Design and synthesis of novel phenylaminopyrimidines with antiproliferative activity against colorectal cancer.

New phenylaminopyrimidine (PAP) derivatives have been designed and synthesised as potential tyrosine kinase inhibitors for the treatment of cancer. The synthesized compounds share a general structure and vary in the substitution pattern at position-2 of the pyridine ring. Several derivatives have demonstrated potent anticancer activities against HCT-116, HT-29 and LS-174T colorectal cancer cells. Furthermore, a number of hits showed good selectivity to Src-kinase. The cytotoxic mechanisms of these compounds were also investigated by studying their effects on cell-cycle distribution. Among all the compounds examined, compound 8b (with a terminal pyridin-3-yl moiety at the pyridine ring) showed the highest inhibitory selectivity towards src-kinase, which was coupled with cell cycle arrest, and apoptotic and autophagic interference, in colorectal cancer cells. This report introduces a novel category of PAP derivatives with promising kinase inhibitory and anticancer effects against colon cancer.