Regioselective Suzuki coupling of dihaloheteroaromatic compounds as a rapid strategy to synthesize potent rigid combretastatin analogues.

Combretastatin A-4 (CA-4) is a potent tubulin depolymerizing agent able to inhibit tumor growth and with antivascular effects. Although it is in clinical trials, the search for novel analogues that may display better/different features is still ongoing. In this manuscript we describe the synthesis of novel constrained analogues of CA-4 obtained in only two synthetic steps exploiting a regioselective Suzuki coupling of dihalogenated heteroaromatic and alicyclic compounds. All the compounds synthesized have been evaluated for cytotoxicity and for their ability to inhibit tubulin assembly. One of them, 38, displayed low nanomolar cytotoxicity and proved to have a pharmacodynamic profile similar to that of CA-4 and a better pharmacokinetic profile, but most important of all, this synthetic strategy may pave the way for the easy and rapid generation of novel rigid analogues of combretastatins.