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并被用作癌症治疗的辅助药物。组蛋白去乙酰化酶（HDACs）是一类表观遗传靶点，HDAC抑制剂对其他抗癌药物具有细胞毒性，表现出协同效应。因此，本研究合理设计和合成了一系列新型的HDAC/CD13双重抑制剂，将CD13抑制剂的抗转移和抗浸润与HDAC抑制剂的细胞毒性结合。代表性化合物12在人CD13、HDAC1-3的抑制活性以及抗增殖活性方面比正对照物bestatin和SAHA更具活性。化合物12有效诱导MV4-11细胞凋亡，同时阻滞A549细胞在G2/M期。此外，化合物12的抗转移和抗浸润效果明显优于单一抑制剂32和38，表明其是一个有前景的抗癌药物，值得进一步研究。版权所有©2023年Elsevier Masson SAS。保留所有权利。

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.Copyright © 2023 Elsevier Masson SAS. All rights reserved.