title: Synthesis, bioevaluation and docking study of 5-substitutedphenyl-1,3,4-thiadiazole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents.
abstract: Since the first histone deacetylase (HDAC) inhibitor (Zolinza®, widely known as suberoylanilide hydroxamic acid; SAHA) was approved by the Food and Drug Administration for the treatment of T-cell lymphoma in 2006, the search for newer HDAC inhibitors has attracted a great deal of interest of medicinal chemists worldwide. As a continuity of our ongoing research in this area, we designed and synthesized a series of 5-substitutedphenyl-1,3,4-thiadiazole-based hydroxamic acids as analogues of SAHA and evaluated their biological activities. A number of compounds in this series, for example, N(1)-hydroxy-N(8)-(5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl)octandiamide (5b), N(1)-hydroxy-N(8)-(5-(3-chlorophenyl-1,3,4-thiadiazol-2-yl)octandiamide (5c) and N(1)-hydroxy-N(8)-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)octandiamide (5d), were found to possess potent anticancer cytotoxicity and HDAC inhibition effects. Compounds 5b-d were generally two- to five-fold more potent in terms of cytotoxicity compared to SAHA against five cancer cell lines tested. Docking studies revealed that these hydroxamic acid displayed higher affinities than SAHA toward HDAC8.
authors.affiliation: Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy , Hanoi , Vietnam .
authors.forename: Nguyen-Hai
authors.initials: NH
authors.lastname: Nam
authors.forename: Tran Lan
authors.initials: TL
authors.lastname: Huong
authors.forename: Do Thi Mai
authors.initials: do TM
authors.lastname: Dung
authors.forename: Phan Thi Phuong
authors.initials: PT
authors.lastname: Dung
authors.forename: Dao Thi Kim
authors.initials: DT
authors.lastname: Oanh
authors.forename: Sang Ho
authors.initials: SH
authors.lastname: Park
authors.forename: Kyungrok
authors.initials: K
authors.lastname: Kim
authors.forename: Byung Woo
authors.initials: BW
authors.lastname: Han
authors.forename: Jieun
authors.initials: J
authors.lastname: Yun
authors.forename: Jong Soon
authors.initials: JS
authors.lastname: Kang
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Han
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; D004354:Drug Screening Assays, Antitumor; 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*; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013830:Thiadiazoles; C058949:1,3,4-thiadiazole; D006655:Histone Deacetylases
keywords: 5-phenyl-1,3,4-thiadiazole; cytotoxicity; heterocycle; histone deacetylase (HDAC) inhibitors