that these often rely on robust biophysical methods such as NMR spectroscopy for detection of ligand binding, hence are less prone to artifacts that too often plague the results from HTS campaigns. In this article, we introduce a screening strategy that takes advantage of both the robustness of protein NMR spectroscopy as the detection method, and the basic principles of combinatorial chemistry to enable the screening of large libraries of fragments (>10(5) compounds) preassembled on a common backbone. We used the method to identify compounds that target protein-protein interactions., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
32. Inhibition of melanoma development in the Nras((Q61K)) ::Ink4a(-/-) mouse model by the small molecule BI-69A11.
- Author
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Feng Y, Lau E, Scortegagna M, Ruller C, De SK, Barile E, Krajewski S, Aza-Blanc P, Williams R, Pinkerton AB, Jackson M, Chin L, Pellecchia M, Bosenberg M, and Ronai ZA
- Subjects
- Animals, Benzimidazoles administration & dosage, Benzimidazoles pharmacology, Cell Proliferation drug effects, Cyclin-Dependent Kinase Inhibitor p16 metabolism, Disease Models, Animal, Gene Expression Regulation, Neoplastic drug effects, Humans, Injections, Intraperitoneal, Ki-67 Antigen metabolism, Leukocyte Common Antigens metabolism, Melanoma genetics, Melanoma pathology, Mice, Precancerous Conditions genetics, Precancerous Conditions pathology, Proto-Oncogene Proteins B-raf genetics, Quinolones administration & dosage, Quinolones pharmacology, Skin Neoplasms genetics, Skin Neoplasms pathology, Small Molecule Libraries pharmacology, Small Molecule Libraries therapeutic use, Xenograft Model Antitumor Assays, Amino Acid Substitution genetics, Benzimidazoles therapeutic use, Cyclin-Dependent Kinase Inhibitor p16 deficiency, Melanoma drug therapy, Precancerous Conditions drug therapy, Quinolones therapeutic use, Skin Neoplasms drug therapy, ras Proteins genetics
- Abstract
To date, there are no effective therapies for tumors bearing NRAS mutations, which are present in 15-20% of human melanomas. Here we extend our earlier studies where we demonstrated that the small molecule BI-69A11 inhibits the growth of melanoma cell lines. Gene expression analysis revealed the induction of interferon- and cell death-related genes that were associated with responsiveness of melanoma cell lines to BI-69A11. Strikingly, the administration of BI-69A11 inhibited melanoma development in genetically modified mice bearing an inducible form of activated Nras and a deletion of the Ink4a gene (Nras((Q61K)) ::Ink4a(-/-) ). Biweekly administration of BI-69A11 starting at 10 weeks or as late as 24 weeks after the induction of mutant Nras expression inhibited melanoma development (100 and 36%, respectively). BI-69A11 treatment did not inhibit the development of histiocytic sarcomas, which constitute about 50% of the tumors in this model. BI-69A11-resistant Nras((Q61K)) ::Ink4a(-/-) tumors exhibited increased CD45 expression, reflective of immune cell infiltration and upregulation of gene networks associated with the cytoskeleton, DNA damage response, and small molecule transport. The ability to attenuate the development of NRAS mutant melanomas supports further development of BI-69A11 for clinical assessment., (© 2012 John Wiley & Sons A/S.)
