69 results on '"Giustiniano, M."'
Search Results
2. α-Amino Acids as Synthons in the Ugi-5-Centers-4-Components Reaction: Chemistry and Applications
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Pelliccia S., Alfano I. A., Galli U., Novellino E., Giustiniano M., Tron G. C., NOVELLINO ETTORE, Pelliccia, S., Alfano, I. A., Galli, U., Novellino, E., Giustiniano, M., Tron, G. C., and Novellino, Ettore
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chemistry.chemical_classification ,Physics and Astronomy (miscellaneous) ,010405 organic chemistry ,Chemistry ,General Mathematics ,lcsh:Mathematics ,Synthon ,Ugi four-component reaction ,Single step ,010402 general chemistry ,lcsh:QA1-939 ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,Amino acid ,Isocyanide ,isocyanides ,Organic reaction ,Chemistry (miscellaneous) ,Atom economy ,Multicomponent reactions ,Computer Science (miscellaneous) ,Multicomponent reaction ,α-amino acids - Abstract
Since the first reports, the Ugi four-component reaction (U-4CR) has been recognized as a keystone transformation enabling the synthesis of peptide mimetics in a single step and with high atom economy. In recent decades, the U-4CR has been a source of inspiration for many chemists fascinated by the possibility of identifying new efficient organic reactions by simply changing one of the components or by coupling in tandem the multicomponent process with a huge variety of organic transformations. Herein we review the synthetic potentialities, the boundaries, and the applications of the U-4CR involving α-amino acids, where the presence of two functional groups—the amino and the carboxylic acids—allowed a 5-center 4-component Ugi-like reaction, a powerful tool to gain access to drug-like multi-functionalized scaffolds.
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- 2019
3. Influence of Surface Free Energy and Wettability on Friction Coefficient between Tire and Road Surface in Wet Conditions
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Mazzola, L., primary, Galderisi, A., additional, Fortunato, G., additional, Ciaravola, V., additional, and Giustiniano, M., additional
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- 2013
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4. ChemInform Abstract: An Efficient Synthesis of 1‐Arylindazole‐3‐carboxamides Using Nitrile Imines, Isocyanides and 2‐Hydroxymethylbenzoic Acid, Followed by a Chemoselective Buchwald—Hartwig Intramolecular Cyclization.
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Giustiniano, M., primary, Mercalli, V., additional, Novellino, E., additional, and Tron, G. C., additional
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- 2016
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5. An efficient synthesis of 1-arylindazole-3-carboxamides using nitrile imines, isocyanides and 2-hydroxymethylbenzoic acid, followed by a chemoselective Buchwald–Hartwig intramolecular cyclization
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Giustiniano, M., primary, Mercalli, V., additional, Novellino, E., additional, and Tron, G. C., additional
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- 2016
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6. Design and synthesis of novel metalloproteinases inhibitors
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Kieres, K., Sala, M., Campiglia, P., Musella, S., Giustiniano, M., Nuti, E., LA REGINA, Giuseppe, Silvestri, Romano, GOMEZ MONTERREY, I., Novellino, E., and Rossello, A.
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- 2009
7. Rubber friction for tire tread compound on road surfaces
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Lorenz, B, primary, Persson, B N J, additional, Fortunato, G, additional, Giustiniano, M, additional, and Baldoni, F, additional
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- 2013
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8. Isocyanide chemistry enabled by continuous flow technology
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Bruno Cerra, Cecile Blondeau, Rolando Cannalire, Mariateresa Giustiniano, Shiva Tali Shandiz, Antimo Gioiello, Cerra, B., Blondeau, C., Cannalire, R., Giustiniano, M., Tali Shandiz, S., and Gioiello, A.
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Fluid Flow and Transfer Processes ,Industrial settings ,Laboratory practices ,Chemistry (miscellaneous) ,Process Chemistry and Technology ,Continuous flow technology ,Isocyanides ,Organic synthesis ,Chemical Engineering (miscellaneous) ,Catalysis - Abstract
Isocyanides are valuable compounds for organic synthesis. However, the poor stability and distressing odour have often limited their widespread applications in common laboratory practice and industrial setting. Herein, a continuous flow approach to enable the synthesis, purification and in-line multicomponent reaction of isocyanides, is presented.
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- 2023
9. Visible light photocatalysis in the late-stage functionalization of pharmaceutically relevant compounds
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Luca Sancineto, Mariateresa Giustiniano, Rolando Cannalire, Sveva Pelliccia, Ettore Novellino, Gian Cesare Tron, Cannalire, R., Pelliccia, S., Sancineto, L., Novellino, E., Tron, G. C., and Giustiniano, M.
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Reaction conditions ,Light ,Pharmaceutical Preparation ,Computer science ,Drug Compounding ,Late stage ,Nanotechnology ,General Chemistry ,Photochemical Processes ,Catalysis ,Catalysi ,Photochemical Processe ,Structure-Activity Relationship ,Pharmaceutical Preparations ,Photocatalysis ,Surface modification ,Critical assessment - Abstract
The late stage functionalization (LSF) of complex biorelevant compounds is a powerful tool to speed up the identification of structure-Activity relationships (SARs) and to optimize ADME profiles. To this end, visible-light photocatalysis offers unique opportunities to achieve smooth and clean functionalization of drugs by unlocking site-specific reactivities under generally mild reaction conditions. This review offers a critical assessment of current literature, pointing out the recent developments in the field while emphasizing the expected future progress and potential applications. Along with paragraphs discussing the visible-light photocatalytic synthetic protocols so far available for LSF of drugs and drug candidates, useful and readily accessible synoptic tables of such transformations, divided by functional groups, will be provided, thus enabling a useful, fast, and easy reference to them.
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- 2021
10. In-water synthesis of isocyanides under micellar conditions
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Francesca Brunelli, Silvio Aprile, Camilla Russo, Mariateresa Giustiniano, Gian Cesare Tron, Brunelli, F., Aprile, S., Russo, C., Giustiniano, M., and Tron, G. C.
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Environmental Chemistry ,Pollution - Abstract
Dehydration of N-formamides to isocyanides using p-toluen sulphonyl chloride, sodium hydrogen carbonate in aqueous micelles is reported.
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- 2022
11. Photocatalytic Isocyanide-Based Multicomponent Domino Cascade toward the Stereoselective Formation of Iminofurans
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Antonella Ilenia Alfano, Davide Ravelli, Gian Cesare Tron, Sveva Pelliccia, Mariateresa Giustiniano, Ettore Novellino, Alberto Massarotti, Paolo Luciano, Pelliccia, S., Alfano, A. I., Luciano, P., Novellino, E., Massarotti, A., Tron, G. C., Ravelli, D., and Giustiniano, M.
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010405 organic chemistry ,Chemistry ,Isocyanide ,Organic Chemistry ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,Domino ,0104 chemical sciences ,chemistry.chemical_compound ,Cascade ,Photocatalysis ,Reactivity (chemistry) ,Domino process ,Stereoselectivity - Abstract
A visible-light-promoted three-component isocyanide-based synthesis of iminofurans is herein reported. The reaction proved to be general in scope and proceeds through a triple domino process. Control experiments with 18O-labeled water and TEMPO provided key mechanistic insights for delineating the reactivity paradigms crucial to design efficient photoredox isocyanide-based domino transformations.
