Derivatives 4i( Shiraz University of Medical Sciences)

Targeting important oncogenic kinases that contribute to hallmarks of cancer has revolutionized cancer therapy. Ten 1,4-naphthoquinone derivatives linked to 1,2,3-triazole (4a-4j) were designed and synthesized as kinase inhibitors especially aimed at blocking CDK2, a validated and important cancer target. Assessment of the antiproliferative activity of the synthesized compounds against lung (EBC-1), pancreatic ductal adenocarcinoma (PDAC, AsPC-1 and Mia-Paca-2), colorectal (HT-29), and breast cancer (MCF-7) cells revealed that most of the derivatives possess considerable antiproliferative potential, with IC₅₀ values as low as 0.3 µM. In contrast, the compounds relatively spared NIH3T3 non-cancer cell line. The kinase inhibitory effect of the best compounds was examined against a panel of 30 important oncogenic kinases. Derivatives 4a (bearing a benzyl ring) and 4i (bearing a p-methyl benzyl ring) inhibited CDK2, FLT4 (VEGFR3) and PDGFRA kinases with IC₅₀ values in the range of 0.55-1.67 and 0.22-11.32 µM, respectively. These compounds also caused S phase arrest and induced characteristic features of apoptosis in PDAC cells. Molecular modeling simulation validated the binding interactions between the synthesized derivatives and the active sites of the 3 target kinases. Finally, the compounds also possessed drug-like features as examined by in silico studies. The results of this study indicate that 1,4-naphthoquinone derivatives could have promising anticancer potential as multi-kinase inhibitors.