- Published
- 2013
- Full Text
- View/download PDF
33. Identification of small molecules that interfere with H1N1 influenza A viral replication.
- Author
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Bottini A, De SK, Baaten BJ, Wu B, Barile E, Soonthornvacharin S, Stebbins JL, Bradley LM, Chanda SK, and Pellecchia M
- Subjects
- Animals, Antiviral Agents pharmacology, Female, Humans, Influenza A Virus, H1N1 Subtype physiology, Influenza, Human drug therapy, Mice, Mice, Inbred C57BL, Orthomyxoviridae Infections virology, Real-Time Polymerase Chain Reaction, Small Molecule Libraries pharmacology, Tetrazoles chemistry, Tetrazoles pharmacology, Tetrazoles therapeutic use, Antiviral Agents chemistry, Antiviral Agents therapeutic use, Influenza A Virus, H1N1 Subtype drug effects, Orthomyxoviridae Infections drug therapy, Small Molecule Libraries chemistry, Small Molecule Libraries therapeutic use, Virus Replication drug effects
- Abstract
Successful replication of the influenza A virus requires both viral proteins and host cellular factors. In this study we used a cellular assay to screen for small molecules capable of interfering with any of such necessary viral or cellular components. We used an established reporter assay to assess influenza viral replication by monitoring the activity of co-expressed luciferase. We screened a diverse chemical compound library, resulting in the identification of compound 7, which inhibits a novel yet elusive target. Quantitative real-time PCR studies confirmed the dose-dependent inhibitory activity of compound 7 in a viral replication assay. Furthermore, we showed that compound 7 is effective in rescuing high-dose influenza infection in an in vivo mouse model. As oseltamivir-resistant influenza strains emerge, compound 7 could be further investigated as a new and potentially suitable scaffold for the development of anti-influenza agents that act on novel targets., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2012
- Full Text
- View/download PDF
34. Antifungal saponins from bulbs of garlic, Allium sativum L. var. Voghiera.
- Author
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Lanzotti V, Barile E, Antignani V, Bonanomi G, and Scala F
- Subjects
- Antifungal Agents chemistry, Botrytis drug effects, Italy, Microbial Sensitivity Tests, Molecular Structure, Plant Roots chemistry, Saponins chemistry, Spirostans chemistry, Trichoderma drug effects, Antifungal Agents isolation & purification, Antifungal Agents pharmacology, Garlic chemistry, Saponins isolation & purification, Saponins pharmacology
- Abstract
A bioassay-guided phytochemical analysis of the polar extract from the bulbs of garlic, Allium sativum L., var. Voghiera, typical of Voghiera, Ferrara (Italy), allowed the isolation of ten furostanol saponins; voghieroside A1/A2 and voghieroside B1/B2, based on the rare agapanthagenin aglycone; voghieroside C1/C2, based on agigenin aglycone; and voghieroside D1/D2 and E1/E2, based on gitogenin aglycone. In addition, we found two known spirostanol saponins, agigenin 3-O-trisaccharide and gitogenin 3-O-tetrasaccharide. The chemical structures of the isolated compounds were established through a combination of extensive nuclear magnetic resonance, mass spectrometry and chemical analyses. High concentrations of two eugenol diglycosides were also found for the first time in Allium spp. The isolated compounds were evaluated for their antimicrobial activity towards two fungal species, the air-borne pathogen Botrytis cinerea and the antagonistic fungus Trichoderma harzianum., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
35. PDK1 inhibitors.
- Author
-
Barile E, De SK, and Pellecchia M
- Subjects
- Animals, Antineoplastic Agents pharmacology, Humans, Neoplasms drug therapy, Neoplasms pathology, Patents as Topic, Phosphatidylinositol 3-Kinases metabolism, Signal Transduction physiology, 3-Phosphoinositide-Dependent Protein Kinases antagonists & inhibitors, Drug Design, Protein Kinase Inhibitors pharmacology
- Abstract
PDK1 is a key member of the AGC protein kinase family. It plays an important role in a variety of cellular functions, leading to the activation of the PI3K signaling pathway, an event often associated with the onset and progression of several human cancers. Numerous recent observations suggest that PDK1 inhibitors may provide novel opportunities for the development of effective classes of therapeutics. On these premises, recent years have witnessed an increased effort by medicinal chemists to develop novel scaffolds to derive potent and selective PDK1 inhibitors. The intent of this review is to update the reader on the recent patent literature, covering applications published between June 2008 and September 2011 that report on PDK1 inhibitors.
