Multicomponent reactions for the synthesis of tetrazole derivatives: Discovery and validation of a novel anticancer agent active against ER positive cancers

Abstract

Chemotherapy is an indispensable tool in medicine where small molecules act as potential cytotoxic, apoptotic, anti-angiogenic and anti-invasive agents targeting cancer cells. Chemotherapeutic agents possessing these multifaceted properties are highly warranted now as the mortality rate is increasing alarmingly. Tetrazole derivatives are well known for their pharmacological activity against various types of cancer progression. Herein, six derivatives of tetrazoles were synthesised by multicomponent reactions (MCR) and assessed their in vitro anticancer effects. The cytotoxic profiling of these compounds demonstrated that these compounds were active against a panel of breast cancer cells with highest anti-proliferative action against MCF-7. Among the six compounds, DTS 3 with a Chlorine atom demonstrated higher anti-proliferative and cytotoxic effects, which was selected for further investigations. Molecular docking and simulation analysis revealed preferential binding affinity of DTS 3 to CDK6;suggesting its likely role as CDK 6 inhibitor. Interestingly, the entire series of compounds were found to be more potent against cells expressing estrogen receptors, suggesting their dependence on ER signaling cascade. Further analysis revealed their potential to exert anti-invasive effects as well, among which DTS 3 possessed maximal anti-proliferative, anti-apoptotic, and anti-invasive properties suggesting its possible potential as a promising multi-faceted anti-cancer agent.