Novel N-hydroxybenzamides incorporating 2-oxoindoline with unexpected potent histone deacetylase inhibitory effects and antitumor cytotoxicity

Tran-Thi-Lan Huong; Do-Thi-Mai Dung; Nguyen-Van Huan; Le-Van Cuong; Pham-The Hai; Le-Thi-Thu Huong; Jisung Kim; Yong-Guk Kim; Sang-Bae Han; Nguyen-Hai Nam

doi:10.1016/j.bioorg.2017.02.002

Novel N-hydroxybenzamides incorporating 2-oxoindoline with unexpected potent histone deacetylase inhibitory effects and antitumor cytotoxicity

Bioorg Chem. 2017 Apr:71:160-169. doi: 10.1016/j.bioorg.2017.02.002. Epub 2017 Feb 8.

Authors

Affiliations

¹ Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Viet Nam.
² School of Medicine and Pharmacy, Hanoi National University, Hanoi, Viet Nam.
³ College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 28160, Republic of Korea.
⁴ College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 28160, Republic of Korea. Electronic address: shan@chungbuk.ac.kr.
⁵ Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Viet Nam. Electronic address: namnh@hup.edu.vn.

PMID: 28196602
DOI: 10.1016/j.bioorg.2017.02.002

Abstract

In our search for novel small molecules targeting histone deacetylases, we have designed and synthesized two series of novel N-hydroxybenzamides incorporating 2-oxoindolines (4a-g, 6a-g). Biological evaluation showed that these benzamides potently inhibited HDAC2 with IC₅₀ values in sub-micromolar range. In three human cancer cell lines the synthesized compounds were up to 4-fold more cytotoxic than SAHA. Docking experiments indicated that the compounds tightly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA. Our present results demonstrate that these novel and simple N-hydroxybenzamides are potential for further development as anticancer agents and further investigation of similarly simple N-hydroxybenzamides should be warranted to obtain more potent HDAC inhibitors.

Keywords: 2-oxoindoline; Click chemistry; Histone deacetylase (HDAC) inhibitors; Hydroxamic acids; N-hydroxybenzamides; Triazole.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Benzamides / chemical synthesis
Benzamides / chemistry
Benzamides / pharmacology
Cell Line, Tumor
Click Chemistry
Crystallography, X-Ray
Drug Screening Assays, Antitumor
Histone Deacetylase 2 / antagonists & inhibitors*
Histone Deacetylase 2 / metabolism
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry*
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylases / metabolism
Humans
Hydroxamic Acids / chemical synthesis
Hydroxamic Acids / chemistry
Hydroxamic Acids / pharmacology
Indoles / chemical synthesis
Indoles / chemistry*
Indoles / pharmacology*
Molecular Docking Simulation
Neoplasms / drug therapy
Neoplasms / enzymology
Structure-Activity Relationship

Substances

Antineoplastic Agents
Benzamides
Histone Deacetylase Inhibitors
Hydroxamic Acids
Indoles
HDAC2 protein, human
Histone Deacetylase 2
Histone Deacetylases