Interfering with the microtubule (MT) dynamic equilibrium, by either inhibiting tubulin polymerization or blocking MT disassembly, prevents proper MT function and ultimately leads to cell death. Inhibiting with these cellular processes has resulted in a productive strategy for the development of efficient anticancer agents [1]. Arylthioindole and aroylindole derivatives are potent inhibitors of tubulin polymerization that bind to the colchicine site on -tubulin [2]. Several derivatives proved to be more potent than colchicine, combretastatin-A4 and showed potential as new anticancer agents. Molecular modelling studies led us to design new 2-phenyl-3-(3,4,5-trimethoxyphenyl)indoles with a sulphur, ketone or methylene bridging group at position 3 of the indole and halogen or methoxy substituent(s) at positions 4-7. New derivatives inhibited tubulin assembly and growth of a panel of cancer cells at low micro- and nanomolar concentrations, respectively. Among these, 6-methoxy-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole and 6,7-dichloro-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole strongly inhibited the growth of the P-glycoprotein-overexpressing multidrug resistant cell lines NCI/ADR-RES and Messa/Dx5. At 10 nM, the same derivatives stimulated the cytotoxic activity of natural killer cells, while at 20-50 nM arrested >80% of HeLa cells in the G2/M phase. Finally, 6,7-dichloro-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole and 2-(1H-imidazol-1-yl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole showed strong inhibition of the Hedgehog signalling pathway, blocking the growth of NIH3T3 Shh-Light II cells with IC50’s of 72 and 38 nM, respectively. References (1) Kavallaris M. Microtubules and resistance to tubulin-binding agents. Nature Rev. Cancer, 2010, 10, 194−204. (2) La Regina G., Bai R.; Rensen W. M., et al. Toward highly potent cancer agents by modulating the C-2 group of the arylthioindole class of tubulin polymerization inhibitors. J. Med. Chem., 2013, 56, 123−149.
Design and synthesis of new potent tubulin polymerization inhibitors / Passacantilli, S.; La Regina, G.; Coluccia, A.; Creta, M.; Hamel, E.; Novellino, E.; Silvestri, R.. - (2015). (Intervento presentato al convegno Workshop sulla Ricerca tenutosi a Roma, Italy).
Design and synthesis of new potent tubulin polymerization inhibitors
Passacantilli, S.;La Regina, G.;Coluccia, A.;Silvestri, R.
2015
Abstract
Interfering with the microtubule (MT) dynamic equilibrium, by either inhibiting tubulin polymerization or blocking MT disassembly, prevents proper MT function and ultimately leads to cell death. Inhibiting with these cellular processes has resulted in a productive strategy for the development of efficient anticancer agents [1]. Arylthioindole and aroylindole derivatives are potent inhibitors of tubulin polymerization that bind to the colchicine site on -tubulin [2]. Several derivatives proved to be more potent than colchicine, combretastatin-A4 and showed potential as new anticancer agents. Molecular modelling studies led us to design new 2-phenyl-3-(3,4,5-trimethoxyphenyl)indoles with a sulphur, ketone or methylene bridging group at position 3 of the indole and halogen or methoxy substituent(s) at positions 4-7. New derivatives inhibited tubulin assembly and growth of a panel of cancer cells at low micro- and nanomolar concentrations, respectively. Among these, 6-methoxy-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole and 6,7-dichloro-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole strongly inhibited the growth of the P-glycoprotein-overexpressing multidrug resistant cell lines NCI/ADR-RES and Messa/Dx5. At 10 nM, the same derivatives stimulated the cytotoxic activity of natural killer cells, while at 20-50 nM arrested >80% of HeLa cells in the G2/M phase. Finally, 6,7-dichloro-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole and 2-(1H-imidazol-1-yl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole showed strong inhibition of the Hedgehog signalling pathway, blocking the growth of NIH3T3 Shh-Light II cells with IC50’s of 72 and 38 nM, respectively. References (1) Kavallaris M. Microtubules and resistance to tubulin-binding agents. Nature Rev. Cancer, 2010, 10, 194−204. (2) La Regina G., Bai R.; Rensen W. M., et al. Toward highly potent cancer agents by modulating the C-2 group of the arylthioindole class of tubulin polymerization inhibitors. J. Med. Chem., 2013, 56, 123−149.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
