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.
Mai, A., Massa, S., Rotili, D., Pezzi, R., Bottoni, P., Scatena, R., Meraner, J., Brosch, G., Exploring the connection unit in the HDAC inhibitor pharmacophore model: noveluracil-based hydroxamates., <<BIOORGANIC & MEDICINAL CHEMISTRY LETTERS>>, 2005; (Novembre): 4656-4661 [http://hdl.handle.net/10807/8904]
Exploring the connection unit in the HDAC inhibitor pharmacophore model: novel uracil-based hydroxamates.
Bottoni, Patrizia;Scatena, Roberto;
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 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.
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