Novel Triazole-Piperazine Hybrid Molecules Induce Apoptosis via Activation of the Mitochondrial Pathway and Exhibit Antitumor Efficacy in Osteosarcoma Xenograft Nude Mice Model.

Mitochondria impart a crucial role in the regulation of programmed cell death and reactive oxygen species (ROS) generation, besides serving as a primary energy source. Mitochondria appeared as an important target for the therapy of cancer due to their significant contribution to cell survival and death. Here, we report the design and synthesis of a novel series of triazole-piperazine hybrids as potent anticancer agents. MCS-5 emerged as an excellent anticancer agent which showed better anticancer activity than the standard drug doxorubicin in in vitro and in vivo studies. MCS-5 displayed an IC50 value of 1.92 μM and induced apoptosis in Cal72 (human osteosarcoma cell line) cells by targeting the mitochondrial pathway. This compound arrested the G2/M phase of the cell cycle and induced ROS production and mitochondrial potential collapse in Cal72 cells. MCS-5 displayed excellent anticancer activity in the Cal72 xenograft nude mice model, where it significantly reduced tumor progression, leading to enhanced life span in treated animals compared to control and doxorubicin treated animals without exerting noticeable toxicity. In addition, a 2DG optical probe guided study clearly evoked that MCS-5 remarkably reduced tumor metastasis in the Cal72 xenograft nude mice model. These results indicate that MCS-5 appeared as a novel chemical entity which is endowed with excellent in vitro as well as in vivo anticancer activity and may contribute significantly to the management of cancer in the future.