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- 2019
12. The 115 Year Old Multicomponent Bargellini Reaction: Perspectives and New Applications
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Gian Cesare Tron, Ilaria Murgia, Mariateresa Giustiniano, Tracey Pirali, Marta Serafini, Serafini, M., Murgia, I., Giustiniano, M., Pirali, T., and Tron, G. C.
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Engineering ,multicomponent reaction ,chlorobutanol ,business.industry ,chloroform ,Organic Chemistry ,Bargellini reaction ,Chemistry, Organic ,Pharmaceutical Science ,Review ,History, 20th Century ,α-aryl isobutyric acids ,Analytical Chemistry ,Epistemology ,lcsh:QD241-441 ,Italy ,lcsh:Organic chemistry ,Chemistry (miscellaneous) ,Drug Discovery ,Molecular Medicine ,Physical and Theoretical Chemistry ,business - Abstract
Despite its uniqueness, the Bargellini multicomponent reaction remains barely known by the most part of chemists. This can be ascribed to the fact that this transformation has not been adequately reviewed in the classic books of named reactions in organic chemistry. Nevertheless, several works on this reaction have been carried out over the years, many of them were written in Italian in the period 1929–1966. In this review article we extensively cover, in a chronological order, the most important applications of the Bargellini reaction reported to date, with the hope that this knowledge-sharing will help chemists to properly use this multicomponent transformation and imagine novel reactivities based on it.
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- 2021
13. Visible-Light Photocatalytic Ugi/Aza-Wittig Cascade towards 2-Aminomethyl-1,3,4-oxadiazole Derivatives
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Paolo Luciano, Rolando Cannalire, Gian Cesare Tron, Francesca Brunelli, Camilla Russo, Mariateresa Giustiniano, Russo, C., Cannalire, R., Luciano, P., Brunelli, F., Tron, G. C., and Giustiniano, M.
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chemistry.chemical_classification ,Organic Chemistry ,Photoredox catalysis ,Substrate (chemistry) ,Combinatorial chemistry ,Catalysis ,Amino acid ,chemistry.chemical_compound ,chemistry ,Wittig reaction ,Functional group ,Photocatalysis ,Ugi reaction ,Surface modification - Abstract
A new visible-light photocatalytic multicomponent reaction (MCR) involving N-alkyl-N-methylanilines, N-isocyanoiminotriphenylphosphorane, and carboxylic acids leading to 1,3,4-oxadiazole derivatives is reported. The developed mild reaction conditions enable a broad substrate scope and good functional group tolerance, as further highlighted in the late-stage functionalization of amino acids and drugs. Additionally, a two-step one-pot protocol for the synthesis of non-symmetrical diacylhydrazines is also reported.
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- 2021
14. The Dark Side of Isocyanides: Visible-Light Photocatalytic Activity in the Oxidative Functionalization of C(sp3)–H Bonds
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Gian Cesare Tron, Jussara Amato, Camilla Russo, Mariateresa Giustiniano, Russo, C., Amato, J., Tron, G. C., and Giustiniano, M.
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Photoexcitation ,chemistry.chemical_compound ,Nucleophile ,Chemistry ,Isocyanide ,Amide ,Organic Chemistry ,Substrate (chemistry) ,Surface modification ,Oxidative coupling of methane ,Photochemistry ,Catalysis - Abstract
The possibility to harness aromatic isocyanides as visible-light photocatalysts in the α-amino C(sp3)-H functionalization is herein presented. Actually, the three-component cross-dehydrogenative coupling of aromatic tertiary amines with isocyanides and water leads to amide products under very mild conditions in high yields and with a good substrate scope. While the reaction with aromatic isocyanides proceeds upon direct photoexcitation, aliphatic isocyanides are able to form a photoactive electron-donor-acceptor complex with aromatic amines. Moreover, the use of a catalytic loading of an aromatic isocyanide promotes the oxidative coupling of N-phenyl-1,2,3,4-tetrahydroisoquinoline with an array of different (pro)nucleophiles in good to excellent yields, thus providing the proof-of-concept for the development of a new highly tunable class of organic visible-light photocatalysts.
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- 2021
15. Back to the Medicinal Chemistry Future
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Christian W. Gruber, Caitlin N. Kent, Mariateresa Giustiniano, Paul C. Trippier, Giustiniano, M., Gruber, C. W., Kent, C. N., and Trippier, P. C.
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World Wide Web ,Pharmaceutical Preparations ,Chemistry ,Chemistry, Pharmaceutical ,Drug Discovery ,MEDLINE ,Humans ,Molecular Medicine - Published
- 2021
16. Visible-Light Photocatalytic Functionalization of Isocyanides for the Synthesis of Secondary Amides and Ketene Aminals
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Rolando Cannalire, Jussara Amato, Gian Cesare Tron, Vincenzo Summa, Ettore Novellino, Mariateresa Giustiniano, Cannalire, R., Amato, J., Summa, V., Novellino, E., Tron, G. C., and Giustiniano, M.
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green chemistry ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Ketene ,Visible light photocatalytic ,010402 general chemistry ,Photochemistry ,01 natural sciences ,Article ,0104 chemical sciences ,isocyanides ,chemistry.chemical_compound ,Photocatalysi ,Photocatalysis ,Surface modification - Abstract
A new visible light-induced photocatalytic protocol enabling the formation of secondary amides from electron-poor organic bromides and isocyanides was developed. In addition, the in situ interception of ketenimine intermediates with nitrogen nucleophiles such as amines, hydrazines, and TMSN3 afforded, in a one-pot two-step procedure, valuable scaffolds such as ketene aminals, pyrazolones, and tetrazoles. Mechanistic evidence confirmed a radical pathway where isocyanides acted as radical geminal acceptors generating key imidoyl radical species.
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- 2020
17. Enriching the Arsenal of Pharmacological Tools against MICAL2
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Ivana Barravecchia, Elisabetta Barresi, Camilla Russo, Francesca Scebba, Chiara De Cesari, Valerio Mignucci, Davide De Luca, Silvia Salerno, Valeria La Pietra, Mariateresa Giustiniano, Sveva Pelliccia, Diego Brancaccio, Greta Donati, Federico Da Settimo, Sabrina Taliani, Debora Angeloni, Luciana Marinelli, Barravecchia, I., Barresi, E., Russo, C., Scebba, F., De Cesari, C., Mignucci, V., De Luca, D., Salerno, S., La Pietra, V., Giustiniano, M., Pelliccia, S., Brancaccio, D., Donati, G., Da Settimo, F., Taliani, S., Angeloni, D., and Marinelli, L.
