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-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
Antonello
A
Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Università degli Studi di Roma La Sapienza, P.le A. Moro 5, 00185 Roma, Italy. antonello.mai@uniroma1.it
Massa
Silvio
S
Rotili
Dante
D
Pezzi
Riccardo
R
Bottoni
Patrizia
P
Scatena
Roberto
R
Meraner
Joachim
J
Brosch
Gerald
G
D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D041681:NIH 3T3 Cells; D014498:Uracil / Q000737:chemistry*
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D014498:Uracil