download report - Istituto Pasteur

P a r t i c i p a n t s :
Giovanna Simonetti, professor; Rino Ragno, researcher;
Dante Rotili, Sergio Valente, Silvia Simeoni, post-doc fellows;
Antonia Caroli, Giorgia Botta, Domenico Tarantino,
PhD students.
C o l l a b o r a t i o n s :
Università di Siena (Prof. Silvio Massa), University of Innsbruck,
Austria (Prof . Gerald Brosch), II Università di Napoli (Prof.
Lucia Altucci), Università di Milano & Istituto Europeo di
Oncologia, Milano (Prof. Saverio Minucci), University of Texas,
USA (Prof. M. T. Bedford, Dr. Donghang Cheng).
Report of Activity
Design, synthesis, and biological validation of
novel, class-selective HDAC inhibitors (HDACi)
Class I-selective HDACi. Following our searches on
class I-selective HDACi bearing a cinnamyl moiety
we prepared some new cinnamyl hydroxamates as
well as 2-aminoanilides (MS-275 analogues) by
replacing the benzene ring with a heteroaromatic
ring, and by adding a (hetero)aryl substituent at the
2-aminoanilide group at the right head of the molecules.
From preliminary data, they should be class Iselective
inhibitors, and some of them were highly
active as apoptotic and/or cytodifferentiating agents.
Moreover, a new series of uracil-based 2aminoanilides
as analogues of the corresponding
hydroxamates have been prepared and characterized
as HDACi.
Class II-selective HDACi. About reactivation of HIV-
1 expression in latent cellular reservoirs, we have no
data for assessing a specific involvement of class I or
class II HDACs for silencing. It has been reported
that NF-κB p50-HDAC1 complexes constitutively
bind the latent HIV LTR and induce histone deacetylation
and repressive changes in chromatin structure
Principal investigator: Antonello Mai
Professor on Medicinal Chemistry
Dipartimento di Chimica e Tecnologie del Farmaco
Tel: (+39) 06 49913392; Fax: (+39) 06 491491
antonello.mai@uniroma1.it
119
New antimicrobial and antiviral agents - AREA 6
Design, synthesis and biological evaluation of small molecule
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of the HIV LTR, changes that impair recruitment of
RNA polymerase II and transcriptional initiation.
Similarly, chromatin immunoprecipitation (ChIP)
assays revealed that c-Myc, Sp1, and HDAC1 coexist
in the same DNA-protein complex at the HIV promoter,
and are absent from the promoter after VPA
treatment in concert with histone acetylation, RNA
polymerase II recruitment, and LTR expression.
Thus, HDAC1 (a class I HDAC) seems to be surely
involved in HIV-1 expression silencing at the promoter,
but an involvement of class II HDACs can not
be ruled out. In cancer therapy also, for example, the
fact that class I HDAC enzymes are clinically relevant
is still controversial and not absolute. Indeed, in
2008 we have shown a specific regulation and activity
of class II HDACs in human breast cancer cells,
and in another paper we will propose a regulatory
role for class II HDACs on class I enzyme activity in
muscle cells. Thus, also in HIV-1 expression reactivation
we could have somehow an involvement of
class II HDACs and/or a regulation of the class I
HDAC functions through the class II enzymes. To
date, we screened a library of our HDACi showing
different degrees of class/isoform selectivity against
HIV-1 to reactivate the virus from its latent reservoirs,
and we are publishing a brief report about the
first obtained data. These data were also filed in a
patent with the ISS.
Sirtuin inhibitors. The human Sir2 ortholog, SIRT1,
is a NAD+-dependent deacetylase implicated in a
variety of important disease-related processes
including silencing of p53, inflammatory response,
cell defence and survival, and fatty acid metabolism.
In a search for potent sirtuin inhibitors as apoptotic
and/or cytodifferentiating agents, we prepared a
series of sirtinol analogues, and the degree of inhibition
was assessed in vitro using recombinant yeast
Sir2, human SIRT1, and human SIRT2, and in vivo
with a yeast phenotypic assay. Two analogues, namely
3- and 4-[(2-hydroxy-1-naphthalenylmethyl-