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Passerini-like 3-CR ,Multicomponent reactions (MCRs) ,Pharmaceutical Science ,CCG-1423 ,MICAL2 ,wound healing assay ,HMEC-1 endothelial cells ,786-O kidney cancer cells ,metastasis ,neoangiogenesis ,multicomponent reactions (MCRs) ,Passerini 3-CR reaction ,Metastasi ,Article ,Analytical Chemistry ,HMEC-1 endothelial cell ,Small Molecule Libraries ,Metastasis ,Neoangiogenesis ,Wound healing assay ,QD241-441 ,Drug Discovery ,Humans ,Enzyme Inhibitor ,Anilides ,Enzyme Inhibitors ,Physical and Theoretical Chemistry ,Molecular Structure ,Microfilament Proteins ,Organic Chemistry ,Microfilament Protein ,Neoangiogenesi ,786-O kidney cancer cell ,Oxidoreductase ,Chemistry (miscellaneous) ,Benzamides ,Molecular Medicine ,Oxidoreductases ,Human - Abstract
Molecule interacting with CasL 2 (MICAL2), a cytoskeleton dynamics regulator, are strongly expressed in several human cancer types, especially at the invasive front, in metastasizing cancer cells and in the neo-angiogenic vasculature. Although a plethora of data exist and stress a growing relevance of MICAL2 to human cancer, it is worth noting that only one small-molecule inhibitor, named CCG-1423 (1), is known to date. Herein, with the aim to develop novel MICAL2 inhibitors, starting from CCG-1423 (1), a small library of new compounds was synthetized and biologically evaluated on human dermal microvascular endothelial cells (HMEC-1) and on renal cell adenocarcinoma (786-O) cells. Among the novel compounds, 10 and 7 gave interesting results in terms of reduction in cell proliferation and/or motility, whereas no effects were observed in MICAL2-knocked down cells. Aside from the interesting biological activities, this work provides the first structure–activity relationships (SARs) of CCG-1423 (1), thus providing precious information for the discovery of new MICAL2 inhibitors.
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- 2021
18. Multicomponent reaction between (Z)-chloroximes, isocyanides and NH-heterocyclic rings
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Mariateresa Giustiniano, Gian Cesare Tron, Ubaldina Galli, Camilla Russo, Francesca Brunelli, Brunelli, F., Russo, C., Galli, U., Giustiniano, M., and Tron, G. C.
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Benzimidazole ,Benzotriazole ,Nitrile ,Organic Chemistry ,Triazole ,Biochemistry ,Cycloaddition ,chemistry.chemical_compound ,chemistry ,Nucleophile ,Drug Discovery ,Polymer chemistry ,Tetrazole ,Nitrilium - Abstract
An operationally simple multicomponent reaction utilizing (Z)-chloroximes, isocyanides and NH-heterocyclic rings (imidazole, benzimidazole, triazole, benzotriazole and tetrazole) affords a hitherto unknown class of compounds which cannot be obtained via a classical multistep two-component reaction. From this work, it appears evident: a) kinetic control dictated by the [3 + 1] cycloaddition between nitrile N-oxides and isocyanides; b) the chemical compatibility between the highly unstable nitrilium ion and the poorly nucleophilic imidazoles and related heterocycles, which quench the reaction allowing for the formation of a single product.
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- 2021
19. Exploiting the Nucleophilicity of the Nitrogen Atom of Imidazoles: One-Pot Three-Component Synthesis of Imidazo-Pyrazines
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Gian Cesare Tron, Erika Del Grosso, Ubaldina Galli, Rejdia Hysenlika, Fiorella Meneghetti, Sveva Pelliccia, Mariateresa Giustiniano, Ettore Novellino, Galli, U., Hysenlika, R., Meneghetti, F., Grosso, E. D., Pelliccia, S., Novellino, E., Giustiniano, M., and Tron, G. C.
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Nitrogen ,Pharmaceutical Science ,Article ,Analytical Chemistry ,Ion ,lcsh:QD241-441 ,chemistry.chemical_compound ,isocyanides ,Nucleophile ,lcsh:Organic chemistry ,Drug Discovery ,Imidazole ,Physical and Theoretical Chemistry ,Nitrilium ,Aldehydes ,Cyanides ,Molecular Structure ,Component (thermodynamics) ,multicomponent reactions ,Organic Chemistry ,Imidazoles ,Combinatorial chemistry ,interrupted Ugi reactions ,Isocyanide ,Nitrogen atom ,chemistry ,Interrupted Ugi reaction ,Chemistry (miscellaneous) ,Pyrazines ,Molecular Medicine ,Amine gas treating ,Methanol - Abstract
A novel one-pot multicomponent reaction to synthesize substituted imidazopyrazines is described. In brief, 1H-(imidazol-5-yl)-N-substituted methanamines react with aldehydes and isocyanides in methanol at room temperature to give imidazopyrazine derivatives in excellent yields. The imidazole nitrogen atom was able to intercept the nascent nitrilium ion, channeling the reaction toward to the sole formation of imidazopyrazines, suppressing the competitive formation of other possible side products deriving from the reaction with the high-energy nitrilium ion. The number of examples and the variability of the nature of isocyanides, aldehydes, and amine components herein employed, witness the robustness of this novel methodology.
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- 2019
20. Aryl Azides as Forgotten Electrophiles in the Van Leusen Reaction: A Multicomponent Transformation Affording 4-Tosyl-1-arylimidazoles
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Erika Del Grosso, Gian Cesare Tron, Fiorella Meneghetti, Antonella Ilenia Alfano, Cristiana Necardo, Ettore Novellino, Mariateresa Giustiniano, Sveva Pelliccia, Ubaldina Galli, Necardo, C., Alfano, A. I., Del Grosso, E., Pelliccia, S., Galli, U., Novellino, E., Meneghetti, F., Giustiniano, M., and Tron, G. C.
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Reaction mechanism ,Green Chemistry ,Chemistry ,multicomponent reactions ,Aryl ,Organic Chemistry ,TosMIC ,Combinatorial chemistry ,chemistry.chemical_compound ,Isocyanide ,Tosyl ,Electrophile ,Molecule ,Van Leusen reaction - Abstract
Considering aryl azides as electrophilic partners for the TosMIC mediated Van Leusen reaction, a novel multicomponent synthesis of 4-tosyl-1-arylimidazoles is reported. In this transformation, two molecules of TosMIC participate in the reaction mechanism in two different ways, with the second molecule undergoing a novel type of fragmentation resulting in the incorporation of a C-H into the final product.
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- 2019
21. Reaction between (Z)-Arylchlorooximes and α-Isocyanoacetamides: A procedure for the synthesis of Aryl-α-ketoamide amides
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Hilde Cassese, Valentina Mercalli, Salvatore Di Maro, Mariateresa Giustiniano, Ubaldina Galli, Gian Cesare Tron, Ettore Novellino, Giustiniano, M., Mercalli, V., Cassese, H., Di Maro, S., Galli, U., Novellino, E., Tron, G. C., Giustiniano, Mariateresa, Cassese, Hilde, DI MARO, Salvatore, and Novellino, Ettore
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Amide ,Molecular Structure ,Aryl ,Organic Chemistry ,Ring (chemistry) ,Combinatorial chemistry ,Amides ,Catalysis ,Oxazole ,Catalysi ,chemistry.chemical_compound ,chemistry ,Nitriles ,Oximes ,Oxazoles ,Nitrile - Abstract
(Z)-Arylchlorooximes and α-isocyanoacetamides undergo a smooth reaction to produce 1,3-oxazol-2-oxime derivatives in good yields. Opening of the oxazole ring and deoximation reaction give a facile access to aryl-α-ketoamide amides, a class of privileged scaffolds in medicinal chemistry and important synthetic intermediates in organic chemistry. © 2014 American Chemical Society.