- Published
- 2012
- Full Text
- View/download PDF
36. An optically pure apogossypolone derivative as potent pan-active inhibitor of anti-apoptotic bcl-2 family proteins.
- Author
-
Wei J, Stebbins JL, Kitada S, Dash R, Zhai D, Placzek WJ, Wu B, Rega MF, Zhang Z, Barile E, Yang L, Dahl R, Fisher PB, Reed JC, and Pellecchia M
- Abstract
Our focus in the past several years has been on the identification of novel and effective pan-Bcl-2 antagonists. We have recently reported a series of Apogossypolone (ApoG2) derivatives, resulting in the chiral compound (±) BI97D6. We report here the synthesis and evaluation on its optically pure (-) and (+) atropisomers. Compound (-) BI97D6 potently inhibits the binding of BH3 peptides to Bcl-X(L), Bcl-2, Mcl-1, and Bfl-1 with IC(50) values of 76 ± 5, 31 ± 2, 25 ± 8, and 122 ± 28 nM, respectively. In a cellular assay, compound (-) BI97D6 effectively inhibits cell growth in the PC-3 human prostate cancer and H23 human lung cancer cell lines with EC(50) values of 0.22 ± 0.08 and 0.14 ± 0.02 μM, respectively. Similarly, compound (-) BI97D6 effectively induces apoptosis in the BP3 human lymphoma cell line in a dose-dependent manner. The compound also shows little cytotoxicity against bax(-/-)/bak(-/-) cells, suggesting that it kills cancers cells predominantly via a Bcl-2 pathway. Moreover, compound (-) BI97D6 displays in vivo efficacy in both a Bcl-2-transgenic mouse model and in a prostate cancer xenograft model in mice. Therefore, compound (-) BI97D6 represents a promising drug lead for the development of novel apoptosis-based therapies for cancer.
- Published
- 2011
- Full Text
- View/download PDF
37. Phytotoxicity, not nitrogen immobilization, explains plant litter inhibitory effects: evidence from solid-state 13C NMR spectroscopy.
- Author
-
Bonanomi G, Incerti G, Barile E, Capodilupo M, Antignani V, Mingo A, Lanzotti V, Scala F, and Mazzoleni S
- Subjects
- Biological Transport, Carbon metabolism, Carbon Isotopes analysis, Germination, Magnetic Resonance Spectroscopy methods, Plant Development, Seeds growth & development, Seeds metabolism, Soil chemistry, Nitrogen metabolism, Plant Leaves chemistry, Plant Roots growth & development, Plants chemistry, Seedlings growth & development
- Abstract
Litter decomposition provides nutrients that sustain ecosystem productivity, but litter may also hamper root proliferation. The objectives of this work were to assess the inhibitory effect of litter decomposition on seedling growth and root proliferation; to study the role of nutrient immobilization and phytotoxicity; and to characterize decomposing litter by (13)C NMR spectroscopy. A litter-bag experiment was carried out for 180 d with 16 litter types. Litter inhibitory effects were assessed by two bioassays: seed germination and root proliferation bioassays. Activated carbon (C) and nutrient solutions were used to evaluate the effects of phytotoxic factors and nutrient immobilization. An inhibitory effect was found for all species in the early phase of decomposition, followed by a decrease over time. The addition of activated C to litter removed this inhibition. No evidence of nutrient immobilization was found in the analysis of nitrogen dynamics. NMR revealed consistent chemical changes during decomposition, with a decrease in O-alkyl and an increase in alkyl and methoxyl C. Significant correlations were found among inhibitory effects, the litter decay rate and indices derived from NMR. The results show that it is possible to predict litter inhibitory effects across a range of litter types on the basis of their chemical composition., (© 2011 The Authors. New Phytologist © 2011 New Phytologist Trust.)
