Dual Induction of Ferroptosis and Apoptosis by Triazolopyrimidinyl Derivatives: Design, Synthesis, and Biological Evaluation for Their Anticancer Efficacy via Calcium/Calmodulin Signaling and Mitochondrial Impairment

Cancer therapy faces significant challenges due to drug resistance and the limitations of conventional treatments that primarily target single mechanisms such as apoptosis. Herein, we designed and synthesized a class of 1,2,4-triazolopyrimidinyl derivatives as multifunctional chemotherapeutic agents that trigger both ferroptosis and apoptosis. These compounds are very effective in reducing the viability of some cancer cell lines. Among them, compound <b>34</b> demonstrated a broad spectrum of antiproliferative effects against nine cancer cell lines. Compound <b>34</b> induced both ferroptosis and apoptosis by causing G₂/M phase cell cycle arrest, disrupting mitochondrial membrane potentials, promoting lipid peroxidation, and increasing the levels of Ca²⁺ and Fe²⁺ through the activation of calcium/calmodulin signaling. Significantly, compound <b>34</b> suppressed tumor growth by 92% in A549 xenografts and 95% in A549/TAX xenografts with minimal toxicity. These findings might shape the rational design in a new wave of dually functioned drugs for the treatment of cancers.