J. Eldo et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2086–2090
2089
Table 1. IC50 values of inhibitors 1–9 and PALA against the catalytic subunit of ATCase
R1
R3
O
P
NH
O
R2 NH
OH
OH
OH
P
O
O
OH
Compounds 5-9
Compounds 1-4
Compound
R1
R2
R3
IC50 (lM)
PALA
COOH
COOH
CH2OH
CONH2
CH2OH
COOH
CONH2
COOH
COOH
CH2OH
0.055
0.087
3.900
0.225
2900
1
2
3
4
5
6
7
8
9
CH(COOH)2
CH(COOH)CH2OH
43.50
30.00
42.00
12500
63.00
CH(COOH)CH(OH)CH3
CH(CH2OH)2
CH(COOH)CH2–p-(C6H4)OH
showed inhibition at the nanomolar level, which is very
close to the inhibition observed for PALA. Compari-
son of inhibitor 1 with PALA indicates that the amide
modification in the a-position does not affect the
inhibition significantly. Among the amide analogues,
the a-amide showed more than twofold better inhibi-
tion than the b-amide, indicating that the b-carboxylate
has more influence than the a-carboxylic group in the
binding of the inhibitor. Though the analogues with
an amide group did not make any dramatic changes
in the observed inhibition as compared to PALA,
introduction of the alcohol functionality resulted in
analogues that were had substantially reduced ability
to inhibit the enzyme. The mono alcohol 2 showed a
100-fold weaker inhibition compared to PALA,
whereas the di-alcohol 4 only inhibited in the millimo-
lar range. All the structurally modified compounds, ex-
cept for 8, exhibited inhibition at the micromolar level.
Inhibitor 5, which has one methylene unit less than
PALA, showed an approximate 103-fold decrease in
ability to inhibit the enzyme. A comparison of the
IC50 values of inhibitors 5, 6, and 7 (see Table 1) indi-
cates that the conversion of the carboxylate group into
a primary or secondary alcohol does not have a signif-
icant influence on the inhibition, and also indicates that
the relative position of the b-carboxylate moiety plays
a crucial role in binding.
Acknowledgment
This work was supported by Grant GM26237 from the
National Institutes of Health.
References and notes
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In summary, we described the synthesis of a series of
novel inhibitors for ATCase with a variety of structural
modifications. Also studied was the effect of these mod-
ifications on the ability of these analogues to inhibit the
activity in ATCase. These studies with functional group
modified PALA derivatives showed that amide groups
can be a useful substitute of the carboxylate group there-
by reducing the charge on the molecule. IC50 values of
these analogues indicated that the methylene unit in
the b-position is more critical than the functional group
itself. Some of the newly synthesized molecules are po-
tent inhibitors of ATCase and detailed functional and
structural studies of these inhibitors of the enzyme are
currently in process.
18. Ben-Bari, M.; Dewynter, G.; Aymard, C.; Jei, T.;
Montero, J.-L. Phosphorus Sulfur Silicon 1995, 105, 129.
19. Heng, S.; Stieglitz, K. A.; Eldo, J.; Xia, J.; Cardia, J. P.;
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