- Published
- 2011
- Full Text
- View/download PDF
38. Targeting metalloproteins by fragment-based lead discovery.
- Author
-
Johnson S, Barile E, Farina B, Purves A, Wei J, Chen LH, Shiryaev S, Zhang Z, Rodionova I, Agrawal A, Cohen SM, Osterman A, Strongin A, and Pellecchia M
- Subjects
- Animals, Cells, Cultured, Coordination Complexes chemical synthesis, Inhibitory Concentration 50, Mice, Molecular Structure, Peptide Fragments chemistry, Zinc chemistry, Coordination Complexes chemistry, Drug Delivery Systems, Metalloproteins chemistry, Small Molecule Libraries chemistry
- Abstract
It has been estimated that nearly one-third of functional proteins contain a metal ion. These constitute a wide variety of possible drug targets including metalloproteinases, dehydrogenases, oxidoreductases, hydrolases, deacetylases, or many others in which the metal ion is either of catalytic or of structural nature. Despite the predominant role of a metal ion in so many classes of drug targets, current high-throughput screening techniques do not usually produce viable hits against these proteins, likely due to the lack of proper metal-binding pharmacophores in the current screening libraries. Herein, we describe a novel fragment-based drug discovery approach using a metal-targeting fragment library that is based on a variety of distinct classes of metal-binding groups designed to reliably anchor the fragments at the target's metal ions. We show that the approach can effectively identify novel, potent and selective agents that can be readily developed into metalloprotein-targeted therapeutics., (© 2011 John Wiley & Sons A/S.)
- Published
- 2011
- Full Text
- View/download PDF
39. Effective inhibition of melanoma by BI-69A11 is mediated by dual targeting of the AKT and NF-κB pathways.
- Author
-
Feng Y, Barile E, De SK, Stebbins JL, Cortez A, Aza-Blanc P, Villanueva J, Heryln M, Krajewski S, Pellecchia M, Ronai ZA, and Chiang GG
- Subjects
- Administration, Oral, Animals, Benzimidazoles administration & dosage, Benzimidazoles pharmacology, Cell Line, Tumor, Cell Proliferation drug effects, Drug Resistance, Neoplasm drug effects, Humans, Melanoma enzymology, Mice, Mice, Nude, NF-kappa B metabolism, Phosphotransferases (Alcohol Group Acceptor) antagonists & inhibitors, Phosphotransferases (Alcohol Group Acceptor) metabolism, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Proto-Oncogene Proteins B-raf metabolism, Proto-Oncogene Proteins c-akt metabolism, Quinolones administration & dosage, Quinolones pharmacology, Skin Neoplasms enzymology, Xenograft Model Antitumor Assays, Benzimidazoles therapeutic use, Melanoma drug therapy, Molecular Targeted Therapy, NF-kappa B antagonists & inhibitors, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Quinolones therapeutic use, Signal Transduction drug effects, Skin Neoplasms drug therapy
- Abstract
In melanoma, the activation of pro-survival signaling pathways, such as the AKT and NF-κB pathways, is critical for tumor growth. We have recently reported that the AKT inhibitor BI-69A11 causes efficient inhibition of melanoma growth. Here, we show that in addition to its AKT inhibitory activity, BI-69A11 also targets the NF-κB pathway. In melanoma cell lines, BI-69A11 inhibited TNF-α-stimulated IKKα/β and IκB phosphorylation as well as NF-κB reporter gene expression. Furthermore, the effective inhibition of melanoma growth by BI-69A11 was attenuated upon NF-κB activation. Mechanistically, reduced NF-κB signaling by BI-69-A11 is mediated by the inhibition of sphingosine kinase 1, identified in a screen of 315 kinases. Significantly, we demonstrate that BI-69A11 is well tolerated and orally active against UACC 903 and SW1 melanoma xenografts. Our results demonstrate that BI-69A11 inhibits both the AKT and the NF-κB pathways and that the dual targeting of these pathways may be efficacious as a therapeutic strategy in melanoma., (© 2011 John Wiley & Sons A/S.)
