Methylsulfanylpyridine based diheteroaryl isocombretastatin analogs as potent anti-proliferative agents

Isocombretastatins are the not isomerizable 1,1-diarylethene isomers of combretastatins. Both families antimitotics poorly soluble and new analogs with improved water solubility needed. The ubiquitous 3,4,5-trimethoxyphenyl ring most its replacements contribute to problem. 39 compounds belonging two series isocombretastatin 2-chloro-6-methylsulfanyl-4-pyridinyl or 2,6-bis(methylsulfanyl)-4-pyridinyl moieties replacing have been synthesized their antimitotic activity aqueous studied. We show here that 2-chloro-6-methylsulfanylpyridines more successful than 2,6-bis(methylsulfanyl)pyridines, giving highly potent tubulin inhibitors cytotoxic solubilities. optimal combination is indole rings carrying polar substitutions at three position. resulting diheteroaryl showed against human cancer cell lines caused by inhibition, as shown in vitro polymerization inhibitory assays, cycle analysis, confocal microscopy studies. Cell analysis also apoptotic responses following G2/M arrest after treatment. Conformational docking studies were applied propose binding modes colchicine site good agreement observed SAR. 2-Chloro-6-methylsulfanylpyridines represent a trimethoxyphenyl substitution for development ligands.