Discovery of piperazine‐tethered N‐heterocycle derivatives as anticancer agents

Abstract Deregulated cell proliferation is a hallmark of carcinogenesis. To develop effective anticancer agents, extensive efforts have been directed toward identifying key regulators of the cell cycle. The piperazine moiety has been reported to possess diverse biological activities; hence, a novel series of piperazine‐based compounds was designed and synthesized as potential anticancer agents. A total of 72 piperazine derivatives were synthesized, and their chemical structures were confirmed by spectral analysis. The in vitro cytotoxic activities of all compounds were evaluated against three human colon tumor cell lines (LS513, WiDR, and HCT‐115). Eight representative compounds showing marked cytotoxicity were further tested against five additional human cancer cell lines: A549 (non‐small cell lung), SK‐OV‐3 (ovarian), HCT‐15 (colon), XF‐498 (CNS), and SK‐MEL‐2 (melanoma). Among them, compounds 1B and 4A exhibited potent cytotoxicity with IC 50 values lower than those of standard reference drugs paclitaxel, colchicine, and doxorubicin. Mechanistic investigations revealed that these compounds induced cell‐cycle arrest at the G 2 /M phase, as evidenced by flow cytometric analysis. Particularly, compound 1B acts as a mitotic inhibitor and may serve as a promising lead structure for the development of new anticancer agents.