title: [Design, synthesis, and biological activities of histone deacetylase inhibitors with diketo ester as zinc binding group].
abstract: Histone deacetylases (HDACs) inhibition causes hyperacetylation of histones leading to growth arrest, differentiation and apoptosis of tumor cells, representing a new strategy in cancer therapy. Many of previously reported HDACs inhibitors are hydroxamic acid derivatives, which could chelate the zinc ion in the active site in a bidentate fashion. However, hydroxamic acids occasionally have produced problems such as poor pharmacokinetics, severe toxicity and low selectivity. Herein we describe the identification of a new series of non-hydroxamate HDACs inhibitors bearing diketo ester moieties as zinc binding group. HDACs inhibition assay and antiproliferation assays in vitro against multiple cancer cell lines were used for evaluation. These compounds displayed low antiproliferative activity against solid tumor cells, while good antiproliferative activity against human leukemic monocyte lymphoma cell line U937. Compound CPUYS707 is the best with GI50 value of 0.31 micromol x L(-1) against U937 cells, which is more potent than SAHA and MS-275. HDACs inhibition activity of these compounds is lower than that expected, further evaluation is needed.
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Lu
authors.forename: Hong
authors.initials: H
authors.lastname: Su
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.forename: Qi-Dong
authors.initials: QD
authors.lastname: You
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004952:Esters / Q000737:chemistry; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D015394:Molecular Structure; D011725:Pyridines / Q000494:pharmacology; D020298:U937 Cells / Q000187:drug effects; D000077337:Vorinostat; D015032:Zinc / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D001713:Biphenyl Compounds; C575129:CPUYS707; D004952:Esters; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011725:Pyridines; C118739:entinostat; D000077337:Vorinostat; D006655:Histone Deacetylases; D015032:Zinc