title: Effect of C7-substitution of 1-arylsulfonyl-5-(N-hydroxyacrylamide)indolines on the selectivity towards a subclass of histone deacetylases.
abstract: This study focused on the substitution effect at position C7 of 1-arylsulfonyl-5-(N-hydroxyacrylamide)indolines. Compound 9, (E)-3-(7-amino-1-(4-methoxyphenylsulfonyl)indolin-5-yl)-N-hydroxyacrylamide, displayed 4- to 14-fold more potent antiproliferative activity than vorinostat (SAHA, 1). Notably, 9 possessed specific histone deacetylase (HDAC) inhibitory activity toward HDAC1 and HDAC2, but had no effect on HDAC6, indicating that 9 has the potential to be developed as a class I HDAC inhibitor. In a xenograft tumor model, 9 suppressed the growth of HCT116 cells at 100 mg kg(−1), which led to a TGI (tumor growth inhibition) of 40.3%. Taken together, the C7 substitutions have a crucial effect on class I HDACs, which is beneficial for synthesizing efficient anticancer agents.
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan. jpl@tmu.edu.tw.
authors.forename: Hsueh-Yun
authors.initials: HY
authors.lastname: Lee
authors.forename: Li-Ting
authors.initials: LT
authors.lastname: Wang
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Li
authors.forename: Shiow-Lin
authors.initials: SL
authors.lastname: Pan
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Chen
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Teng
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Liou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000599632:3-(7-amino-1-(4-methoxyphenylsulfonyl)indolin-5-yl)-N-hydroxyacrylamide; D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; D006655:Histone Deacetylases