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Based on the marine natural products piperafizine B, XR334, and our previously reported compound <b>4m</b>, fourteen novel 3,6-diunsaturated 2,5-diketopiperazine (2,5-DKP) derivatives (<b>1</b>, <b>2</b>, <b>4</b>–<b>6</b>, <b>8</b>–<b>16</b>), together with two known ones (<b>3</b> and <b>7</b>), were designed and synthesized as anticancer agents against the A549 and Hela cell lines. The MTT assay results showed that the derivatives <b>6</b>, <b>8</b>–<b>12,</b> and <b>14</b> had moderate to good anticancer capacities, with IC₅₀ values ranging from 0.7 to 8.9 μM. Among them, compound <b>11,</b> 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 (IC₅₀ = 1.2 μM) and Hela (IC₅₀ = 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-<i>N</i>-alkylated derivatives have high liposolubilities (>1.0 mg mL⁻¹). Compound <b>11</b> can be further developed, aiming at the discovery of a novel anticancer candidate.