title: Ring-opened tetrahydro-γ-carbolines display cytotoxicity and selectivity with histone deacetylase isoforms.
abstract: This study is focused on modification of the indole moiety and the N1-zinc binding domain of tubastatin A, and the effects of such changes on biological activity. Fourteen N-substituted indoles (5-18) were synthesized and structure-activity relationship studies indicated that the change of the tetrahydro-γ-carboline in tubastatin A led to substituted indoles (compounds 7, 11, and 15) which showed significant improvements of selective inhibition for HDAC6 over HDAC1 and HDAC2 in comparison to ACY1215, a compound undergoing clinical trials. In addition, attachment of different hydroxamic acid groups, the zinc binding motif at the N1 position, contributes to the antiproliferative activity in cancer cells. Several synthetic compounds exhibited potent growth inhibition in a broad spectrum of tumor cell lines, induced irreversible growth arrest capacities by suppressing colony formation ability and activated the apoptosis pathway. The data provide compelling evidence that our newly synthesized compounds with type B to D hydroxamic acid groups as the zinc binding motif at the N1 position are potent selective inhibitors of HDAC6 and could be investigated preclinically as potential anticancer drugs.
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan.
authors.forename: Kunal
authors.initials: K
authors.lastname: Nepali
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan.
authors.forename: Hsueh-Yun
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Center for Translational Medicine, Taipei Medical University, Taiwan.
authors.forename: Mei-Jung
authors.initials: MJ
authors.lastname: Lai
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan.
authors.forename: Ritu
authors.initials: R
authors.lastname: Ojha
authors.affiliation: Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, College of Pharmacy, Taipei Medical University, Taiwan.
authors.forename: Tung-Yun
authors.initials: TY
authors.lastname: Wu
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan.
authors.forename: Gu-Xian
authors.initials: GX
authors.lastname: Wu
authors.affiliation: Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, College of Pharmacy, Taipei Medical University, Taiwan. Electronic address: mcchen1250@tmu.edu.tw.
authors.forename: Mei-Chuan
authors.initials: MC
authors.lastname: Chen
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan; School of Pharmacy, National Defense Medical Center, Taipei, Taiwan. Electronic address: jpl@tmu.edu.tw.
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Liou
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002243:Carbolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D002243:Carbolines; D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; C055572:gamma-carboline; D006655:Histone Deacetylases
keywords: Anticancer agents; Histone deacetylase inhibitors