- Published
- 2011
- Full Text
- View/download PDF
40. Design, synthesis, and structure-activity relationship studies of thiophene-3-carboxamide derivatives as dual inhibitors of the c-Jun N-terminal kinase.
- Author
-
De SK, Barile E, Chen V, Stebbins JL, Cellitti JF, Machleidt T, Carlson CB, Yang L, Dahl R, and Pellecchia M
- Subjects
- Adenosine Triphosphate, Binding Sites, Cell Line, Drug Design, Humans, Molecular Mimicry, Protein Binding, Protein Kinase Inhibitors pharmacology, Structure-Activity Relationship, Thiophenes chemistry, JNK Mitogen-Activated Protein Kinases antagonists & inhibitors, Protein Kinase Inhibitors chemical synthesis, Thiophenes pharmacology
- Abstract
We report comprehensive structure-activity relationship studies on a novel series of c-Jun N-terminal kinase (JNK) inhibitors. Intriguingly, the compounds have a dual inhibitory activity by functioning as both ATP and JIP mimetics, possibly by binding to both the ATP binding site and to the docking site of the kinase. Several of such novel compounds display potent JNK inhibitory profiles both in vitro and in cell., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
41. Design and NMR studies of cyclic peptides targeting the N-terminal domain of the protein tyrosine phosphatase YopH.
- Author
-
Leone M, Barile E, Dahl R, and Pellecchia M
- Subjects
- Escherichia coli, Kinetics, Magnetic Resonance Spectroscopy, Models, Molecular, Protein Binding, Protein Interaction Domains and Motifs, Yersinia Infections prevention & control, Bacterial Outer Membrane Proteins chemistry, Bacterial Outer Membrane Proteins metabolism, Peptides, Cyclic chemistry, Peptides, Cyclic metabolism, Phosphotyrosine chemistry, Phosphotyrosine metabolism, Protein Tyrosine Phosphatases chemistry, Protein Tyrosine Phosphatases metabolism, Recombinant Fusion Proteins chemistry, Recombinant Fusion Proteins metabolism, Yersinia chemistry, Yersinia enzymology
- Abstract
We report on the design and evaluation of novel cyclic peptides targeting the N-terminal domain of the protein tyrosine phosphatase YopH from Yersinia. Cyclic peptides have been designed based on a short sequence from the protein SKAP-HOM [DE(pY)DDPF (pY=phosphotyrosine)], and they all contain the motif DEZXDPfK (where Z is a phosphotyrosine or a non-hydrolyzable phosphotyrosine mimetic, X is an aspartic acid or a leucine and f is a d-phenylalanine). These peptides present a 'head to tail' architecture, enabling cyclization through formation of an amide bond in between the side chains of the first aspartic acid and the lysine residues. Chemical shift perturbation studies have been carried out to monitor the binding of these peptides to the N-terminal domain of YopH. Peptides containing a phosphotyrosine moiety exhibit binding affinities in the low micromolar range; substitution of the phosphotyrosine with one of its non-hydrolyzable derivatives dramatically reduces the binding affinities. These preliminary studies may pave the way for the discovery of more potent and selective peptide-based ligands of the YopH N-terminal domain which could be further investigated for their ability to inhibit Yersiniae infections., (© 2010 John Wiley & Sons A/S.)
- Published
- 2011
- Full Text
- View/download PDF
42. Design, synthesis, and structure-activity relationships of 3-ethynyl-1H-indazoles as inhibitors of the phosphatidylinositol 3-kinase signaling pathway.
