New indolesulfonamide derivatives targeting the colchicine site of tubulin: synthesis, anti-tumour activity, structure–activity relationships, and molecular modelling

Abstract

Searching for improved indolesulfonamides with higher polarities, 45 new analogues with modifications on the sulfonamide nitrogen, the methoxyaniline, and/or the indole 3-position were synthesised. They show submicromolar to nanomolar antiproliferative IC₅₀ values against four human tumour cell lines and they are not P-glycoprotein substrates as their potencies against HeLa cells did not improve upon cotreatment with multidrug resistance (MDR) inhibitors. The compounds inhibit tubulin polymerisation in vitro and in cells, thus causing a mitotic arrest followed by apoptosis as shown by cell cycle distribution studies. Molecular modelling studies indicate binding at the colchicine site. Methylated sulfonamides were more potent than those with large and polar substitutions. Amide, formyl, or nitrile groups at the indole 3-position provided drug-like properties for reduced toxicity, with Polar Surface Areas (PSA) above a desirable 75 Ų. Nitriles 15 and 16 are potent polar analogues and represent an interesting class of new antimitotics.

Funding Statement

This work was financially supported by the Consejería de Educación de la Junta de Castilla y León [SA262P18 and SA116P20], co-funded by the EU’s European Regional Development Fund-FEDER, and the Spanish Ministry of Science, Innovation, and Universities [RTI2018-099474-B-I00 and SAF2017-89672-R].