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.

SUBMITTER: Vicente-Blazquez A 

PROVIDER: S-EPMC8439230 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature