Design, synthesis, and evaluation of 9-(pyrimidin-2-yl)-9H-carbazole derivatives disrupting mitochondrial homeostasis in human lung adenocarcinoma

Since more than 85% of lung cancer cases are non-small cell lung cancer (NSCLC), finding novel agents with anti-tumor activities is meaningful for NSCLC patients. Mitochondria is essential for cellular energy metabolism in cancer, and regulating mitochondrial bioenergetics is emerging as a practical approach for cancer treatment and prevention. The carbazole scaffold is an active structure showing anti-cancer biological activity, and the structural diversity has been expanded through the improvement and optimization of synthesizing methods. To find novel carbazole derivatives with great anti-tumor potential and explore structures variety, we designed and synthesized a series of 9-(pyrimidin-2-yl)-9H-carbazole derivatives based on the previously reported Cp∗Rh(III)/H + tandem catalytic system. With thoroughly bioactivity exploration, we found benzo[d] [ 1,3 ] dioxol- 5-yl (9-(pyrimidin- 2-yl )-9H-carbazol- 1-yl )methanone (compound 5n ) showed notable activity in disrupting the mitochondrial homeostasis, induced cell cycle arrest and apoptosis in human adenocarcinoma cells, and finally showed anti-tumor activity in an NSCLC-xenograft mice model. • We found a series of novel carbazole derivatives with anti-lung cancer potentials. • The half inhibitory concentrations of the compounds were on a nanomolar scale. • The promising compound 5n disrupted the mitochondrial homeostasis. • 5n showed good anti-tumor activity in a lung-cancer-cell xenograft mice model.