title: 3-Aroylindoles display antitumor activity in vitro and in vivo: Effects of N1-substituents on biological activity.
abstract: A series of 3-aroylindole hydroxamic acids (10-17) were developed based on the concept of a structural combination of tubulin and histone deacetylase (HDAC) inhibitors. This was accomplished by introducing hydroxamic acid-containing moieties at the N1 position of the tubulin assembly inhibitor, compound 9 (SCB01A, BPR0L075, phase II trial). Most of synthetic compounds produced in this way displayed comparable HDAC inhibitory activity, and four (10, 12-14) of them also inhibit tubulin assembly. Notably, compound 12 possesses not only tubulin and HDAC inhibitory activity but also shows HDAC6 selectivity over other HDAC isoforms. In addition, it exhibits remarkable inhibitory activity against the growth cancer cells in vitro and in vivo (PC3 and RPMI-8226 cells). Notably, it suppresses the growth of multiple myeloma xenografts without leading to the death of teated animals like reference compound. In sum, this study provided potential compounds with safer profiles for cancer treatment.
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Hsueh-Yun
authors.initials: HY
authors.lastname: Lee
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Jiann-Fong
authors.initials: JF
authors.lastname: Lee
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Sunil
authors.initials: S
authors.lastname: Kumar
authors.affiliation: School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Wu
authors.affiliation: The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: HuangFu
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, Taipei 11031, Taiwan.
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Li
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Hsiang-Ling
authors.initials: HL
authors.lastname: Huang
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Fei-Chiao
authors.initials: FC
authors.lastname: Kuo
authors.affiliation: Department of Pharmacology, College of Medicine, Taipei Medical University, Taiwan.
authors.forename: Che-Jen
authors.initials: CJ
authors.lastname: Hsiao
authors.affiliation: The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chun-Chun
authors.initials: CC
authors.lastname: Cheng
authors.affiliation: School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: cryang@ntu.edu.tw.
authors.forename: Chia-Ron
authors.initials: CR
authors.lastname: Yang
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan. Electronic address: jpl@tmu.edu.tw.
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Liou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D015195:Drug Design; D006367:HeLa Cells; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008819:Mice, Nude; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D014404:Tubulin; D050257:Tubulin Modulators; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: 3-Aroylindoles; Anticancer agents; Histone deacetylase inhibitors; Tubulin polymerization inhibition