Exploring the connection unit in the HDAC inhibitor pharmacophore model: Novel uracil-based hydroxamates

被引：44
作者：
Mai, A
Mass, S
Rotili, D
Pezzi, R
Bottoni, P
Scatena, R
Meraner, J
Brosch, G
机构：
[1] Univ Roma La Sapienza, Ist Pasteur, Fdn Cenci Bolognetti, Dipartimento Studi Farmaceut, I-00185 Rome, Italy
[2] Univ Siena, Dipartimento Farm Chim Technol, I-53100 Siena, Italy
[3] Univ Cattolica Sacro Cuore, Ist Biochim & Biochim Clin, I-00168 Rome, Italy
[4] Innsbruck Med Univ, Bioctr, Div Mol Biol, A-6020 Innsbruck, Austria
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2005年 / 15卷 / 21期
关键词：
D O I：
10.1016/j.bmcl.2005.07.081
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Starting from the pharmacophore model for HDAC inhibitor design, a novel series of hydroxamates bearing a uracil moiety as connecting unit (CU) has been prepared and tested. Almost all compounds exhibited HDAC inhibiting activity at low nanomolar concentrations, the N-hydroxy-6-(3,4-dihydro-4-oxo-6-benzyl- and -6-phenyl-2-pyrimidinylthio)hexanamides 1d and 11 being more potent than SAHA in enzymatic assays. Such compounds also caused hyperacetylation in NIH3T3 cell core histones and were endowed with interesting antiproliferative and cytodifferentiating effects in human leukemia (HL-60) cells. (c) 2005 Elsevier Ltd. All rights reserved.
引用
收藏
页码：4656 / 4661
页数：6
相关论文
共 42 条
  • [11] Histone-deacetylase inhibitors: Novel drugs for the treatment of cancer
    Johnstone, RW
    [J]. NATURE REVIEWS DRUG DISCOVERY, 2002, 1 (04) : 287 - 299
  • [12] The fundamental role of epigenetic events in cancer
    Jones, PA
    Baylin, SB
    [J]. NATURE REVIEWS GENETICS, 2002, 3 (06) : 415 - 428
  • [13] Histone deacetylase inhibitors: from target to clinical trials
    Kelly, WK
    O'Connor, OA
    Marks, PA
    [J]. EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2002, 11 (12) : 1695 - 1713
  • [14] Different types of maize histone deacetylases are distinguished by a highly complex substrate and site specificity
    Kölle, D
    Brosch, G
    Lechner, T
    Pipal, A
    Helliger, W
    Taplick, J
    Loidl, P
    [J]. BIOCHEMISTRY, 1999, 38 (21) : 6769 - 6773
  • [15] Histone acetylases and deacetylases in cell proliferation
    Kouzarides, T
    [J]. CURRENT OPINION IN GENETICS & DEVELOPMENT, 1999, 9 (01) : 40 - 48
  • [16] RPD3-type histone deacetylases in maize embryos
    Lechner, T
    Lusser, A
    Pipal, A
    Brosch, G
    Loidl, A
    Goralik-Schramel, M
    Sendra, R
    Wegener, S
    Walton, JD
    Loidl, P
    [J]. BIOCHEMISTRY, 2000, 39 (07) : 1683 - 1692
  • [17] Differentiation therapy of human cancer: basic science and clinical applications
    Leszczyniecka, M
    Roberts, T
    Dent, P
    Grant, S
    Fisher, PB
    [J]. PHARMACOLOGY & THERAPEUTICS, 2001, 90 (2-3) : 105 - 156
  • [18] Identification of maize histone deacetylase HD2 as an acidic nucleolar phosphoprotein
    Lusser, A
    Brosch, G
    Loidl, A
    Haas, H
    Loidl, P
    [J]. SCIENCE, 1997, 277 (5322) : 88 - 91
  • [19] Histone acetylation modifiers in the pathogenesis of malignant disease
    Mahlknecht, U
    Hoelzer, D
    [J]. MOLECULAR MEDICINE, 2000, 6 (08) : 623 - 644
  • [20] Mai A, 2005, Med Chem, V1, P245, DOI 10.2174/1573406053765431
12345