Synthesis and evaluation of N-heteroaromatic ring-based analogs of piperlongumine as potent anticancer agents

Piperlongumine (PL) selectively targets a wide spectrum of Cancer cells and induces their death by triggering various pathways, including Apoptosis, necrosis and Autophagy. However, the poor solubility is a serious concern for intensive study and clinical application. We synthesized its analogs 1-9 by replacement of the trimethoxyphenyl of PL with an N-heteroaromatic ring and/or not introduction of 2-Cl. These compounds improved aqueous solubility and displayed potent Anticancer activity. The most active compound 9 selectively enhanced ROS levels in colon Cancer cells and inhibited the cell proliferation but sparing non-tumor colon cells. Importantly, 9 significantly repressed tumor growth in an HCT-116 xenograft mouse model, suggesting that these N-heteroaromatic ring-based analogs of PL warrant further investigation.

Anticancer activity; N-heteroaromatic ring; Piperlongumine; ROS; Solubility.