New indole-based chalconoids as tubulin-targeting antiproliferative agents

Abstract

Tubulin-targeting compounds have a broad anticancer spectrum and are an important class of chemotherapeutic agents. Due to the importance of 3-bromo-3,5-dimethoxyphenyl scaffold in the anticancer activity of microtubule inhibitors such as crolibulin (EPC2407), we introduced this functionality into the indole-derived chalcones. Thus, we describe here the synthesis and biological evaluation of new indole-based chalconoids as tubulin-targeting antiproliferative agents. The best result was obtained by compound 9b against A549 cell with IC₅₀ of 4.3µg/mL, being more potent than the reference drug etoposide. Further biological evaluations revealed that compound 9b can inhibit tubulin polymerization and decrease the mitochondrial thiol content, resulting the induction of apoptosis in cancer cells. Docking studies with tubulin indicated that compound 9b could bind to the colchicine binding site.

Keywords: 1,3-Diaryl-2-propen-1-ones; Anticancer; Chalcones; Cytotoxic activity; Indole; Tubulin polymerization.