Substitution at the indole 3 position yields highly potent indolecombretastatins with reduced susceptibility to MDR resistance
Tubulin polymerization inhibiton
Fecha de publicación
Elsevier Science Publishers (Amsterdam, Países Bajos)
Álvarez, R., Gajate, C., Puebla, P., Mollinedo, F., Medarde, M., Peláez, R. (2018). Substitution at the indole 3 position yields highly potent indolecombretastatins with reduced susceptibility to MDR resistance. European Journal of Medicinal Chemistry
[EN]Resistance to combretastatin A-4 is mediated by metabolic modification of the phenolic hydroxyl and ether groups of the 3-hydroxy-4-methoxyphenyl (B ring). Replacement of the B ring of combretastatin A-4 by a N-methyl-5-indolyl reduces tubulin polymerization inhibition (TPI) and cytotoxicity against human cancer cell lines but cyano, methoxycarbonyl, formyl, and hydroxyiminomethyl substitutions at the indole 3-position restores potent TPI and cytotoxicity against sensitive human cancer cell lines. These highly potent substituted derivatives displayed low nanomolar cytotoxicity against several human cancer cell lines due to tubulin inhibition, as shown by cell cycle analysis, confocal microscopy, and tubulin polymerization inhibitory activity studies and promoted cell killing mediated by caspase-3 activation. Binding at the colchicine site was suggested by molecular modeling studies. Substituted combretastatins displayed higher potencies than the isomeric isocombretastatins and the highest potencies were achieved for the hydroxyiminomethyl (21) and cyano (23) groups, with TPI values in the submicromolar range and cytotoxicities in the subnanomolar range. Dose-response and time-course studies showed that drug concentrations as low as 1 nM (23) or 10 nM (21) led to a complete G2/M cell cycle arrest after 15 h treatment followed by a high apoptosis-like cell § These authors contributed equally to this work. 3 response after 48-72 h treatment. The P-glycoprotein and calcium antagonist verapamil increased 21 and 23 cytotoxicity to IC50 values of 10-10 M, and highly potentiated the cytotoxic activity in 100-fold of the CHO derivative (17), in A549 human non-small cell lung cancer cells. The differences in cytotoxic potency observed between the highly potent cyano (23) and hydroxyiminomethyl (21) groups and other substituents with similar TPI values (17) were very much reduced upon co-treatment with verapamil. A 3,4,5-trimethoxyphenyl ring always afforded more potent derivatives than a 2,3,4-trimethoxyphenyl ring.