Design and synthesis of formononetin-piperazine hybrids that inhibit the migration and growth of MGC-803 cells

Formononetin, derived from Orostachys japonica (a traditional Chinese medicine), has been reported to have anti-cancer activity. In continuation of work on the exploration of formononetin derivative development, we designed and synthesized a novel series of formononetin-piperazine hybrids as anticancer agents, followed by evaluation of their antiproliferative activities against three cancer cell lines. Among these derivatives, compounds 6g (IC₅₀ = 5.87 ± 0.96 μM) and 6h (IC₅₀ = 3.50 ± 0.65 μM) emerged as the most potent analogues, demonstrating the best inhibitory activities against MGC-803 human gastric cancer cells. The structure-activity relationships (SARs) indicated that the introduction of substituents at meta-position of piperazine-linked phenyl moiety was helpful to enhance the anticancer potency. Further mechanistic investigations revealed that 6g and 6h exerted multimodal antitumor effects through G2/M phase arrest induction, apoptosis promotion, and migration suppression in MGC-803 cells. Thus, 6g and 6h could be deeply developed for the development of formononetin-based anti-cancer candidates.