Novel Piperlongumine derivatives exert multimodal antitumor effects in prostate cancer via MAPK pathway activation, poly-mechanistic apoptosis induction, and DNMT3A-mediated DNA methylation reduction.

The high mortality rate of prostate cancer remains a major threat to men's health worldwide, highlighting an urgent need for novel therapeutic agents with improved efficacy and safety profiles. In this study, we employed a rational structural modification strategy to synthesize 14 novel 1,2,3-triazole-hybridized derivatives of piperlongumine (PL), a natural alkaloid with proven anticancer activity. The antiproliferative activity of these derivatives was evaluated in vitro against multiple cancer cell lines (PC-3, A549, T47D, and SMMC-7721), with normal HEK293 cells used to assess their selectivity. All synthesized derivatives (1 M-14 M) exhibited significant antitumor efficacy, with lead compound 11 M showing pronounced inhibition of PC-3 cell proliferation and migration. Mechanistic studies revealed that 11 M induced G2/M phase arrest and triggered mitochondrial-dependent apoptosis, while concurrently activating the ROS-MAPK signaling pathway and autophagic flux. Notably, 11 M attenuated DNMT3A-mediated global DNA hypomethylation. In vivo validation in PC-3 xenograft mice confirmed that 11 M exerted robust tumor growth suppression with low systemic toxicity, accompanied by DNMT3A downregulation and MAPK pathway activation, substantiating its multi-target therapeutic mechanism.