title: Identification of N-(6-mercaptohexyl)-3-(4-pyridyl)-1H-pyrazole-5-carboxamide and its disulfide prodrug as potent histone deacetylase inhibitors with in vitro and in vivo anti-tumor efficacy.
abstract: In this study, a collection of N-(6-mercaptohexyl)-3-substituted-1H-pyrazole-5-carboxamide HDAC inhibitors was developed. Among them, 15k was identified as the most potent inhibitor against total HDACs with IC50 of 0.008 μM. Further isoenzyme assays revealed that 15k and its analogs have a preference for HDAC1-3 (class I) and HDAC6 (class IIb) isoforms. The enzyme-based potencies of 15k were 2- to 11-fold higher than those of Vorinostat. The disulfide prodrug 18 was found to be potent cytotoxic agent against a panel of seven tumor cells, causing hyper-acetylation of histone and non-histone proteins in cellular level. In addition, 18 demonstrated a notable in vivo anti-tumor activity in HCT-116 xenografted model. This study provides further possibility of developing novel thiol-based HDAC inhibitors for the treatment of cancer.
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Jiachen
authors.initials: J
authors.lastname: Wen
authors.affiliation: School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Niu
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Yang
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Yinbo
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: yongkui.jing@mssm.edu.
authors.forename: Yongkui
authors.initials: Y
authors.lastname: Jing
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: linxiang.zhao@vip.sina.com.
authors.forename: Linxiang
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: sammyld@163.com.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004220:Disulfides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D004220:Disulfides; D056572:Histone Deacetylase Inhibitors; D011355:Prodrugs; D011720:Pyrazoles; D006655:Histone Deacetylases
keywords: Anti-tumor; Disulfide; Histone deacetylase inhibitor; Prodrug; Structure-activity relationship; Thiol