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- 2014
22. Shooting for selective druglike G-quadruplex binders: evidence for telomeric DNA damage and tumor cell death
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Angela Maria Rizzo, Luciana Marinelli, Sandro Cosconati, Stefano De Tito, Annamaria Biroccio, Bruno Pagano, Iolanda Fotticchia, Concetta Giancola, Ettore Novellino, Antonio Randazzo, Ilaria Lauri, Roberta Trotta, Sara Iachettini, Mariateresa Giustiniano, Cosconati, S., Rizzo, A., Trotta, Roberta, Pagano, Bruno, Iachettini, S., DE TITO, Stefano, Lauri, Ilaria, Fotticchia, Iolanda, Giustiniano, Mariateresa, Marinelli, Luciana, Giancola, Concetta, Novellino, Ettore, Biroccio, A., Randazzo, Antonio, AAVV, S., Cosconati, A., Rizzo, S., Iachettini, A., Biroccio, Cosconati, Sandro, Rizzo, A, Trotta, R, Pagano, B, Iachettini, S, De Tito, S, Lauri, I, Fotticchia, I, Giustiniano, M, Marinelli, L, Giancola, C, Novellino, E, Biroccio, A, and Randazzo, A.
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Senescence ,Magnetic Resonance Spectroscopy ,Stereochemistry ,DNA damage ,Fluorescent Antibody Technique ,Antineoplastic Agents ,Apoptosis ,G-quadruplex ,ligand ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,Structure–activity relationship ,Humans ,heterocyclic compounds ,Cells, Cultured ,Cellular Senescence ,antitumor ,Molecular Structure ,Circular Dichroism ,Cell Cycle Checkpoints ,Fibroblasts ,Telomere ,Flow Cytometry ,Small molecule ,NMR ,G-Quadruplexes ,chemistry ,Biochemistry ,Duplex (building) ,Molecular Medicine ,DNA ,DNA Damage ,HeLa Cells - Abstract
Targeting of DNA secondary structures, such as G-quadruplexes, is now considered an appealing opportunity for drug intervention in anticancer therapy. So far, efforts made in the discovery of chemotypes able to target G-quadruplexes mainly succeeded in the identification of a number of polyaromatic compounds featuring end-stacking binding properties. Against this general trend, we were persuaded that the G-quadruplex grooves can recognize molecular entities with better drug-like and selectivity properties. From this idea, a set of small molecules was identified and the structural features responsible for G-quadruplex recognition were delineated. These compounds were demonstrated to have enhanced affinity and selectivity for the G-quadruplex over the duplex structure. Their ability to induce selective DNA damage at telomeric level and to induction of apoptosis and senescence on tumor cells is herein experimentally proven. © 2012 American Chemical Society.
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- 2012
23. Progresses in the pursuit of aldose reductase inhibitors: The structure-based lead optimization step
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Vita Maglio, Sara Angiuoli, Ettore Novellino, Federico Da Settimo, Mariateresa Giustiniano, Sandro Cosconati, Stefania Sartini, Salvatore Di Maro, Valeria La Pietra, Luciana Marinelli, Concettina La Motta, Anna Ramunno, Ramunno, A, Cosconati, Sandro, Sartini, S, Maglio, V, Angiuoli, S, La Pietra, V, DI MARO, Salvatore, Giustiniano, M, La Motta, C, Da Settimo, F, Marinelli, L, Novellino, E., Cosconati, S, LA PIETRA, Valeria, Giustiniano, Mariateresa, Marinelli, Luciana, and Novellino, Ettore
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Models, Molecular ,medicine.medical_specialty ,Diabetic neuropathy ,Drug Evaluation, Preclinical ,Aldose reductase ,Inflammation ,Pharmacology ,Diabete ,Fidarestat ,Metastasis ,Docking ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,User-Computer Interface ,Aldehyde Reductase ,Diabetes mellitus ,Internal medicine ,Catalytic Domain ,Drug Discovery ,medicine ,Enzyme Inhibitors ,Receptor ,Chemistry ,Organic Chemistry ,General Medicine ,Aldose reductase inhibitors ,medicine.disease ,Endocrinology ,Docking (molecular) ,Enzyme ,medicine.symptom - Abstract
Aldose reductase (ALR2) is a crucial enzyme in the development of the major complications of diabetes mellitus. Very recently it has been demonstrated that the ARL2 inhibitor, fidarestat, significantly prevents inflammatory signals (TNF-α, LPS) that cause cancer (colon, breast, prostate and lung), metastasis, asthma, and other inflammatory diseases. Currently, fidarestat is in phase III clinical trial for diabetic neuropathy and was found to be safe. Thus the finding of novel, potent ARL2 inhibitors is today more than in the past in great demand as they can pave the way for a novel therapeutic approach for a number of diseases besides the diabetes. Herein, starting from the virtual screening-derived ALR2 inhibitor S12728 (1), a rational receptor-based lead optimization has been undertaken. The design and synthetic efforts here reported led to the discovery of several new compounds endowed with low micromolar/submicromolar activities. © 2012 Elsevier Masson SAS. All rights reserved.
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- 2012
24. Isonitrile Photochemistry: A Functional Group Class Coming in from the Cold.
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Giustiniano M
- Abstract
Starting from a historical background that acknowledges isonitriles as a neglected class of compounds due to their unpleasant smell and hardly controlled reaction conditions with open shell species, the present concept article aims at highlighting the seeds of the modern isonitrile photochemistry. Representative essential transformations achieved via either UV light irradiation or radical initiators at high temperatures are brought into play to draw a parallel with the current literature relying on the exploitation of visible light photochemical methods. Such a comparison points out the potential of this enabling technology to further expand the scope of isonitrile chemistry and the unmet challenges which makes it a very stimulating field., (© 2024 Wiley‐VCH GmbH.)
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- 2024
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25. Visible Light-promoted C(sp 3 )-H α-Carbamoylation of Cyclic Ethers with Isocyanides.
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Russo C, Volpe C, Santoro F, Brancaccio D, Di Porzio A, Carotenuto A, Randazzo A, Grimaud L, Vitale MR, Protti S, and Giustiniano M
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A protocol exploiting isocyanides as carbamoylating agents for the α-C(sp
3 )-H functionalization of cyclic ethers has been optimized via a combined visible light-driven hydrogen atom transfer/Lewis acid-catalyzed approach. The isocyanide substrate scope revealed an exquisite functional group compatibility (18 examples, with yields up to 99 %). Both radical and polar trapping, kinetic isotopic effect and real-time NMR studies support the mechanistic hypothesis and provide insightful details for the design of new chemical processes involving the generation of oxocarbenium ions., (© 2024 The Author(s). Chemistry - A European Journal published by Wiley-VCH GmbH.)- Published
- 2024
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26. Exploiting the Different Nucleophilicity of the Isocyano Group: A Strategy for the Isocyanide Functionalization.
