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A. Mai - Design, synthesis and biological evaluation of small molecule epigenetic modulators
ene)amino]-N-(1-phenylethyl)benzamide (ie, metaand
para-sirtinol) were from 2- to 10-fold more
potent than sirtinol against human SIRT1 and
SIRT2 enzymes. Among the prepared compounds,
obtained by replacement of the benzamide linkage of
the prototype with other bioisoster groups such as
anilide, sulfonamide, sulfide, 1-oxopropyl groups,
salermide (N-{3-[(2-hydroxynaphthalen-1-ylmethylene)amino]phenyl}-2-phenylpropionamide)
emerged as a sirtuin inhibitor with a strong cancerspecific
proapoptotic effect, due to the reactivation of
proapoptotic genes epigenetically repressed exclusively
in cancer cells by SIRT1.
Design, synthesis, and biological evaluation
of histone methyltransferase inhibitors
Protein arginine N-methyltransferases (PRMTs) and
histone lysine N-methyltransferases (HKMTs) have
been implicated in a variety of processes, including
biosynthesis, nuclear receptor-regulated transcription,
signal transduction, chromatin regulation, gene
silencing, protein repair, and protein trafficking.
PRMTs are known coactivators for nuclear receptors,
so they may represent likely candidates to be overexpressed
in the hormone-dependent prostate and breast
cancers. Among HKMTs, SET7/9 has been reported
to act not only on histones, but it also methylates the
tumor suppressor p53 leading to gene silencing.
In an effort to find small molecules that could represent
lead compounds MT inhibitors, we designed
and synthesize a series of compounds bearing two 1hydroxy-2,6-dibromophenyl
moieties connected by a
spacer. We hypothesized that the 1-hydroxy-2,6dibromophenyl
group could act as a pharmacophore
in these molecules; in fact the same or similar groups
are present in eosin, recently reported as PRMTi,
and in psammaplins, a series of natural compounds
endowed with anti-HDAC and anti-DNMT activi-
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ties. Some of the prepared compounds were effectively
active against PRMTs, others were able to
selectively inhibit a limited range of MTs (for example
against CARM1 or EZH2), and others behaved as
epigenetic multiple ligands, by inhibiting at the same
time and in the same range sirtuins (SIRT1 and -2),
HAT (p300), PRMTs and HKMTs. These last derivatives
displayed high apoptotic and/or cytodifferentiating
properties, higher than those shown by the
related single-target inhibitors.
Selected publications
Mai A, Jelicic K, Rotili D, Di Noia A, Alfani E,
Valente S, Altucci L, Nebbioso A, Massa S,
Galanello R, Brosch G, Migliaccio AR, Migliaccio
G. Identification of two new synthetic histone
deacetylase inhibitors that modulate globin gene
expression in erythroid cells from healthy donors
and patients with thalassemia. Mol Pharmacol. 2007,
72:1111-23.
Colussi C, Mozzetta C, Gurtner A, Illi B, Rosati J,
Straino S, Ragone G, Pescatori M, Zaccagnini G,
Antonini A, Minetti G, Martelli F, Piaggio G,
Gallinari P, Steinkulher C, Clementi E, Dell'Aversana
C, Altucci L, Mai A, Capogrossi MC, Puri PL,
Gaetano C. HDAC2 blockade by nitric oxide and histone
deacetylase inhibitors reveals a common target
in Duchenne muscular dystrophy treatment. Proc
Natl Acad Sci USA 2008, 105:19183-7.
Mai A, Cheng D, Bedford MT, Valente S, Nebbioso
A, Perrone A, Brosch G, Sbardella G, De Bellis F,
Miceli M, Altucci L. Epigenetic multiple ligands:
mixed histone/protein methyltransferase, acetyltransferase,
and class III deacetylase (sirtuin)
inhibitors. J Med Chem. 2008, 51:2279-90.