title: Discovery, bioactivity and docking simulation of Vorinostat analogues containing 1,2,4-oxadiazole moiety as potent histone deacetylase inhibitors and antitumor agents.
abstract: In our study, three series of hydroxamate, 2-aminobenzamide, and trifluoromethyl ketone analogues have been designed and synthesized. The synthesized compounds were investigated for their in vitro antiproliferative activities using the MTT-based assay against three human cancer cell lines including A549, NCI-H661, and U937. Most analogues exhibited higher antiproliferative activities against human acute myeloid leukemia cell U937 than the other two human lung cancer cell lines. Furthermore, the compounds were examined against HDAC1, 2, and 8 isoforms. Docking study of compounds 6h, 9b, and 10a suggested that they might bind tightly to the binding pocket of HDAC2 and/or HDAC8. The results suggest that these compounds might have potential as lead compounds for the development of anti-tumor drugs with HDACs inhibitory activities.
authors.affiliation: School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210096, PR China.
authors.forename: Jin
authors.initials: J
authors.lastname: Cai
authors.affiliation: College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao 266109, PR China.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Wei
authors.affiliation: Department of Medicinal Chemistry and the Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN 55414, USA.
authors.forename: Kwon Ho
authors.initials: KH
authors.lastname: Hong
authors.affiliation: Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Wu
authors.affiliation: School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210096, PR China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zong
authors.affiliation: School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, PR China.
authors.forename: Meng
authors.initials: M
authors.lastname: Cao
authors.affiliation: School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, PR China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, PR China.
authors.forename: Lushen
authors.initials: L
authors.lastname: Li
authors.affiliation: School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210096, PR China.
authors.forename: Chunlong
authors.initials: C
authors.lastname: Sun
authors.affiliation: School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.affiliation: School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, PR China.
authors.forename: Gaoxing
authors.initials: G
authors.lastname: Zhou
authors.affiliation: School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210096, PR China.
authors.forename: Junqing
authors.initials: J
authors.lastname: Chen
authors.affiliation: School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, 87 Dingjiaqiao, 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.forename: Min
authors.initials: M
authors.lastname: Ji
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007659:Ketones / Q000737:chemistry; D062105:Molecular Docking Simulation; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000077337:Vorinostat; D062367:ortho-Aminobenzoates / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007659:Ketones; D010069:Oxadiazoles; D012097:Repressor Proteins; D062367:ortho-Aminobenzoates; D000077337:Vorinostat; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; C409470:HDAC8 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; C000219:anthranilamide
keywords: 2-Aminobenzamide; Antiproliferative activity; Docking simulation; Histone deacetylases (HDAC); Hydroxamate; Trifluoromethyl ketone