- Author
-
Barile E, De SK, Carlson CB, Chen V, Knutzen C, Riel-Mehan M, Yang L, Dahl R, Chiang G, and Pellecchia M
- Subjects
- Cell Line, Tumor, Drug Design, Enzyme Inhibitors chemical synthesis, Humans, Indazoles chemical synthesis, Magnetic Resonance Spectroscopy, Mass Spectrometry, Molecular Docking Simulation, Structure-Activity Relationship, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Indazoles chemistry, Indazoles pharmacology, Phosphatidylinositol 3-Kinases metabolism, Signal Transduction drug effects
- Abstract
A new series of 3-ethynyl-1H-indazoles has been synthesized and evaluated in both biochemical and cell-based assays as potential kinase inhibitors. Interestingly, a selected group of compounds identified from this series exhibited low micromolar inhibition against critical components of the PI3K pathway, targeting PI3K, PDK1, and mTOR kinases. A combination of computational modeling and structure-activity relationship studies reveals a possible novel mode for PI3K inhibition, resulting in a PI3Kα isoform-specific compound. Hence, by targeting the most oncogenic mutant isoform of PI3K, the compound displays antiproliferative activity both in monolayer human cancer cell cultures and in three-dimensional tumor models. Because of its favorable physicochemical, in vitro ADME and drug-like properties, we propose that this novel ATP mimetic scaffold could prove useful in deriving novel selecting and multikinase inhibitors for clinical use.
- Published
- 2010
- Full Text
- View/download PDF
43. Synthesis and optimization of thiadiazole derivatives as a novel class of substrate competitive c-Jun N-terminal kinase inhibitors.
- Author
-
De SK, Chen V, Stebbins JL, Chen LH, Cellitti JF, Machleidt T, Barile E, Riel-Mehan M, Dahl R, Yang L, Emdadi A, Murphy R, and Pellecchia M
- Subjects
- Drug Design, HeLa Cells, Humans, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors chemistry, Structure-Activity Relationship, Thiadiazoles chemistry, JNK Mitogen-Activated Protein Kinases antagonists & inhibitors, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacology, Thiadiazoles chemical synthesis, Thiadiazoles pharmacology
- Abstract
A series of thiadiazole derivatives has been designed as potential allosteric, substrate competitive inhibitors of the protein kinase JNK. We report on the synthesis, characterization and evaluation of a series of compounds that resulted in the identification of potent and selective JNK inhibitors targeting its JIP-1 docking site., (Copyright 2009 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
44. Structure-activity relationship studies of a novel series of anthrax lethal factor inhibitors.
- Author
-
Johnson SL, Chen LH, Barile E, Emdadi A, Sabet M, Yuan H, Wei J, Guiney D, and Pellecchia M
- Subjects
- Animals, Anthrax drug therapy, Bacillus anthracis metabolism, HeLa Cells, Humans, Mice, Models, Molecular, Molecular Structure, Protease Inhibitors chemical synthesis, Protease Inhibitors chemistry, Protease Inhibitors pharmacology, Stereoisomerism, Structure-Activity Relationship, Sulfonamides chemical synthesis, Antigens, Bacterial chemistry, Antitoxins chemistry, Antitoxins pharmacology, Bacterial Toxins antagonists & inhibitors, Bacterial Toxins chemistry, Sulfonamides chemistry, Sulfonamides pharmacology
- Abstract
We report on the identification of a novel small molecule inhibitor of anthrax lethal factor using a high-throughput screening approach. Guided by molecular docking studies, we carried out structure-activity relationship (SAR) studies and evaluated activity and selectivity of most promising compounds in in vitro enzyme inhibition assays and cellular assays. Selected compounds were further analyzed for their in vitro ADME properties, which allowed us to select two compounds for further preliminary in vivo efficacy studies. The data provided represents the basis for further pharmacology and medicinal chemistry optimizations that could result in novel anti-anthrax therapies.
- Published
- 2009
- Full Text
- View/download PDF
45. Design, synthesis, and structure-activity relationship of substrate competitive, selective, and in vivo active triazole and thiadiazole inhibitors of the c-Jun N-terminal kinase.
