Synthesis, biological evaluation and kinase profiling of novel S-benzo[4,5]thiazolo[2,3-c][1,2,4]triazole derivatives as cytotoxic agents with apoptosis-inducing activity

Abstract

A novel set of S-benzo[4,5]thiazolo[2,3-c][1,2,4]triazoles was synthesized. Cytotoxicity of these compounds was evaluated against three cancer cell lines of different origins, Hep3B, A549, and MCF-7. Three of these compounds were screened by NCI for growth inhibitory activities against 60 cancer cell lines. The results revealed significant cytotoxic activities for compounds 13a-i. Among these derivatives, compounds 13c and 13f-13i exhibited the highest cytotoxicity against the selected cancer cell lines with IC50 values between 3.17 and 14.18 μM. The structure-activity relationship of compounds 13a-i indicated favorable cytotoxic results on the expansion of the cyclic amine and the substitution with aminothiazole moiety. A mechanistic study revealed the activation of caspase-3/7 in A549 cells on treatment with compounds 13f-i at 5–20 μM. Moreover, the results of flow cytometric analysis suggested that compound 13i efficiently induced apoptosis in a dose-dependent manner. Compounds 13f,g,i also exhibited a weak to moderate inhibition of multiple kinases where compound 13i was the most active in inhibiting the activity of CDK2/Cyclin A1 (IC50 = 4.65 μM). The current work provided a novel set of compounds with cytotoxic, kinase inhibition, and apoptosis-inducing activities, which can serve as a lead for further optimization.