Synthesis and biological properties of novel, uracil-containing histone deacetylase inhibitors

Antonello Mai; Silvio Massa; Dante Rotili; Silvia Simeoni; Rino Ragno; Giorgia Botta; Angela Nebbioso; Marco Miceli; Lucia Altucci; Gerald Brosch

doi:10.1021/jm0605536

Synthesis and biological properties of novel, uracil-containing histone deacetylase inhibitors

J Med Chem. 2006 Oct 5;49(20):6046-56. doi: 10.1021/jm0605536.

Authors

Antonello Mai¹, Silvio Massa, Dante Rotili, Silvia Simeoni, Rino Ragno, Giorgia Botta, Angela Nebbioso, Marco Miceli, Lucia Altucci, Gerald Brosch

Affiliation

¹ 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

PMID: 17004718
DOI: 10.1021/jm0605536

Abstract

A novel series of compounds containing a uracil moiety as the connection unit between a phenyl/phenylalkyl portion and a N-hydroxy-polymethylenealkanamide or -methylenecinnamylamide group (uracil-based hydroxamic acids, UBHAs) was tested against maize histone deacetylases (HDACs) and mouse HDAC1. Compounds with a phenyl/benzyl ring at the uracil-C6 position and bearing 4-5 carbon units as well as a m- or p-methylenecinnamyl moiety as a spacer were the most potent inhibitors. In cell-based human HDAC1 and HDAC4 assays, the two UBHAs tested inhibited the HDAC1 but not HDAC4 immunoprecipitate activity. When tested in human leukemia U937 cells, some UBHAs produced G1 phase arrest of the cell cycle. Moreover, 1j showed high antiproliferative and dose-dependent granulocytic differentiation properties. The tested UBHAs displayed weak p21WAF1/CIP1 induction in U937 cells, and 1d and 1j showed high histone H3 and alpha-tubulin acetylation effects.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Cell Cycle / drug effects
Cell Proliferation / drug effects
Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
Drug Screening Assays, Antitumor
Granulocytes / cytology
Granulocytes / drug effects
Histone Deacetylase 1
Histone Deacetylase Inhibitors*
Histone Deacetylases
Histones / metabolism
Humans
Hydroxamic Acids / chemical synthesis*
Hydroxamic Acids / chemistry
Hydroxamic Acids / pharmacology
Mice
Repressor Proteins / antagonists & inhibitors
Structure-Activity Relationship
Tubulin / metabolism
U937 Cells
Uracil / analogs & derivatives*
Uracil / chemical synthesis*
Uracil / pharmacology
Zea mays / enzymology

Substances

Antineoplastic Agents
CDKN1A protein, human
Cyclin-Dependent Kinase Inhibitor p21
Histone Deacetylase Inhibitors
Histones
Hydroxamic Acids
Repressor Proteins
Tubulin
Uracil
HDAC1 protein, human
HDAC4 protein, human
Hdac1 protein, mouse
Histone Deacetylase 1
Histone Deacetylases