- Author
-
De SK, Stebbins JL, Chen LH, Riel-Mehan M, Machleidt T, Dahl R, Yuan H, Emdadi A, Barile E, Chen V, Murphy R, and Pellecchia M
- Subjects
- Activating Transcription Factor 2 metabolism, Animals, Binding Sites, Diabetes Mellitus, Type 2 drug therapy, Drug Design, HeLa Cells, Humans, Hypoglycemic Agents chemistry, Hypoglycemic Agents pharmacology, Insulin Resistance, JNK Mitogen-Activated Protein Kinases metabolism, Male, Mice, Phosphorylation, Protein Binding, Structure-Activity Relationship, Substrate Specificity, Thiadiazoles chemistry, Thiadiazoles pharmacology, Thiazoles chemistry, Thiazoles pharmacology, Triazoles chemistry, Triazoles pharmacology, Hypoglycemic Agents chemical synthesis, JNK Mitogen-Activated Protein Kinases antagonists & inhibitors, Thiadiazoles chemical synthesis, Thiazoles chemical synthesis, Triazoles chemical synthesis
- Abstract
We report comprehensive structure-activity relationship studies on a novel series of c-Jun N-terminal kinase (JNK) inhibitors. The compounds are substrate competitive inhibitors that bind to the docking site of the kinase. The reported medicinal chemistry and structure-based optimizations studies resulted in the discovery of selective and potent thiadiazole JNK inhibitors that display promising in vivo activity in mouse models of insulin insensitivity.
- Published
- 2009
- Full Text
- View/download PDF
46. Discovery of 2-(5-nitrothiazol-2-ylthio)benzo[d]thiazoles as novel c-Jun N-terminal kinase inhibitors.
- Author
-
De SK, Chen LH, Stebbins JL, Machleidt T, Riel-Mehan M, Dahl R, Chen V, Yuan H, Barile E, Emdadi A, Murphy R, and Pellecchia M
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Allosteric Regulation, Benzothiazoles chemical synthesis, Benzothiazoles pharmacology, Computer Simulation, Drug Discovery, JNK Mitogen-Activated Protein Kinases metabolism, Peptide Fragments metabolism, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacology, Structure-Activity Relationship, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors, p38 Mitogen-Activated Protein Kinases metabolism, Benzothiazoles chemistry, JNK Mitogen-Activated Protein Kinases antagonists & inhibitors, Protein Kinase Inhibitors chemistry
- Abstract
A new series of 2-thioether-benzothiazoles has been synthesized and evaluated for JNK inhibition. The SAR studies led to the discovery of potent, allosteric JNK inhibitors with selectivity against p38.
- Published
- 2009
- Full Text
- View/download PDF
47. Discovery of a new series of jatrophane and lathyrane diterpenes as potent and specific P-glycoprotein modulators.
- Author
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Barile E, Borriello M, Di Pietro A, Doreau A, Fattorusso C, Fattorusso E, and Lanzotti V
- Subjects
- Animals, Magnetic Resonance Spectroscopy, Mice, Models, Molecular, Molecular Structure, NIH 3T3 Cells, Stereoisomerism, ATP Binding Cassette Transporter, Subfamily B, Member 1 chemistry, Diterpenes chemistry
- Abstract
A new series of diterpenes, the jatrophanes euphoscopin M (1), euphoscopin N (2) and euphornin L (3), and the lathyrane euphohelioscopin C (7) were isolated from plants of Euphorbia helioscopia L., together with four other known analogues, euphoscopin C (4), euphornin (5), epieuphoscopin B (6) and euphohelioscopin A (8). The new compound stereostructures were elucidated by NMR analysis and computational data. The resulting isolated diterpenes were found to be potent inhibitors of P-glycoprotein (ABCB1), while showing an absence of significant activity against BCRP (ABCG2), despite the high substrate overlapping of these transporters, thus including them in the third-generation class of specific multidrug transporter modulators.
