Discovery and structure-activity relationships of (2-(arylthio)benzylideneamino)guanidines as a novel series of potent apoptosis inducers.

Abstract 1-(2-(2,5-Dimethoxyphenylthio)benzylidene)semicarbazide ( 2a ) was discovered as a potent apoptosis inducer through our cell based HTS assay. SAR study led to the discovery of a more aqueous soluble analog (2-(2,5-dimethoxyphenylthio)-6-methoxybenzylideneamino)guanidine ( 5e ) with EC 50 value of 60 nM in the caspase activation assay and GI 50 value of 62 nM in the growth inhibition assay in T47D cells. Compound 5e was found to be an inhibitor of tubulin polymerization and efficacious in a MX-1 breast tumor model.