Microtubules are formed from alpha,beta-tubulin heterodimers and play a fundamental role in many cellular functions. They undergo a dynamic equilibrium, and preventing proper microtubule function by either inhibiting tubulin polymerization or blocking microtubule disassembly invariably causes cell death. We have developed arylthioindole and aroylindole antimitotic agents as potent inhibitors of tubulin polymerization and of cancer cell growth [1]. These compounds bind to the colchicine site on β-tubulin and inhibit the binding of [3H]colchicine to tubulin. Several compounds of this class were more potent than colchicine, combretastatin A-4, vinblastine, and paclitaxel, and have potential as novel therapeutic agents to treat cancer. Here, we reported 3-aroyl-1-arylpyrroles (ARAPs) as a new class of tubulin polymerization inhibitors. New compounds was designed via benzocracking approach by shifting of the indole benzene ring to position 1 of the pyrrole nucleus. New derivatives were prepared in high yields by microwave-assisted reaction of the appropriate pyrrole derivative with the right benzoyl chloride in the presence of anhydrous aluminum chloride in 1,2-dichloroethane at 110 °C (150 W) for 2 min. ARAPs exhibited a potent inhibiton of tubulin assembly and growth of a panel of cancer cells at low micromolar and nanomolar concentrations, respectively. In particular, (1-(3-aminophenyl)-1H-pyrrol-3-yl)(3,4,5-trimethoxyphenyl)methanone showed strong inhibition of the Pgp-overexpressing NCI-ADR-RES and Messa/Dx5 MDR cell lines and suppressed in vitro the Hedgehog molecular signalling pathway. References [1] La Regina, G. et al.: (a) J. Med. Chem. 2004, 47, 6120−6123. (b) J. Med. Chem. 2006, 49, 947−954. (c) J. Med. Chem. 2007, 50, 2865−2874. (d) J. Med. Chem. 2009, 52, 7512−7527. (e) J. Med. Chem. 2011, 54, 8394−8406. (f) J. Med. Chem. 2013, 56, 123−149. Acknowledgments. This research was supported by Bando Futuro in Ricerca 2010 (grant No. RBFR10ZJQT) and Sapienza Università di Roma (grant No. C26H135FL5).
3-Aroyl-1-arylpyrroles: a new class of potent inhibitors of tubulin polymerization / LA REGINA, Giuseppe; Coluccia, Antonio; Passacantilli, Sara; Famiglini, Valeria; Pelliccia, S.; Hamel, E.; Novellino, E.; Silvestri, R.. - (2014). ( Fifth European Workshop in Drug Synthesis Siena, Italy ).
3-Aroyl-1-arylpyrroles: a new class of potent inhibitors of tubulin polymerization
LA REGINA, GIUSEPPE
;COLUCCIA, Antonio;PASSACANTILLI, SARA;FAMIGLINI, VALERIA;
2014
Abstract
Microtubules are formed from alpha,beta-tubulin heterodimers and play a fundamental role in many cellular functions. They undergo a dynamic equilibrium, and preventing proper microtubule function by either inhibiting tubulin polymerization or blocking microtubule disassembly invariably causes cell death. We have developed arylthioindole and aroylindole antimitotic agents as potent inhibitors of tubulin polymerization and of cancer cell growth [1]. These compounds bind to the colchicine site on β-tubulin and inhibit the binding of [3H]colchicine to tubulin. Several compounds of this class were more potent than colchicine, combretastatin A-4, vinblastine, and paclitaxel, and have potential as novel therapeutic agents to treat cancer. Here, we reported 3-aroyl-1-arylpyrroles (ARAPs) as a new class of tubulin polymerization inhibitors. New compounds was designed via benzocracking approach by shifting of the indole benzene ring to position 1 of the pyrrole nucleus. New derivatives were prepared in high yields by microwave-assisted reaction of the appropriate pyrrole derivative with the right benzoyl chloride in the presence of anhydrous aluminum chloride in 1,2-dichloroethane at 110 °C (150 W) for 2 min. ARAPs exhibited a potent inhibiton of tubulin assembly and growth of a panel of cancer cells at low micromolar and nanomolar concentrations, respectively. In particular, (1-(3-aminophenyl)-1H-pyrrol-3-yl)(3,4,5-trimethoxyphenyl)methanone showed strong inhibition of the Pgp-overexpressing NCI-ADR-RES and Messa/Dx5 MDR cell lines and suppressed in vitro the Hedgehog molecular signalling pathway. References [1] La Regina, G. et al.: (a) J. Med. Chem. 2004, 47, 6120−6123. (b) J. Med. Chem. 2006, 49, 947−954. (c) J. Med. Chem. 2007, 50, 2865−2874. (d) J. Med. Chem. 2009, 52, 7512−7527. (e) J. Med. Chem. 2011, 54, 8394−8406. (f) J. Med. Chem. 2013, 56, 123−149. Acknowledgments. This research was supported by Bando Futuro in Ricerca 2010 (grant No. RBFR10ZJQT) and Sapienza Università di Roma (grant No. C26H135FL5).I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
