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.
Exploring the connection unit in the HDAC inhibitor pharmacophore model: Novel uracil-based hydroxamates / Mai, Antonello; Silvio, Massa; Rotili, Dante; Riccardo, Pezzi; Patrizia, Bottoni; Roberto, Scatena; Joachim, Meraner; Gerald, Brosch. - In: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS. - ISSN 0960-894X. - 15:21(2005), pp. 4656-4661. [10.1016/j.bmcl.2005.07.081]
Exploring the connection unit in the HDAC inhibitor pharmacophore model: Novel uracil-based hydroxamates
MAI, Antonello;ROTILI, Dante;
2005
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
