当前位置： SCI文献检索 > EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Design, synthesis and biological evaluation of novel thioquinazolinone-based 2-aminobenzamide derivatives as potent histone deacetylase (HDAC) inhibitors.

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

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.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Cheng C,Yun F,He J,Ullah S,Yuan Q

doi

10.1016/j.ejmech.2019.04.017

subject

Has Abstract

pub_date

2019-07-01 00:00:00

pages

185-202

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(19)30323-X

journal_volume

173

pub_type

杂志文章

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