title: Discovery and preliminary evaluation of 2-aminobenzamide and hydroxamate derivatives containing 1,2,4-oxadiazole moiety as potent histone deacetylase inhibitors.
abstract: Using Entinostat as a lead compound, 2-aminobenzamide and hydroxamate derivatives have been designed and synthesized. The entire target compounds were investigated for their in vitro antiproliferative activities using the MTT-based assay against five human cancer cell lines including U937, A549, NCI-H661, MDA-MB-231 and HCT116. 2-Aminobenzamide series of compounds (10a-10j) demonstrated the most significant inhibition against human acute monocytic myeloid leukemia cell line U937, but no or poor activities against two human lung cancer cell lines. Furthermore, the target compounds were screened for their inhibitory activities against HDAC 1, 2, and 8. 2-Aminobenzamide derivatives (10) manifested a higher selectivity for HDAC 1 over HDAC 2, but were not active against HDAC 8. In contrast, most hydroxamate derivatives (11) inhibit HDAC 8 with lower IC50 values than SAHA and Entinostat. Docking study with selected compounds 10f and 11a revealed that the compounds might bind tightly to the binding pockets in HDAC 2 and HDAC 8, respectively. The results suggest that they may be promising lead compounds for the development of novel anti-tumor drug potentially via inhibiting HDACs.
authors: School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, Nanjing, Jiangsu 210096, PR China.
authors: Jin
authors: J
authors: Cai
authors: College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao 266109, PR China.
authors: Hongtao
authors: H
authors: Wei
authors: Department of Medicinal Chemistry and the Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN 55414, USA.
authors: Kwon Ho
authors: KH
authors: Hong
authors: Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA.
authors: Xiaoqing
authors: X
authors: Wu
authors: School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, PR China.
authors: Meng
authors: M
authors: Cao
authors: School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, Nanjing, Jiangsu 210096, PR China.
authors: Xi
authors: X
authors: Zong
authors: School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, PR China.
authors: Lushen
authors: L
authors: Li
authors: School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, Nanjing, Jiangsu 210096, PR China.
authors: Chunlong
authors: C
authors: Sun
authors: School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, Nanjing, Jiangsu 210096, PR China.
authors: Junqing
authors: J
authors: Chen
authors: School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, Nanjing, Jiangsu 210096, PR China; School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, PR China; Suzhou Key Laboratory of Biomaterials and Technologies & Collaborative Innovation Center of Suzhou Nano Science and Technology, Suzhou 215123, PR China. Electronic address: jimin@seu.edu.cn.
authors: Min
authors: M
authors: Ji
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; 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*; D008958:Models, Molecular; D015394:Molecular Structure; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010069:Oxadiazoles; D012097:Repressor Proteins; D062367:ortho-Aminobenzoates; C533423:HDAC2 protein, human; C409470:HDAC8 protein, human; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; C000219:anthranilamide
keywords: 2-Aminobenzamide; Antiproliferative activity; Cancer cell; Docking simulation; Histone deacetylases; Hydroxamate