4828 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 23
Ta ble 2. Maize HD2 Inhibitory Activities of 3a -ga
Letters
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compd
R
IC50, µM
3a
3b
3c
3d
3e
3f
3g
H
2-Cl
3-Cl
4-Cl
2-Me
3-Me
4-Me
0.28 ( 0.01
5.2 ( 0.2
24.2 ( 1.2
25.2 ( 1.3
0.27 ( 0.01
7.9 ( 0.24
10.2 ( 0.41
7.2 ( 0.3b
TSAb
SAHA
0.05 ( 0.001
a
Data represent mean values of at least three separate experi-
b
ments. Data in nM concentrations.
Ta ble 3. HD1-B and HD1-A Inhibitory Activities of 3a -ga
IC50, µM
fold selectivity
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compd
R
HD1-B
HD1-A
class I class IIa
3a
3b
3c
3d
3e
3f
3g
H
0.3 ( 0.02
1.6 ( 0.08
0.2 ( 0.01
0.05 ( 0.003
0.4 ( 0.02
2-Cl
32
78
3-Cl 31.4 ( 1.3
4-Cl 29.4 ( 1.2
2-Me
3-Me
4-Me
18.6 ( 1.1
0.4 ( 0.02
2.5 ( 0.07
4.8 ( 0.3
0.06 ( 0.002
0.2 ( 0.007
0.5 ( 0.02
7
12
10
TSAb
SAHA
0.4 ( 0.01b
0.03 ( 0.001
0.8 ( 0.03b
0.2 ( 0.009
2
7
a
Data represent mean values of at least three separate experi-
ments. Data in nM concentrations.
b
or a methyl group at each position of the benzene ring
caused a dramatic change in the inhibiting effect of
pyrrole derivatives on the two deacetylases. Particu-
larly, 2-substituted compounds 3b,e were the most
potent against both the enzymes, being the anti-HD1-A
activities higher than those against HD1-B. Thus, 3b,e
showed a class IIa selectivity (IC50HD1-B/IC50HD1-A ratio)
of 32 and 7, respectively (Table 3). Introduction of the
chlorine atom (or the methyl group) at the 3-position of
the benzene ring afforded pyrrole derivatives (3c,f)
which were inactive (3c) or low active (3f) against HD1-
B, but retained inhibitory activity against HD1-A. Such
compounds were the most class IIa selective among the
two (Cl and Me) series, with values of fold selectivity of
78 (3c) or 12 (3f) (Table 3). Benzene C4-chlorine sub-
stitution (compound 3d ) abated both the anti-HD1-B
and HD1-A activities of pyrrole derivatives, while the
C4-methyl compound 3g was less active than its 2- and
3-substituted counterparts 3e and 3f against both
deacetylases, still retaining a submicromolar IC50 value
against class IIa homologue HD1-A (Table 3).
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Further synthetic and molecular modeling studies are
in progress to optimize both the potency and class IIa
selectivity of such 3-[4-(3-aryl-3-oxopropen-1-yl)-1-meth-
yl-1H-pyrrol-2-yl]-N-hydroxy-2-propenamides.
Ack n ow led gm en t. This work was supported by
grants of “Progetto Finalizzato Ministero della Salute
2002” (A.M.), “AIRC proposal 2003” (A.M.), and the
Austrian Science Foundation P13209 (G.B.) and P13620
(P.L.).
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Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and chemical and physical data for compounds 3a -
g. This material is available free of charge via the Internet at
http://pubs.acs.org.
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