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Brunelli F, Russo C, Giustiniano M, and Tron GC
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By exploiting the different nucleophilicity of aromatic and aliphatic isocyanides, we selectively react aliphatic isocyano groups while preserving aromatic ones in Passerini and Ugi multicomponent reactions. This simple approach allows the synthesis of α-acyloxy carboxamides or α-acylamino carboxamides possessing one or two isocyanide groups, which are challenging to achieve through traditional formylation and dehydration protocols. These analogues have the potential to serve as valuable building blocks with diverse applications.
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- 2024
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27. Each Interruption is an Opportunity: Novel Synthetic Strategies Explored Through Interrupted Click Reactions.
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Brunelli F, Russo C, Giustiniano M, and Tron GC
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The particular and unique mechanism of the copper-catalyzed reaction between azides and alkynes (CuAAC) has not only allowed for the efficient synthesis of 1,2,3-trisubstituted 1,4-triazoles in excellent yields and under mild conditions, becoming the quintessential click reaction, but it has also enabled the straightforward formation of a metallocycle intermediate, the copper triazolyl. This, under suitable reaction conditions able to suppress its protonolysis, can be used either for the creation of new bicyclic triazolyl structures or for the generation of novel three or four-component reactions. The aim of this review is to rationalize and unify all these transformations, which are collectively referred to as "interrupted click reactions"., (© 2024 Wiley‐VCH GmbH.)
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- 2024
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28. Discovery of 2,3-Diaminoindole Derivatives as a Novel Class of NOD Antagonists.
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Russo C, Russomanno P, D'Amore VM, Alfano AI, Santoro F, Guzelj S, Gobec M, Amato J, Pagano B, Marinelli L, Carotenuto A, Tron GC, Di Leva FS, Jakopin Ž, Brancaccio D, and Giustiniano M
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- Nod2 Signaling Adaptor Protein metabolism, Indoles chemistry, Indoles metabolism, Immunity, Innate, Nod1 Signaling Adaptor Protein
- Abstract
NOD1 and NOD2 are members of the pattern recognition receptors involved in the innate immune response. Overactivation of NOD1 is implicated in inflammatory disorders, multiple sclerosis, and cancer cell metastases. NOD1 antagonists would represent valuable pharmacological tools to gain further insight into protein roles, potentially leading to new therapeutic strategies. We herein report the expansion of the chemical space of NOD1 antagonists via a multicomponent synthetic approach affording a novel chemotype, namely, 2,3-diaminoindoles. These efforts resulted in compound 37 , endowed with low micromolar affinity toward NOD1. Importantly, a proof-of-evidence of direct binding to NOD1 of Noditinib-1 and derivative 37 is provided here for the first time. Additionally, the combination of computational studies and NMR-based displacement assays enabled the characterization of the binding modality of 37 to NOD1, thus providing key unprecedented knowledge for the design of potent and selective NOD1 antagonists.
- Published
- 2024
- Full Text
- View/download PDF
29. Isocyanides as Catalytic Electron Acceptors in the Visible Light Promoted Oxidative Formation of Benzyl and Acyl Radicals.
- Author
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Russo C, Donati G, Giustiniano F, Amato J, Marinelli L, Whitby RJ, and Giustiniano M
- Abstract
The recent disclosure of the ability of aromatic isocyanides to harvest visible light and act as single electron acceptors when reacting with tertiary aromatic amines has triggered a renewed interest in their application to the development of green photoredox catalytic methodologies. Accordingly, the present work explores their ability to promote the generation of both alkyl and acyl radicals starting from radical precursors such as Hantzsch esters, potassium alkyltrifluoroborates, and α-oxoacids. Mechanistic studies involving UV-visible absorption and fluorescence experiments, electrochemical measurements of the ground-state redox potentials along with computational calculations of both the ground- and the excited-state redox potentials of a set of nine different aromatic isocyanides provide key insights to promote a rationale design of a new generation of isocyanide-based organic photoredox catalysts. Importantly, the green potential of the investigated chemistry is demonstrated by a direct and easy access to deuterium labeled compounds., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)
- Published
- 2023
- Full Text
- View/download PDF
30. eHydrogenation: Hydrogen-free Electrochemical Hydrogenation.
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Russo C, Leech MC, Walsh JM, Higham JI, Giannessi L, Lambert E, Kiaku C, Poole DL, Mason J, Goodall CAI, Devo P, Giustiniano M, Radi M, and Lam K
- Abstract
Hydrogenation reactions are staple transformations commonly used across scientific fields to synthesise pharmaceuticals, natural products, and various functional materials. However, the vast majority of these reactions require the use of a toxic and costly catalyst leading to unpractical, hazardous and often functionally limited conditions. Herein, we report a new, general, practical, efficient, mild and high-yielding hydrogen-free electrochemical method for the reduction of alkene, alkyne, nitro and azido groups. Finally, this method has been applied to deuterium labelling., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
- Published
- 2023
- Full Text
- View/download PDF
31. Visible-Light Photoredox Catalysis in Water.
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Russo C, Brunelli F, Tron GC, and Giustiniano M
- Abstract
The use of water in organic synthesis draws attention to its green chemistry features and its unique ability to unveil unconventional reactivities. Herein, literature about the use of water as a reaction medium under visible-light photocatalytic conditions is summarized in order to highlight challenges and opportunities. Accordingly, this Synopsis has been divided into four different sections focused on (1) the unconventional role of water in photocatalytic reactions, (2) in -/ on- water reactions, (3) water-soluble photocatalysts, and (4) photomicellar catalytic systems.
- Published
- 2023
- Full Text
- View/download PDF
32. Isocyanide-Based Multicomponent Reactions Promoted by Visible Light Photoredox Catalysis.
- Author
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Russo C, Brunelli F, Cesare Tron G, and Giustiniano M
- Abstract
Isocyanide-based multicomponent reactions claim a one century-old history of flourishing developments. On the other hand, the enormous impact of recent progresses in visible light photocatalysis has boosted the identification of new straightforward and green approaches to both new and known chemical entities. In this context, the application of visible light photocatalytic conditions to multicomponent processes has been promoting key stimulating advancements. Spanning from radical-polar crossover pathways, to photoinduced and self-catalyzed transformations, to reactions involving the generation of imidoyl radical species, the present literature analysis would provide a general and critical overview about the potentialities and challenges of exploiting isocyanides in visible light photocatalytic multicomponent reactions., (© 2022 Wiley-VCH GmbH.)
- Published
- 2023
- Full Text
- View/download PDF
33. Domino synthesis of 5-aminoimidazoles from Strecker multicomponent adducts via ytterbium-promoted isocyanide insertion/5-exo-dig cyclization.
- Author
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Cannalire R, Russo C, Luciano P, Cerra B, Gioiello A, Brunelli F, Tron GC, and Giustiniano M
- Subjects
- Cyclization, Imidazoles chemistry, Cyanides chemistry, Ytterbium
- Abstract
A new Lewis acid promoted domino isocyanide insertion/5-exo-dig cyclization of readily available Strecker 3-component adducts to 4-substituted 5-aminoimidazole derivatives is herein reported. Despite their potential as relevant heterocyclic scaffolds in medicinal chemistry programs, this class of compounds is still underrepresented, with current synthetic strategies poorly efficient in terms of timing and yields. To this end, we show how the exploitation of unconventional reactivities of isocyanides, promoted by ytterbium-triflate, could represent a key resource to enable a fast and easy access to such an unexplored area of the chemical space., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
- Published
- 2023
- Full Text
- View/download PDF
34. The Dark Side of Isocyanides: Visible-Light Photocatalytic Activity in the Oxidative Functionalization of C(sp 3 )-H Bonds.
