Design, synthesis, anti-cancer evaluation and binding mode studies of benzimidazole/benzoxazole linked β-carboline derivatives

Abstract

A new series of benzimidazole/benzoxazole linked β-carbolines (9a-j) were rationally designed and synthesized by combining two different anti-cancer fragments. The new hybrid β-carbolines are subjected to anti-cancer screening against four different human cancer cell lines such as MCF-7 (breast), A549 (lung), Colo-205 (colon) and A2780 (ovarian) by using standard MTT assay. These hybrid β-carbolines exhibited significant and high fold anti-cancer activity against MCF-7 cell lines than reference standard. They are also proved to be effective against A549 and Colo-205 cell lines. Further, compound 9b, 9c from benzimidazole and 9i from benzoxazole series have exhibited maximum anti-cancer activity among these hybrid β-carbolines. Later, all of the hybrid β-carbolines were subjected to molecular interaction analysis against a few selected kinase targets such as cdc-like kinase (CLK-1 to CLK-4), epidermal growth factor reductase (EGFR) kinase, protein (ATR) kinase along with APC-Asef interface. The violin plot of binding energies of 9a-9j have suggested them as good kinase binders. Result interpretation suggested hybrid β-carbolines as promising CLK binders. The anti-cancer data of new hybrid β-carbolines against MCF-7 cell lines are in agreement with parent β-carboline skeleton.