title: Structure-based optimization of click-based histone deacetylase inhibitors.
abstract: Previously, we reported a click-chemistry based approach to the synthesis of a novel class of histone deacetylase (HDAC) inhibitors [1]. The lead compound NSC746457 was found to be as potent as SAHA (Vorinostat). Further optimization of NSC746457 by using the HDAC2-TSA crystal structure is described herein. Docking of NSC746457 into HDAC2 binding domain suggested that the hydrophobic residue Phe210 flanking the cap-group binding-motif could be exploited for structural optimization. Substitution on the methylene group of cinnamic cap region led to identification of more potent HDAC inhibitors: isopropyl derivative 5 and tert-butyl derivative 6, with an IC(50) value of 22 nM and 18 nM, respectively.
authors.affiliation: College of Pharmacy, Nankai University, 94 weijin Road, Nankai District, Tianjin 300071, China.
authors.forename: Jingli
authors.initials: J
authors.lastname: Hou
authors.forename: Congran
authors.initials: C
authors.lastname: Feng
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Li
authors.forename: Qinghong
authors.initials: Q
authors.lastname: Fang
authors.forename: Huihui
authors.initials: H
authors.lastname: Wang
authors.forename: Guoxian
authors.initials: G
authors.lastname: Gu
authors.forename: Yikang
authors.initials: Y
authors.lastname: Shi
authors.forename: Pi
authors.initials: P
authors.lastname: Liu
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yin
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D057930:Click Chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D056284:Histone Deacetylase 1 / Q000737:chemistry* / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000737:chemistry / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D010649:Phenylalanine / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D000077337:Vorinostat
chemical_list: C539552:3-(1-cinnamyl-1H-1,2,3-triazol-4-yl)-N-hydroxyacrylamide; D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D014230:Triazoles; D010649:Phenylalanine; D000077337:Vorinostat; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2