Aminopeptidase N (APN/CD13) plays a role in tumors progression, but its inhibitor lacks cytotoxicity and is used as an adjuvant drug in cancer treatment. Histone deacetylases (HDACs) are a type of epigenetic targets, and HDAC inhibitors are cytotoxic and exhibit synergistic effects with other anticancer agents. Herein, a novel series of HDAC/CD13 dual inhibitors were rationally designed and synthesized to combine the anti-metastasis and anti-invasion of CD13 inhibitor with the cytotoxic of HDAC inhibitor. The representative compound 12 exhibited more potent inhibitory activity against human CD13, HDAC1-3, and antiproliferative activity than positive controls bestatin and SAHA. Compound 12 effectively induced apoptosis in MV4-11 cells, while arresting A549 cells in G2/M phase. Moreover, 12 exhibited significantly better anti-metastasis and anti-invasion effects than mono-inhibitors 32 and 38, indicating that it is a promising anti-cancer agent for further investigation.

氨肽酶N（APN/CD13）在肿瘤进展中发挥作用，但其抑制剂缺乏细胞毒性，在癌症治疗中用作辅助药物。组蛋白脱乙酰酶 (HDAC) 是一种表观遗传靶标，HDAC 抑制剂具有细胞毒性，并与其他抗癌药物表现出协同作用。本研究合理设计合成了一系列新型HDAC/CD13双重抑制剂，将CD13抑制剂的抗转移、抗侵袭作用与HDAC抑制剂的细胞毒作用结合起来。代表性化合物12对人CD13、HDAC1-3表现出比阳性对照贝他汀和SAHA更有效的抑制活性和抗增殖活性。化合物12有效诱导MV4-11细胞凋亡，同时将A549细胞阻滞在G2/M期。此外，12比单一抑制剂32和38表现出明显更好的抗转移和抗侵袭作用，表明它是一种有前景的抗癌药物，有待进一步研究。