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.

Maytansinol Derivatives: Side Reactions as a Chance for New Tubulin Binders

“…Pursuing our interest in the chemistry and biological activity of tubulin binders,[ 26 , 27 , 28 , 29 ] we report here a set of new maytansinoids, obtained as a result of maytansinol acylation reaction. Apart from the formation of esters at C3 position, maytansinol has been discovered to undergo a range of other structural transformations not previously reported.…”

Two Important Anticancer Mechanisms of Natural and Synthetic Chalcones

“…For these reasons, microtubules are one of the most studied targets of anticancer therapy. They actively participate in the formation of the centrosome, a formation characteristic of the G2/M phase of the cell cycle [ 208 , 209 , 210 , 211 , 212 ]. The unique feature of microtubule-binding agents, which is not present in other classes of anticancer agents, is their complexity and structural diversity, which determine many possibilities for optimization and modulation [ 213 ].…”

Regioselective approach to colchiceine tropolone ring functionalization at C(9) and C(10) yielding new anticancer hybrid derivatives containing heterocyclic structural motifs

“…The amide-alkyl-ester bridge at C(7) was used to conjugate 1 with cobalamine in order to obtain tumour-targeted cytotoxin, whereas the presence of an amide linkage with a disulphide bond at C(7) enabled the formation of the thiocolchicine-podophyllotoxin hybrid 38 , 39 . Thiocolchicine conjugates bearing at C(7) long polyamide-lactone chains shown to be active in ovarian carcinoma line A2780 at IC 50 ∼ 200 nM 40 . Dipolar cycloaddition and other modern synthetic methods as the Heck reaction yield chemically stable bonds and are worth considering at combining different bioactive blocks into a hybrid scaffold 41 , 42 .…”