Synthesis, anticancer evaluation, preliminary mechanism study of novel 1, 2, 3-triazole-piperlongumine derivatives.

Abstract

Piperlongumine, a natural product from traditional Chinese medicine, shows promising antitumor effects but suffers from high toxicity. In this study, X and Q series Piperlongumine derivatives containing 1, 2, 3-triazole were designed and synthesized using the principle of molecular hybridization. The antitumor activity of these target compounds was evaluated, revealing significant activity compared to piperlongumine across four cancer cell lines. The structure-activity relationship of these compounds was analyzed using 3D-QSAR. Among these derivatives, compound 6Q demonstrated the highest antitumor activity against human chronic myeloid leukemia (K562) cells, with an IC₅₀ value of 0.31 μM, low toxicity to normal cells, and a selectivity index (SI) of 11.2. Further in vitro experiments confirmed that 6Q induced apoptosis in K562 cells by disrupting mitochondrial membrane potential, activating the MAPK signaling pathway, and causing cell cycle arrest in the G2/M phase. These findings underscored the potential of the natural product derivative 6Q as a promising candidate for further development in cancer therapy.