- Author
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Russo C, Amato J, Tron GC, and Giustiniano M
- Abstract
The possibility to harness aromatic isocyanides as visible-light photocatalysts in the α-amino C(sp
3 )-H functionalization is herein presented. Actually, the three-component cross-dehydrogenative coupling of aromatic tertiary amines with isocyanides and water leads to amide products under very mild conditions in high yields and with a good substrate scope. While the reaction with aromatic isocyanides proceeds upon direct photoexcitation, aliphatic isocyanides are able to form a photoactive electron-donor-acceptor complex with aromatic amines. Moreover, the use of a catalytic loading of an aromatic isocyanide promotes the oxidative coupling of N -phenyl-1,2,3,4-tetrahydroisoquinoline with an array of different (pro)nucleophiles in good to excellent yields, thus providing the proof-of-concept for the development of a new highly tunable class of organic visible-light photocatalysts.- Published
- 2021
- Full Text
- View/download PDF
35. Enriching the Arsenal of Pharmacological Tools against MICAL2.
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Barravecchia I, Barresi E, Russo C, Scebba F, De Cesari C, Mignucci V, De Luca D, Salerno S, La Pietra V, Giustiniano M, Pelliccia S, Brancaccio D, Donati G, Da Settimo F, Taliani S, Angeloni D, and Marinelli L
- Subjects
- Humans, Molecular Structure, Anilides chemistry, Anilides pharmacology, Benzamides chemistry, Benzamides pharmacology, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Microfilament Proteins antagonists & inhibitors, Microfilament Proteins metabolism, Oxidoreductases antagonists & inhibitors, Oxidoreductases metabolism, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology
- Abstract
Molecule interacting with CasL 2 (MICAL2), a cytoskeleton dynamics regulator, are strongly expressed in several human cancer types, especially at the invasive front, in metastasizing cancer cells and in the neo-angiogenic vasculature. Although a plethora of data exist and stress a growing relevance of MICAL2 to human cancer, it is worth noting that only one small-molecule inhibitor, named CCG-1423 (1), is known to date. Herein, with the aim to develop novel MICAL2 inhibitors, starting from CCG-1423 (1), a small library of new compounds was synthetized and biologically evaluated on human dermal microvascular endothelial cells (HMEC-1) and on renal cell adenocarcinoma (786-O) cells. Among the novel compounds, 10 and 7 gave interesting results in terms of reduction in cell proliferation and/or motility, whereas no effects were observed in MICAL2-knocked down cells. Aside from the interesting biological activities, this work provides the first structure-activity relationships (SARs) of CCG-1423 (1), thus providing precious information for the discovery of new MICAL2 inhibitors.
- Published
- 2021
- Full Text
- View/download PDF
36. Photomicellar Catalyzed Synthesis of Amides from Isocyanides: Optimization, Scope, and NMR Studies of Photocatalyst/Surfactant Interactions.
- Author
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Cannalire R, Santoro F, Russo C, Graziani G, Tron GC, Carotenuto A, Brancaccio D, and Giustiniano M
- Abstract
The merging of micellar and photoredox catalysis represents a key issue to promote "in water" photochemical transformations. A photomicellar catalyzed synthesis of amides from N -methyl- N -alkyl aromatic amines and both aliphatic and aromatic isocyanides is herein presented. The mild reaction conditions enabled a wide substrate scope and a good functional groups tolerance, as further shown in the late-stage functionalization of complex bioactive scaffolds. Furthermore, solution 1D and 2D NMR experiments performed, for the first time, in the presence of paramagnetic probes enabled the study of the reaction environment at the atomic level along with the localization of the photocatalyst with respect to the micelles, thus providing experimental data to drive the identification of optimum photocatalyst/surfactant pairing., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)
- Published
- 2021
- Full Text
- View/download PDF
37. Back to the Medicinal Chemistry Future.
- Author
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Giustiniano M, Gruber CW, Kent CN, and Trippier PC
- Subjects
- Humans, Chemistry, Pharmaceutical, Pharmaceutical Preparations chemistry
- Published
- 2021
- Full Text
- View/download PDF
38. Medicinal Chemistry of Isocyanides.
- Author
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Massarotti A, Brunelli F, Aprile S, Giustiniano M, and Tron GC
- Abstract
In eons of evolution, isocyanides carved out a niche in the ecological systems probably thanks to their metal coordinating properties. In 1859 the first isocyanide was synthesized by humans and in 1950 the first natural isocyanide was discovered. Now, at the beginning of XXI century, hundreds of isocyanides have been isolated both in prokaryotes and eukaryotes and thousands have been synthesized in the laboratory. For some of them their ecological role is known, and their potent biological activity as antibacterial, antifungal, antimalarial, antifouling, and antitumoral compounds has been described. Notwithstanding, the isocyanides have not gained a good reputation among medicinal chemists who have erroneously considered them either too reactive or metabolically unstable, and this has restricted their main use to technical applications as ligands in coordination chemistry. The aim of this review is therefore to show the richness in biological activity of the isocyanide-containing molecules, to support the idea of using the isocyanide functional group as an unconventional pharmacophore especially useful as a metal coordinating warhead. The unhidden hope is to convince the skeptical medicinal chemists of the isocyanide potential in many areas of drug discovery and considering them in the design of future drugs.
- Published
- 2021
- Full Text
- View/download PDF
39. The 115 Year Old Multicomponent Bargellini Reaction: Perspectives and New Applications.
- Author
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Serafini M, Murgia I, Giustiniano M, Pirali T, and Tron GC
- Subjects
- History, 20th Century, Italy, Chemistry, Organic history, Drug Discovery history
- Abstract
Despite its uniqueness, the Bargellini multicomponent reaction remains barely known by the most part of chemists. This can be ascribed to the fact that this transformation has not been adequately reviewed in the classic books of named reactions in organic chemistry. Nevertheless, several works on this reaction have been carried out over the years, many of them were written in Italian in the period 1929-1966. In this review article we extensively cover, in a chronological order, the most important applications of the Bargellini reaction reported to date, with the hope that this knowledge-sharing will help chemists to properly use this multicomponent transformation and imagine novel reactivities based on it.
- Published
- 2021
- Full Text
- View/download PDF
40. Visible light photocatalysis in the late-stage functionalization of pharmaceutically relevant compounds.
- Author
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Cannalire R, Pelliccia S, Sancineto L, Novellino E, Tron GC, and Giustiniano M
- Subjects
- Catalysis, Drug Compounding, Pharmaceutical Preparations chemistry, Photochemical Processes, Structure-Activity Relationship, Light, Pharmaceutical Preparations chemical synthesis
- Abstract
The late stage functionalization (LSF) of complex biorelevant compounds is a powerful tool to speed up the identification of structure-activity relationships (SARs) and to optimize ADME profiles. To this end, visible-light photocatalysis offers unique opportunities to achieve smooth and clean functionalization of drugs by unlocking site-specific reactivities under generally mild reaction conditions. This review offers a critical assessment of current literature, pointing out the recent developments in the field while emphasizing the expected future progress and potential applications. Along with paragraphs discussing the visible-light photocatalytic synthetic protocols so far available for LSF of drugs and drug candidates, useful and readily accessible synoptic tables of such transformations, divided by functional groups, will be provided, thus enabling a useful, fast, and easy reference to them.
