title: Novel isatin-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents.
abstract: Accumulated clinical studies have demonstrated that histone deacetylase (HDAC) inhibitors show great potential for the treatment of cancer. SAHA (Vorinostat, trade name Zolinza) was approved by the FDA in 2006 for the treatment of the cutaneous manifestations of cutaneous T-cell lymphoma. As a continuity of our ongoing effort to identify novel small molecules targeting these important enzymes, we designed and synthesized two series of isatin-3'-oxime- and isatin-3'-methoxime-based hydroxamic acids (3a-g and 6a-g) as analogues of SAHA. Generally in both series it was found that, compounds bearing no substituent or with 5'-F, 5'-Cl, 7'-Cl substitutents on the isatin moiety exhibited good inhibition against histone-H3 and histone-H4 deacetylation at the concentrations of 1 μM, as evaluated by Western Blot assay. The compounds also displayed potent cytotoxicity against five cancer cell lines with IC50 values of as low as 0.08 μM, more than 45-fold lower than that of SAHA. Docking study performed with selected compounds 3a and 6a revealed that these compounds bound to HDAC8 with higher affinities compared to SAHA. Compounds 3a and 6a also bound to HDAC2 at the binding site with high binding affinity. These findings should encourage further elaboration with the isatin moiety to produce more potent HDAC inhibitors with potential anticancer activity.
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
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: Do
authors.initials: D
authors.lastname: Quyen
authors.forename: Le Thi
authors.initials: le T
authors.lastname: Thao
authors.forename: Sang Ho
authors.initials: SH
authors.lastname: Park
authors.forename: Kyung Rok
authors.initials: KR
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; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007510:Isatin / Q000737:chemistry*; D015394:Molecular Structure; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D007510:Isatin; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: Heterocycle; Histone deacetylase (HDAC) inhibitors; Hydroxamic acids; Isatin