Design, Synthesis, and Anticancer Activity of Novel 3,6-Diunsaturated 2,5-Diketopiperazines.

Based on the marine natural products piperafizine B, XR334, and our previously reported compound , fourteen novel 3,6-diunsaturated 2,5-diketopiperazine (2,5-DKP) derivatives (, , -, -), together with two known ones ( and ), were designed and synthesized as anticancer agents against the A549 and Hela cell lines. The MTT assay results showed that the derivatives , - and had moderate to good anticancer capacities, with IC values ranging from 0.7 to 8.9 μM. Among them, compound with naphthalen-1-ylmethylene and 2-methoxybenzylidene functions at the 3 and 6 positions of 2,5-DKP ring, respectively, displayed good inhibitory activities toward both A549 (IC = 1.2 μM) and Hela (IC = 0.7 μM) cancer cells. It could also induce apoptosis and obviously block cell cycle progression in the G2/M phases in both cells at 1.0 μM. The electron-withdrawing functions might not be favorable for the derivatives with high anticancer activities. Additionally, compared to piperafizine B and XR334, these semi--alkylated derivatives have high liposolubilities (>1.0 mg mL). Compound can be further developed, aiming at the discovery of a novel anticancer candidate.