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

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. Impact of the linker: Four different hybrid compounds have been efficiently synthesized by conjugation of N‐deacetyl‐10‐thiocolchicine with pironetin‐inspired derivatives. The study better clarifies the design of bivalent compounds for targeting hetero microtubules.