新型噻吩并[2,3-d]嘧啶酮类 2-氨基苯甲酰胺衍生物的设计、合成及生物评价作为有效的组蛋白去乙酰化酶（HDAC）抑制剂。

Design, synthesis and biological evaluation of novel thioquinazolinone-based 2-aminobenzamide derivatives as potent histone deacetylase (HDAC) inhibitors.

机构信息

Key Laboratory of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Ministry of Education. College of Life Science and Technology, Beijing University of Chemical Technology, 15 Beisanhuan East Road, Beijing, 100029, China.

出版信息

Eur J Med Chem. 2019 Jul 1;173:185-202. doi: 10.1016/j.ejmech.2019.04.017. Epub 2019 Apr 11.

DOI:10.1016/j.ejmech.2019.04.017

PMID:31003060

Abstract

A series of novel 2-aminobenzamide derivatives decorated with thioquinazolinone were designed and synthesized as histone deacetylase (HDAC) inhibitors. These derivatives were evaluated for their antiproliferative activities against several human cancer cell lines including A375, Hela, A549, HCT116 and SMMC7721. It's significantly indicated that some inhibitors exhibited potent antiproliferative activities towards all the studied cancer cell lines. Compounds 7a, 4i, 4o, and 4p exhibited higher antiproliferative activities towards three cancer cell lines: A375, A549 and SMMC7721 compared to CS055, MS275, and CI994. Compound 4p showed more than 4000-fold the isoform selectivity for HDAC1 and more than 250-fold selectivity for HDAC2 compared with HDAC6. The molecular docking analysis reasonably explained the HDAC inhibitory activity and isoform selectivity. In addition, compounds 7a, 4i, 4o, and 4p showed potent inhibitory activities in migration assay and colony formation analysis, and also promoted cell apoptosis. Moreover, compounds 7a, 4i, and 4o inhibited the growth of SMMC7721 cells at S phase of the cell cycle. The immunofluorometric analysis indicated that compounds 7a, 4i, 4o, and 4p could increase the acetylation status of H3K9. Furthermore, in vivo anticancer efficacy of compound 4p was assessed in the A549 xenograft models, and 4p demonstrated potent antitumor activity (TGI = 62.5%). This study provided an effective strategy for further development of tumor-targeting therapy.

摘要

设计并合成了一系列带有硫代喹唑啉酮的新型 2-氨基苯甲酰胺衍生物，作为组蛋白去乙酰化酶（HDAC）抑制剂。评估了这些衍生物对包括 A375、Hela、A549、HCT116 和 SMMC7721 在内的多种人癌细胞系的抗增殖活性。结果表明，一些抑制剂对所有研究的癌细胞系均表现出很强的抗增殖活性。与 CS055、MS275 和 CI994 相比，化合物 7a、4i、4o 和 4p 对三种癌细胞系（A375、A549 和 SMMC7721）的抗增殖活性更高。与 HDAC6 相比，化合物 4p 对 HDAC1 的亚型选择性超过 4000 倍，对 HDAC2 的选择性超过 250 倍。分子对接分析合理地解释了 HDAC 抑制活性和亚型选择性。此外，化合物 7a、4i、4o 和 4p 在迁移实验和集落形成分析中表现出很强的抑制活性，并且还促进了细胞凋亡。此外，化合物 7a、4i 和 4o 抑制 SMMC7721 细胞周期 S 期的生长。免疫荧光分析表明，化合物 7a、4i、4o 和 4p 可以增加 H3K9 的乙酰化状态。此外，在 A549 异种移植模型中评估了化合物 4p 的体内抗癌疗效，4p 表现出很强的抗肿瘤活性（TGI=62.5%）。本研究为进一步开发肿瘤靶向治疗提供了有效的策略。