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 4m , fourteen novel 3,6-diunsaturated 2,5-diketopiperazine (2,5-DKP) derivatives ( 1 , 2 , 4 - 6 , 8 - 16 ), together with two known ones ( 3 and 7 ), were designed and synthesized as anticancer agents against the A549 and Hela cell lines. The MTT assay results showed that the derivatives 6 , 8 - 12, and 14 had moderate to good anticancer capacities, with IC 50 values ranging from 0.7 to 8.9 μM. Among them, compound 11, 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 50 = 1.2 μM) and Hela (IC 50 = 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- N -alkylated derivatives have high liposolubilities (>1.0 mg mL -1 ). Compound 11 can be further developed, aiming at the discovery of a novel anticancer candidate.