Synthesis of Thicolchicine-Based Conjugates: Investigation towards Bivalent Tubulin/Microtubules Binders

Abstract

Four different hybrid compounds have been efficiently synthesized by conjugation of deacetylthiocolchicine with pironetin-inspired derivatives. The modest bioactivity and the apparent absence of interaction with α-tubulin is explained by a posteriori in silico investigation, which suggests a relevant distance between the thiocolchicine binding site and the proper pocket on the α-tubulin. The modest activity on resistant cells suggested that the lipophilic nature of the linker used renders the resulting compounds better substrates for p-Gp efflux pumps. The study better clarifies the design of bivalent compounds that target hetero tubulin/microtubules.

Keywords: bivalent binders; microtubules; pironetin; thiocolchicine; tubulin binders.