title: Pyrimidinedione-mediated selective histone deacetylase 6 inhibitors with antitumor activity in colorectal cancer HCT116 cells.
abstract: We synthesized a series of pyrimidinedione derivatives and evaluated their activities. The results indicate that compound 6, 4-[5-fluoro-2,6-dioxo-3-(tetrahydro-furan-2-yl)-3,6-dihydro-2H-pyrimidin-1-ylmethyl]-N-hydroxy-benzamide, exhibits potent antiproliferative activity, apoptosis induction with cleavage of caspase and PARP, and enhanced tendency to inhibit HDAC6 (IC50 = 12.4 nM) activity over HDAC1 (IC50 = 1710 nM) and HDAC2 (IC50 = 5500 nM). Compound 6 also inhibits tumor growth and is less toxic than parent 4 in vivo. These data provide compelling evidence that compound 6 is a potential antitumor compound with HDAC6 targeted inhibitory activity and may be tested for preclinical investigation for cancer treatment.
authors: School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan. jpl@tmu.edu.tw.
authors: Yi-Min
authors: YM
authors: Liu
authors: Hsueh-Yun
authors: HY
authors: Lee
authors: Mei-Jung
authors: MJ
authors: Lai
authors: Shiow-Lin
authors: SL
authors: Pan
authors: Hsiang-Ling
authors: HL
authors: Huang
authors: Fei-Chiao
authors: FC
authors: Kuo
authors: Mei-Chuan
authors: MC
authors: Chen
authors: Jing-Ping
authors: JP
authors: Liou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D011744:Pyrimidinones; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases