http://www.cnr.it/ontology/cnr/individuo/prodotto/ID11844
Design and Synthesis of 2-Heterocyclyl-3-arylthio-1H-indoles as Potent Tubulin Polymerization and Cell Growth Inhibitors with Improved Metabolic Stability (Articolo in rivista)
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- Design and Synthesis of 2-Heterocyclyl-3-arylthio-1H-indoles as Potent Tubulin Polymerization and Cell Growth Inhibitors with Improved Metabolic Stability (Articolo in rivista) (literal)
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- 2011-01-01T00:00:00+01:00 (literal)
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- 10.1021/jm2012886 (literal)
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La Regina G, Bai R, Rensen W, Coluccia A, Piscitelli F, Gatti V, Bolognesi A, Lavecchia A, Granata I, Porta A, Maresca B, Soriani A, Iannitto ML, Mariani M, Santoni A, Brancale A, Ferlini C, Dondio MG, Varasi M, Mercurio C, Hamel E, Lavia P, Novellino E, Silvestri R. (2011)
Design and Synthesis of 2-Heterocyclyl-3-arylthio-1H-indoles as Potent Tubulin Polymerization and Cell Growth Inhibitors with Improved Metabolic Stability
in Journal of medicinal chemistry; ACS, American chemical society, Washington, DC (Stati Uniti d'America)
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- La Regina G, Bai R, Rensen W, Coluccia A, Piscitelli F, Gatti V, Bolognesi A, Lavecchia A, Granata I, Porta A, Maresca B, Soriani A, Iannitto ML, Mariani M, Santoni A, Brancale A, Ferlini C, Dondio MG, Varasi M, Mercurio C, Hamel E, Lavia P, Novellino E, Silvestri R. (literal)
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- This work was a collaborative effort in the frame of the PRIN 2008 Grant No. 200879X9N9, of which IBPM was a partner unit (literal)
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- Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma; Screening Technologies Branch, Developmental Therapeutics Program, National Cancer Institute-NIH, Frederick, MD 21702, US; CNR, National Research Council, Institute of Molecular Biology and Pathology, I-00185 Roma, Italy; Dipartimento di Scienze Farmaceutiche, Università di Salerno, Italy; Welsh School of Pharmacy, Cardiff University, CF10 3NB, U.K.; Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli Federico II, I-80131, Napoli, Italy; Dipartimento di Medicina Sperimentale e Patologia, Sapienza Università di Roma, I-00161 Roma, Italy; Danbury Hospital Research Institute, Tumor Reproductive Biology Research Laboratory, Danbury, CT 06810, US; NiKem Research Srl, 20021 Baranzate, Milano, Italy; European Institute of Oncology, 20139 Milan, Italy; Genextra Group, 20139 Milan, Italy. (literal)
- Titolo
- Design and Synthesis of 2-Heterocyclyl-3-arylthio-1H-indoles as Potent Tubulin Polymerization and Cell Growth Inhibitors with Improved Metabolic Stability (literal)
- Abstract
- New arylthioindoles (ATIs) were obtained by replacing the 2-alkoxycarbonyl group with a bioisosteric 5-membered heterocycle nucleus. The new ATIs 5, 8, and 10 inhibited tubulin polymerization, reduced cell growth of a panel of human transformed cell lines, and showed higher metabolic stability than the reference ester 3. These compounds induced mitotic arrest and apoptosis at a similar level as combretastatin A-4 and vinblastine and triggered caspase-3 expression in a significant fraction of cells in both p53-proficient and p53-defective cell lines. Importantly, ATIs 5, 8, and 10 were more effective than vinorelbine, vinblastine, and paclitaxel as growth inhibitors of the P-glycoprotein-overexpressing cell line NCI/ADR-RES. Compound 5 was shown to have medium metabolic stability in both human and mouse liver microsomes, in contrast to the rapidly degraded reference ester 3, and a pharmacokinetic profile in the mouse characterized by a low systemic clearance and excellent oral bioavailability. (literal)
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