- Published
- 2021
- Full Text
- View/download PDF
41. Visible-Light Photocatalytic Functionalization of Isocyanides for the Synthesis of Secondary Amides and Ketene Aminals.
- Author
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Cannalire R, Amato J, Summa V, Novellino E, Tron GC, and Giustiniano M
- Abstract
A new visible light-induced photocatalytic protocol enabling the formation of secondary amides from electron-poor organic bromides and isocyanides was developed. In addition, the in situ interception of ketenimine intermediates with nitrogen nucleophiles such as amines, hydrazines, and TMSN
3 afforded, in a one-pot two-step procedure, valuable scaffolds such as ketene aminals, pyrazolones, and tetrazoles. Mechanistic evidence confirmed a radical pathway where isocyanides acted as radical geminal acceptors generating key imidoyl radical species.- Published
- 2020
- Full Text
- View/download PDF
42. Bio-Inspired Dual-Selective BCL-2 / c-MYC G-Quadruplex Binders: Design, Synthesis, and Anticancer Activity of Drug-like Imidazo[2,1- i ]purine Derivatives.
- Author
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Pelliccia S, Amato J, Capasso D, Di Gaetano S, Massarotti A, Piccolo M, Irace C, Tron GC, Pagano B, Randazzo A, Novellino E, and Giustiniano M
- Subjects
- Antineoplastic Agents chemistry, Biological Products metabolism, DNA-Binding Proteins antagonists & inhibitors, HCT116 Cells, Humans, Imidazoles chemistry, Imidazoles metabolism, Jurkat Cells, MCF-7 Cells, Molecular Docking Simulation methods, Protein Binding physiology, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Purines chemistry, Purines metabolism, Transcription Factors antagonists & inhibitors, Antineoplastic Agents metabolism, Biological Products chemistry, DNA-Binding Proteins metabolism, Drug Design, G-Quadruplexes, Proto-Oncogene Proteins c-bcl-2 metabolism, Transcription Factors metabolism
- Abstract
In the search for new drug-like selective G-quadruplex binders, a bioinspired design focused on the use of nucleobases as synthons in a multicomponent reaction was herein proved to be viable and successful. Hence, a new class of multifunctionalized imidazo[2,1- i ]purine derivatives, easily synthesized with a convergent approach, allowed for the identification of the first dual BCL2 / c-MYC gene promoter G-quadruplex ligand. Biophysical studies involving circular dichroism melting experiments, microscale thermophoresis measurements, NMR titrations, and computational docking calculations, as well as biological investigations including cytotoxicity and apoptotic assays, and quantitative polymerase chain reaction and Western blot analyses, were performed to assess the potency and to characterize the binding mode of the newly identified lead compound. The absence of toxicity toward normal cells, together with the small molecular weight (≅500 Da), the water solubility, the ease of functionalization, and the selectivity profile, are promising and desirable features to develop G-quadruplex binders as safe and effective anticancer agents.
- Published
- 2020
- Full Text
- View/download PDF
43. Photocatalytic Isocyanide-Based Multicomponent Domino Cascade toward the Stereoselective Formation of Iminofurans.
- Author
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Pelliccia S, Alfano AI, Luciano P, Novellino E, Massarotti A, Tron GC, Ravelli D, and Giustiniano M
- Abstract
A visible-light-promoted three-component isocyanide-based synthesis of iminofurans is herein reported. The reaction proved to be general in scope and proceeds through a triple domino process. Control experiments with
18 O-labeled water and TEMPO provided key mechanistic insights for delineating the reactivity paradigms crucial to design efficient photoredox isocyanide-based domino transformations.- Published
- 2020
- Full Text
- View/download PDF
44. Aryl Azides as Forgotten Electrophiles in the Van Leusen Reaction: A Multicomponent Transformation Affording 4-Tosyl-1-arylimidazoles.
- Author
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Necardo C, Alfano AI, Del Grosso E, Pelliccia S, Galli U, Novellino E, Meneghetti F, Giustiniano M, and Tron GC
- Abstract
Considering aryl azides as electrophilic partners for the TosMIC mediated Van Leusen reaction, a novel multicomponent synthesis of 4-tosyl-1-arylimidazoles is reported. In this transformation, two molecules of TosMIC participate in the reaction mechanism in two different ways, with the second molecule undergoing a novel type of fragmentation resulting in the incorporation of a C-H into the final product.
- Published
- 2019
- Full Text
- View/download PDF
45. Exploiting the Nucleophilicity of the Nitrogen Atom of Imidazoles: One-Pot Three-Component Synthesis of Imidazo-Pyrazines.
- Author
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Galli U, Hysenlika R, Meneghetti F, Del Grosso E, Pelliccia S, Novellino E, Giustiniano M, and Tron GC
- Subjects
- Aldehydes chemistry, Imidazoles chemistry, Molecular Structure, Pyrazines chemistry, Cyanides chemistry, Imidazoles chemical synthesis, Nitrogen chemistry, Pyrazines chemical synthesis
- Abstract
A novel one-pot multicomponent reaction to synthesize substituted imidazopyrazines is described. In brief, 1 H -(imidazol-5-yl)- N -substituted methanamines react with aldehydes and isocyanides in methanol at room temperature to give imidazopyrazine derivatives in excellent yields. The imidazole nitrogen atom was able to intercept the nascent nitrilium ion, channeling the reaction toward to the sole formation of imidazopyrazines, suppressing the competitive formation of other possible side products deriving from the reaction with the high-energy nitrilium ion. The number of examples and the variability of the nature of isocyanides, aldehydes, and amine components herein employed, witness the robustness of this novel methodology., Competing Interests: The authors declare no conflict of interest.
- Published
- 2019
- Full Text
- View/download PDF
46. Rational modifications on a benzylidene-acrylohydrazide antiviral scaffold, synthesis and evaluation of bioactivity against Chikungunya virus.
