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 depolymeriz- ingagentabletoinhibittumorgrowthandwithantivasculareffects.Although it is in clinical trials, the search for novel analogues that may display better/ differentfeaturesisstillongoing.Inthismanuscriptwedescribethesynthesis 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 eval- uated 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 pharmacoki- netic 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.