title: Novel N-hydroxybenzamides incorporating 2-oxoindoline with unexpected potent histone deacetylase inhibitory effects and antitumor cytotoxicity.
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 IC50values 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.
authors.affiliation: Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Viet Nam.
authors.forename: Tran-Thi-Lan
authors.initials: TT
authors.lastname: Huong
authors.affiliation: Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Viet Nam.
authors.forename: Do-Thi-Mai
authors.initials: DT
authors.lastname: Dung
authors.affiliation: Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Viet Nam.
authors.forename: Nguyen-Van
authors.initials: NV
authors.lastname: Huan
authors.affiliation: Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Viet Nam.
authors.forename: Le-Van
authors.initials: LV
authors.lastname: Cuong
authors.affiliation: Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Viet Nam.
authors.forename: Pham-The
authors.initials: PT
authors.lastname: Hai
authors.affiliation: School of Medicine and Pharmacy, Hanoi National University, Hanoi, Viet Nam.
authors.forename: Le-Thi-Thu
authors.initials: LT
authors.lastname: Huong
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 28160, Republic of Korea.
authors.forename: Jisung
authors.initials: J
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 28160, Republic of Korea.
authors.forename: Yong-Guk
authors.initials: YG
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 28160, Republic of Korea. Electronic address: shan@chungbuk.ac.kr.
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Han
authors.affiliation: Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Viet Nam. Electronic address: namnh@hup.edu.vn.
authors.forename: Nguyen-Hai
authors.initials: NH
authors.lastname: Nam
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D057930:Click Chemistry; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases
keywords: 2-oxoindoline; Click chemistry; Histone deacetylase (HDAC) inhibitors; Hydroxamic acids; N-hydroxybenzamides; Triazole