- Author
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Giancotti G, Cancellieri M, Balboni A, Giustiniano M, Novellino E, Delang L, Neyts J, Leyssen P, Brancale A, and Bassetto M
- Subjects
- Animals, Antiviral Agents chemistry, Benzylidene Compounds pharmacology, Chlorocebus aethiops, Humans, Hydrazines pharmacology, Structure-Activity Relationship, Vero Cells, Virus Replication drug effects, Antiviral Agents chemical synthesis, Benzylidene Compounds chemical synthesis, Chikungunya virus drug effects, Hydrazines chemical synthesis
- Abstract
Chikungunya virus is a re-emerging arbovirus transmitted to humans by Aedes mosquitoes, responsible for an acute febrile illness associated with painful and debilitating arthralgia, which can persist for several months or become chronic. Over the past few years, infection with this virus has spread worldwide with a previously unknown virulence. No specific antiviral treatments nor vaccines are currently available against this important pathogen. Starting from the structure of a class of selective anti-CHIKV agents previously identified in our research group, different modifications to this scaffold were rationally designed, and 69 novel small-molecule derivatives were synthesised and evaluated for their inhibition of Chikungunya virus replication in Vero cells. Further structure-activity relationships associated with this class of antiviral agents were elucidated for the original scaffolds, and novel antiviral compounds with EC
50 values in the low micromolar range were identified. This work provides the foundation for further investigation of these new structures as antivirals against Chikungunya virus., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
47. Targeting the BCL2 Gene Promoter G-Quadruplex with a New Class of Furopyridazinone-Based Molecules.
- Author
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Amato J, Pagano A, Capasso D, Di Gaetano S, Giustiniano M, Novellino E, Randazzo A, and Pagano B
- Subjects
- Dose-Response Relationship, Drug, Humans, Models, Molecular, Molecular Structure, Pyridazines chemistry, Structure-Activity Relationship, G-Quadruplexes drug effects, Promoter Regions, Genetic genetics, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Pyridazines pharmacology
- Abstract
Targeting of G-quadruplex-forming DNA in the BCL2 gene promoter to inhibit the expression of anti-apoptotic Bcl-2 protein is an attractive approach to cancer treatment. So far, efforts made in the discovery of molecules that are able to target the BCL2 G-quadruplex have succeeded mainly in the identification of ligands with poor drug-like properties. Here, a small series of furo[2,3-d]pyridazin-4(5H)-one derivatives were evaluated as a new class of drug-like G-quadruplex-targeting compounds. Biophysical studies showed that two derivatives could effectively bind to BCL2 G-quadruplex with good selectivity. Moreover, one such ligand was found to appreciably inhibit BCL2 gene transcription, with a substantial decrease in protein expression levels, and also showed significant cytotoxicity toward the Jurkat human T-lymphoblastoid cell line., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2018
- Full Text
- View/download PDF
48. Bax Activation Blocks Self-Renewal and Induces Apoptosis of Human Glioblastoma Stem Cells.
- Author
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Daniele S, Pietrobono D, Costa B, Giustiniano M, La Pietra V, Giacomelli C, La Regina G, Silvestri R, Taliani S, Trincavelli ML, Da Settimo F, Novellino E, Martini C, and Marinelli L
- Subjects
- Apoptosis drug effects, Apoptosis physiology, Caspase 3 metabolism, Caspase 7 metabolism, Cell Cycle drug effects, Cell Cycle physiology, Cell Line, Tumor, Cell Proliferation drug effects, Cell Proliferation physiology, Cell Survival drug effects, Cell Survival physiology, Central Nervous System Neoplasms metabolism, Central Nervous System Neoplasms pathology, Dacarbazine analogs & derivatives, Dacarbazine pharmacology, Drug Therapy, Combination, Glioblastoma metabolism, Glioblastoma pathology, Humans, Hydrazones pharmacology, Membrane Potential, Mitochondrial drug effects, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Pyrazoles pharmacology, Temozolomide, Antineoplastic Agents pharmacology, Central Nervous System Neoplasms drug therapy, Glioblastoma drug therapy, Neoplastic Stem Cells drug effects, bcl-2-Associated X Protein metabolism
- Abstract
Glioblastoma (GBM) is characterized by a poor response to conventional chemotherapeutic agents, attributed to the insurgence of drug resistance mechanisms and to the presence of a subpopulation of glioma stem cells (GSCs). GBM cells and GSCs present, among others, an overexpression of antiapoptotic proteins and an inhibition of pro-apoptotic ones, which help to escape apoptosis. Among pro-apoptotic inducers, the Bcl-2 family protein Bax has recently emerged as a promising new target in cancer therapy along with first BAX activators (BAM7, Compound 106, and SMBA1). Herein, a derivative of BAM-7, named BTC-8, was employed to explore the effects of Bax activation in different human GBM cells and in their stem cell subpopulation. BTC-8 inhibited GBM cell proliferation, arrested the cell cycle, and induced apoptosis through the induction of mitochondrial membrane permeabilization. Most importantly, BTC-8 blocked proliferation and self-renewal of GSCs and induced their apoptosis. Notably, BTC-8 was demonstrated to sensitize both GBM cells and GSCs to the alkylating agent Temozolomide. Overall, our findings shed light on the effects and the relative molecular mechanisms related to Bax activation in GBM, and they suggest Bax-targeting compounds as promising therapeutic tools against the GSC reservoir.
- Published
- 2018
- Full Text
- View/download PDF
49. Computer-Aided Identification and Lead Optimization of Dual Murine Double Minute 2 and 4 Binders: Structure-Activity Relationship Studies and Pharmacological Activity.
- Author
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Giustiniano M, Daniele S, Pelliccia S, La Pietra V, Pietrobono D, Brancaccio D, Cosconati S, Messere A, Giuntini S, Cerofolini L, Fragai M, Luchinat C, Taliani S, La Regina G, Da Settimo F, Silvestri R, Martini C, Novellino E, and Marinelli L
- Subjects
- Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Computer-Aided Design, Drug Design, Genes, p53, High-Throughput Screening Assays, Humans, Magnetic Resonance Spectroscopy, Models, Molecular, Neoplastic Stem Cells, Proto-Oncogene Proteins drug effects, Proto-Oncogene Proteins c-mdm2 drug effects, Structure-Activity Relationship, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-mdm2 metabolism
- Abstract
The function of p53 protein, also known as "genome guardian", might be impaired by the overexpression of its primary cellular inhibitor, the murine double minute 2 protein (MDM2). However, the recent finding that MDM2-selective inhibitors induce high levels of its homologue MDM4, prompt us to identify, through a receptor-based virtual screening on an in house database, dual MDM2/MDM4 binders. Compound 1 turned out to possess an IC
50 of 93.7 and of 4.6 nM on MDM2 and MDM4, respectively. A series of compounds were synthesized to optimize its activity on MDM2. As a result, compound 12 showed low nanomolar IC50 for both targets. NMR studies confirmed the pocket of binding of 12 as predicted by the Glide docking software. Notably, 12 was able to cause concentration-dependent inhibition of cell proliferation, yielding an IC50 value of 356 ± 21 nM in neuroblastoma SHSY5Y cells and proved even to efficiently block cancer stem cell growth.- Published
- 2017
- Full Text
- View/download PDF
50. To each his own: isonitriles for all flavors. Functionalized isocyanides as valuable tools in organic synthesis.
- Author
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Giustiniano M, Basso A, Mercalli V, Massarotti A, Novellino E, Tron GC, and Zhu J
- Abstract
The term functionalized isocyanides refers to all those isocyanides in which a neighbouring functional group can finely tune the reactivity of the isocyano group or can be exploited in post-functionalization processes. In this manuscript, we have reviewed all the isocyanides in which the pendant functional group causes either deviation from or reinforces the normal reactivity of the isocyano group and categorized them to highlight their common features and differences. An analysis of their synthetic potential and the possible unexplored directions for future research studies is also addressed.
- Published
- 2017
- Full Text
- View/download PDF
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