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E. M. Gargano et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
Compound 8 was synthesized using an identical method, start-
ing from the commercially available 4-(4-chlorophenyl)cyclohex-
ane-1-carboxylic acid 8a (Scheme 1).
The 3-(4-phenylpiperazin-1yl) sulfonyls 9a–11a were prepared
through the sulfonamide bond formation (Scheme 2), achieved by
reaction of commercially available 1-phenylpiperazines 9b–11b
with 3-methoxybenzenesulfonyl chloride 9c, according to
a
described procedure.14 The following ether cleavage of 9a–11a,
using BF3ꢁSMe2 in presence of triethylamine, as already
described,14 yielded the hydroxy compounds 9–11.
The synthesis of the phenylpiperazin-1-yl methanones 12–14
and 15a are depicted in Scheme 3. The amide bond was formed,
by reacting the commercially available 1-phenylpiperazines 9b,
10b, 12b and 13b and 3-methoxybenzoyl chloride 10c, using
triethylamine and dichloromethane as solvent. Compounds
12a–14a were submitted to ether cleavage using boron trifluo-
ride–dimethyl sulfide complex yielding the hydroxy compounds
12–14. Conditions of both reactions were previously described.7
All final compounds as well as their intermediates were fully
characterized (1H NMR, 13C NMR and LRMS) to confirm their
chemical structure. The data of the representative compounds 4,
8, 9a and 12 are presented as examples.16–19
The inhibitory activities of compounds 7a, 10a, 11a, 13a–15a
and 1–15 on 17b-HSD2 and 17b-HSD1 obtained from human
placental source, were determined as previously described.20
The 4-phenoxybenzamides 7a and 1–7, as well as the phenylcy-
clohexanecarboxamide 8 (Table 1) displayed a good inhibition of
17b-HSD2. Compound 4, with a bent shape and 8, lacking the cen-
tral aromatic ring, but conserving the overall linear shape, showed
an inhibitory activity in the same order of magnitude as compound
A and significantly improved selectivity against 17b-HSD1, thus
demonstrating that neither the linearity of the biphenyl moiety
nor the aromaticity of the central ring are essential for inhibitory
activity.
The phenylpiperazin-1-yl sulfonyls 9a–11a and 9–11 (Table 2)
displayed poor inhibition of the 17b-HSD2 enzyme, when com-
pared to compounds A and B. Compound 10, which can be directly
compared to B, is a much weaker inhibitor of 17b-HSD2. Com-
pound 11 is the best in the series. The improvement in activity
between 10 and 11 comes from the introduction of the fluorine
in ortho to the OH group. The F likely positively influences the
hydrogen bond on the OH group next to it. In comparison to com-
pound B, the sulfonyl derivatives bear a much more hydrophilic
central ring, which might explain the loss of activity. They also bear
a sulfonamide function condensed in the piperazine ring, which
renders the molecules shorter than B. This feature might lead to
a loss of important interactions with the enzyme, thus further
explaining the lower inhibitory activity.
Figure 1. Estrogens (E2) and androgens (T) contribute to the maintenance of the
overall bone quality. Blocking the oxidation of estradiol and testosterone by using
an inhibitor of 17b-HSD2 should rebalance the steroid level in the bones.
the sulfonamide of B were both taken as starting point for the design
of the new inhibitors, in order to obtain a greater chemical diversity.
In order to develop new 17b-HSD2 inhibitors with a better
toxicity profile and a good 17b-HSD2 inhibitory activity, we applied
four strategies: (1) introduction of an ether bridge between the two
phenyl rings, compounds 1–7; (2) exchange of the phenyl central
ring by a cyclohexane ring, compound 8; (3) the exchange of the cen-
tral ring by a piperazine ring linked to a sulfonyl group, compounds
9a–11a and 9–11 and (4) the exchange of the sulfonyl function by an
acyl function, compounds 12a–14a and 12–15 (Fig. 2).
The reaction steps involved in the synthesis of the target
compounds 1–8 are shown in Scheme 1. The 4-phenoxybenzoyl
chlorides were obtained from the commercially available
corresponding 4-phenoxybenzoic acids 1a–6a and 7b by reaction
with SOCl2 and subsequently reacted with different anilines,
according to the already described procedure,15 providing
compounds 1–6 and 7a.
Compound 7a was submitted to ether cleavage, using boron
trifluoride–dimethyl sulfide complex BF3ꢁSMe2 yielding the
hydroxy compound 7, as previously described.15
Figure 2. Four different classes of inhibitors derived from the lead compounds A and B.
Gargano, Emanuele Marco
