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 34 demonstrated
a broad spectrum of antiproliferative effects against nine cancer
cell lines. Compound 34 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 34 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.