title: New benzothiazole/thiazole-containing hydroxamic acids as potent histone deacetylase inhibitors and antitumor agents.
abstract: Results from clinical studies have demonstrated that inhibitors of histone deacetylase (HDAC) enzymes possess promise for the treatment of several types of cancer. Zolinza(®) (widely known as SAHA) has been approved by the FDA for the treatment of T-cell lymphoma. As a continuity of our ongoing research to find novel small molecules to target these important enzymes, we synthesized a series of benzothiazole-containing analogues of SAHA and found several compounds with very potent anticancer cytotoxicity. In this study, three more compounds of this type, including N(1)-(6-chlorobenzo[d]thiazol-2-yl)-N(8)-hydroxyoctanediamide (3a), N(1)-[6-(trifluoromethyl)benzo[d]thiazol-2-yl]-N(8)-hydroxyoctanediamide (3b) and N(1)-(thiazol-2-yl)-N(8)-hydroxyoctanediamide (6) were synthesized and evaluated for HDAC inhibition and cytotoxic activities. All three compounds showed very potent HDAC inhibitory effects. Docking revealed that both two compounds 3a, 3b showed higher affinities towards HDAC(8) compared to SAHA. In vitro, compound 3a exhibited cytotoxicity equipotent to SAHA against five human cancer cell lines. In term of in vivo activity, compound 3a demonstrated equivalent efficacy to SAHA in mouse xenograft model.
authors.affiliation: Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Vietnam. namnh@hup.edu.vn.
authors.forename: Truong Thanh
authors.initials: TT
authors.lastname: Tung
authors.forename: Dao Thi Kim
authors.initials: DT
authors.lastname: Oanh
authors.forename: Phan Thi Phuong
authors.initials: PT
authors.lastname: Dung
authors.forename: Van Thi My
authors.initials: VT
authors.lastname: Hue
authors.forename: Sang Ho
authors.initials: SH
authors.lastname: Park
authors.forename: Byung Woo
authors.initials: BW
authors.lastname: Han
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
authors.forename: Jin-Tae
authors.initials: JT
authors.lastname: Hong
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Han
authors.forename: Nguyen-Hai
authors.initials: NH
authors.lastname: Nam
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000737:chemistry*; 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; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013844:Thiazoles; D006655:Histone Deacetylases; C005465:benzothiazole