- Published
- 2008
- Full Text
- View/download PDF
48. Quantification of major flavonoids in carnation tissues (Dianthus caryophyllus) as a tool for cultivar discrimination.
- Author
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Galeotti F, Barile E, Lanzotti V, Dolci M, and Curir P
- Subjects
- Apigenin analysis, Chromatography, High Pressure Liquid, Flavonoids chemistry, Glycosides analysis, Kaempferols analysis, Models, Molecular, Molecular Conformation, Spectrophotometry, Dianthus chemistry, Dianthus classification, Flavonoids analysis
- Abstract
One flavone-C-glycoside and two flavonol-O-glycosides were recognized and isolated as the main flavonoidal components in nine different carnation cultivars, and their chemical structures have been determined by spectroscopic methods, including UV detection, MS and NMR. The distribution of these three compounds in flowers, leaves, stems, young sprouts, and roots of each cultivar was evaluated by a simple HPLC-UV method: the graphic representation of their content in the different tissues allows to identify and characterize unambiguously each considered carnation cultivar. The presented method could be an easy, inexpensive and reliable tool for carnation cultivar discrimination.
- Published
- 2008
- Full Text
- View/download PDF
49. Pavietin, a coumarin from Aesculus pavia with antifungal activity.
- Author
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Curir P, Galeotti F, Dolci M, Barile E, and Lanzotti V
- Subjects
- Aesculus microbiology, Antifungal Agents chemistry, Coumarins chemistry, Molecular Structure, Plant Leaves chemistry, Plants, Medicinal microbiology, Aesculus chemistry, Antifungal Agents isolation & purification, Antifungal Agents pharmacology, Coumarins isolation & purification, Coumarins pharmacology, Plants, Medicinal chemistry
- Abstract
A new prenylated coumarin, S-6-[2-(hydroxymethyl)butoxy]-7-hydroxy-4-methyl-2 H-chromen-2-one ( 1), named pavietin, has been isolated from the leaves of an Aesculus pavia genotype along with three known flavonol glycosides, quercetin 3- O-alpha-rhamnoside (quercitrin, 2), quercetin 3- O-alpha-arabinoside ( 3), and isorhamnetin 3- O-alpha-arabinoside (distichin, 4). The chemical structure of compound 1 was determined by chemical and spectroscopic methods, inclusive of UV, MS, and 1D and 2D NMR experiments. It showed appreciable antimicrobial properties against several pathogens, displaying a significant antifungal activity toward one of the main fungal parasites of Aesculus species, Guignardia aesculi. The same biological tests performed with a mixture of flavonoids 2- 4 resulted in weak or no activity. Compound 1 was undetectable in Aesculus hippocastanum, a closely related species lacking resistance to fungal pathogens. The possible role of 1 in plant resistance is discussed.
- Published
- 2007
- Full Text
- View/download PDF
50. Biogenetical related highly oxygenated macrocyclic diterpenes from sea spurge Euphorbia paralias.
- Author
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Barile E and Lanzotti V
- Subjects
- Diterpenes isolation & purification, Magnetic Resonance Spectroscopy, Molecular Structure, Diterpenes chemistry, Euphorbia chemistry, Macrocyclic Compounds chemistry
- Abstract
A new tricyclic diterpenoid, named pre-segetanin (1), and two new diterpenes, named segetanin A and B (2 and 3), the latter based on the rare segetane skeleton, have been identified from the whole plant of sea spurge along with four known segetane diterpenes (4-7). Among them, pre-segetanin (1) has an unprecedented carbon skeleton, whose isolation provides a first insight into the biosynthesis of diterpenoids with a segetane skeleton. The stereostructure elucidation of the isolated metabolites was determined by extensive spectroscopic analysis, including 1D and 2D NMR (COSY, TOCSY, HSQC, HMBC, and ROESY) and HRFABMS experiments.
- Published
- 2007
- Full Text
- View/download PDF
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