title: Discovery and extensive in vitro evaluations of NK-HDAC-1: a chiral histone deacetylase inhibitor as a promising lead.
abstract: Herein, further SAR studies of lead compound NSC746457 (Shen, J.; Woodward, R.; Kedenburg, J. P.; Liu, X. W.; Chen, M.; Fang, L. Y.; Sun; D. X.; Wang. P. G. J. Med. Chem. 2008, 51, 7417-7427) were performed, including the replacement of the trans-styryl moiety with a 2-substituted benzo-hetero aromatic ring and the introduction of a substituent onto the central methylene carbon. A promising chiral lead, S-(E)-3-(1-(1-(benzo[d]oxazol-2-yl)-2-methylpropyl)-1H-1,2,3-triazol-4-yl)-N-hydroxyacrylamide (12, NK-HDAC-1), was discovered and showed about 1 order of magnitude more potency than SAHA in both enzymatic and cellular assays. For the in vitro safety tests, NK-HDAC-1 was far less toxic to nontransformed cells than tumor cells and showed no significant inhibition activity against CYP-3A4. The pharmaceutical properties (LogD, solubility, liver micrsomal stability (t1/2), plasma stability (t1/2), and apparent permeability) strongly suggested that NK-HDAC-1 might be superior to SAHA in bioavailability and in vivo half-life.
authors.affiliation: College of Pharmacy, Nankai University, Tianjin,China.
authors.forename: Jingli
authors.initials: J
authors.lastname: Hou
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Li
authors.forename: Qinghong
authors.initials: Q
authors.lastname: Fang
authors.forename: Congran
authors.initials: C
authors.lastname: Feng
authors.forename: Hanwen
authors.initials: H
authors.lastname: Zhang
authors.forename: Weikang
authors.initials: W
authors.lastname: Guo
authors.forename: Huihui
authors.initials: H
authors.lastname: Wang
authors.forename: Guoxian
authors.initials: G
authors.lastname: Gu
authors.forename: Yinping
authors.initials: Y
authors.lastname: Tian
authors.forename: Pi
authors.initials: P
authors.lastname: Liu
authors.forename: Ruihua
authors.initials: R
authors.lastname: Liu
authors.forename: Jianping
authors.initials: J
authors.lastname: Lin
authors.forename: Yi-Kang
authors.initials: YK
authors.lastname: Shi
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yin
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Peng George
authors.initials: PG
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D057930:Click Chemistry; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004354:Drug Screening Assays, Antitumor; D056464:Histone Deacetylase 2 / Q000737:chemistry; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D010539:Permeability; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C574634:3-(1-(1-(benzo(d)oxazol-2-yl)-2-methylpropyl)-1H-1,2,3-triazol-4-yl)-N-hydroxyacrylamide; C539552:3-(1-cinnamyl-1H-1,2,3-triazol-4-yl)-N-hydroxyacrylamide; D000970:Antineoplastic Agents; D001583:Benzoxazoles; D065692:Cytochrome P-450 CYP3A Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D014230:Triazoles; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D056464:Histone Deacetylase 2