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

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-...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2005-11, Vol.15 (21), p.4656-4661
Main Authors: Mai, Antonello, Massa, Silvio, Rotili, Dante, Pezzi, Riccardo, Bottoni, Patrizia, Scatena, Roberto, Meraner, Joachim, Brosch, Gerald
Format: Article
Language:English
Subjects:
Acetylation
Animals
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Biological and medical sciences
Cell Differentiation - drug effects
Cell Proliferation - drug effects
Drug Design
General aspects
Histone Deacetylase Inhibitors
Histones - metabolism
HL-60 Cells
Humans
Hydroxamic Acids - chemical synthesis
Hydroxamic Acids - pharmacology
Medical sciences
Mice
Models, Molecular
NIH 3T3 Cells
Pharmacology. Drug treatments
Uracil - chemistry
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Summary: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 1l 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2005.07.081