Design, synthesis and pharmacological evaluation of 1,4-naphthoquinone- 1,2,3-triazole hybrids as new anticancer agents with multi-kinase inhibitory activity
Pegah Mardaneh, Somayeh Pirhadi, Maryam Mohabbati, Mehdi Khoshneviszadeh, Zahra Rezaei, Luciano Saso, Najmeh Edraki, Omidreza Firuzi
Abstract
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 IC 50 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 IC 50 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.