title: Structure and property based design, synthesis and biological evaluation of γ-lactam based HDAC inhibitors: part II.
abstract: Histone deacetylases (HDACs) are involved in post-translational modification and epi-genetic expression, and have been the intriguing targets for treatment of cancer. In previous study, we reported synthesis and the biological preliminary results of γ-lactam based HDAC inhibitors. Based on the previous results, smaller γ-lactam core HDAC inhibitors are more active than the corresponding series of larger δ-lactam based analogues and the hydrophobic and bulky cap groups are required for better potency which decreased microsomal stability. Thus, γ-lactam analogues with methoxy, trifluoromethyl groups of ortho-, meta-, para-positions of cap group were prepared and evaluated their biological potency. Among them, trifluoromethyl analogues, which have larger lipophilicity, showed better HDAC inhibitory activity than other analogues. In overall, lipophilicity leads to increase hydrophobic interaction between surface of HDAC active site and HDAC inhibitor, improves HDAC inhibitory activity.
authors.affiliation: Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Chulho
authors.initials: C
authors.lastname: Lee
authors.forename: Eunhyun
authors.initials: E
authors.lastname: Choi
authors.forename: Misun
authors.initials: M
authors.lastname: Cho
authors.forename: Boah
authors.initials: B
authors.lastname: Lee
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Oh
authors.forename: Song-Kyu
authors.initials: SK
authors.lastname: Park
authors.forename: Kiho
authors.initials: K
authors.lastname: Lee
authors.forename: Hwan Mook
authors.initials: HM
authors.lastname: Kim
authors.forename: Gyoonhee
authors.initials: G
authors.lastname: Han
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D007769:Lactams / Q000138:chemical synthesis* / Q000494:pharmacology; D008958:Models, Molecular; D008970:Molecular Weight; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D007769:Lactams; D006655:Histone Deacetylases