Discovery and structure–activity relationship of 2-phenyl-oxazole-4-carboxamide derivatives as potent apoptosis inducers

Novel 2-phenyl-oxazole-4-carboxamide-containing apoptosis inducers were discovered from a cell-based assay for caspase-3 activation. Synthesis, in vitro, and in vivo activity profiles are reported. As a continuation of our efforts to discover novel apoptosis inducers as anticancer agents using a cell-based caspase HTS assay, 2-phenyl-oxazole-4-carboxamide derivatives were identified. The structure–activity relationships of this class of molecules were explored. Compound 1k, with EC 50 of 270 nM and GI 50 of 229 nM in human colorectal DLD-1 cells, was selected and demonstrated the ability to cleave PARP and displayed DNA laddering, the hallmarks of apoptosis. Compound 1k showed 63% tumor growth inhibition in human colorectal DLD-1 xenograft mouse model at 50 mpk, bid.