Evaluation of the cyclopentane-1,2-dione as a potential bio-isostere of the carboxylic acid functional group

Article abstract of DOI:10.1016/j.bmcl.2014.07.047

Cycloalkylpolyones hold promise in drug design as carboxylic acid bio-isosteres. To investigate cyclopentane-1,2-diones as potential surrogates of the carboxylic acid functional group, the acidity, tautomerism, and geometry of hydrogen bonding of representative compounds were evaluated. Prototypic derivatives of the known thromboxane A₂ prostanoid (TP) receptor antagonist, 3-(3-(2-((4-chlorophenyl)sulfonamido)-ethyl)phenyl)propanoic acid, in which the carboxylic acid moiety is replaced by the cyclopentane-1,2-dione unit, were synthesized and evaluated as TP receptor antagonists. Cyclopentane-1,2-dione derivative 9 was found to be a potent TP receptor antagonist with an IC₅₀ value comparable to that of the parent carboxylic acid. These results indicate that the cyclopentane-1,2-dione may be a potentially useful carboxylic acid bio-isostere.

Full text of DOI:10.1016/j.bmcl.2014.07.047

Bioorganic & Medicinal Chemistry Letters 24 (2014) 4171–4175
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Evaluation of the cyclopentane-1,2-dione as a potential bio-isostere
of the carboxylic acid functional group
a
a
b
b
Carlo Ballatore a,b, , Bryant Gay , Longchuan Huang , Katie Herbst Robinson , Michael J. James ,
⇑
John Q. Trojanowski b, Virginia M.-Y. Lee b, Kurt R. Brunden b, Amos B. Smith III a,
⇑
a Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, 231 South 34th St., Philadelphia, PA 19104-6323, United States
b Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 19104-6323, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Cycloalkylpolyones hold promise in drug design as carboxylic acid bio-isosteres. To investigate cyclopen-
tane-1,2-diones as potential surrogates of the carboxylic acid functional group, the acidity, tautomerism,
and geometry of hydrogen bonding of representative compounds were evaluated. Prototypic derivatives
of the known thromboxane A2 prostanoid (TP) receptor antagonist, 3-(3-(2-((4-chlorophenyl)sulfon-
amido)-ethyl)phenyl)propanoic acid, in which the carboxylic acid moiety is replaced by the
cyclopentane-1,2-dione unit, were synthesized and evaluated as TP receptor antagonists.
Cyclopentane-1,2-dione derivative 9 was found to be a potent TP receptor antagonist with an IC50 value
comparable to that of the parent carboxylic acid. These results indicate that the cyclopentane-1,2-dione
may be a potentially useful carboxylic acid bio-isostere.
Received 20 June 2014
Revised 14 July 2014
Accepted 16 July 2014
Available online 23 July 2014
Keywords:
Carboxylic acid bio-isosteres
Cyclopentane-1,2-dione
Thromboxane A2 receptor
Ó 2014 Elsevier Ltd. All rights reserved.
The carboxylic acid moiety is a privileged structure in drug
design,1 due to the fact that this functional group can establish rel-
atively strong ionic and hydrogen-bond interactions with biologi-
cal targets, leading to the formation of relatively stable
complexes. The presence of this functional group in a drug or a
drug candidate, however, can have undesired consequences, which
presents two non-equivalent points of attachment (see Fig. 1A and
B). Notable differences in physicochemical properties however exist
between the two cyclic diones, which may ultimately lead to impor-
tant ramifications, particularly in the context of isosteric replace-
ment of the carboxylic acid functional group. For example, the
enol-ketone tautomers of the cyclopentane-1,2-dione, unlike those
of the corresponding 1,3-dione system, are not vinylogous acid
structures, thus resulting in relatively high pKa values.11 Moreover,
typically include metabolic instability, toxicity, and often
a
reduced rate of passive diffusion across biological membranes.
Under such circumstances, isosteric replacement strategies, in
which the carboxylic acid moiety is substituted with a surrogate
structure, can lead to derivatives with improved properties, rela-
tive to the parent carboxylic acid compound.2
Cyclic polyone systems comprise a promising source of carbox-
ylic acid bio-isosteres. For example, squaric acid and related deriv-
atives have been successfully employed as carboxylic acid
surrogates in drug design.3–6 In similar fashion, cyclopentane-
1,3-diones (Fig. 1A) are effective substitutes for the carboxylic acid
moiety of known thromboxane A2 (TP) receptor antagonists (e.g.,
1,7 Fig. 1C), leading to potent derivatives.8
Cyclopentane-1,2-diones (Fig. 1B) may also be considered as a
potential carboxylic acid bio-isosteres, however, a systematic eval-
uation of this fragment as a carboxylic acid surrogate has not been
reported. Like the cyclopentane-1,3-diones, the cyclopentane-1,2-
dione system exists predominantly in enol-ketone form,9,10 and
Figure 1. Tautomers of cyclopentane-1,3-dione (A) and cyclopentane-1,2-dione;
(B) dotted lines indicate non-equivalent point of attachments on the two cyclic
diones; (C) representative examples of TP receptor antagonists.
⇑
Corresponding authors.
http://dx.doi.org/10.1016/j.bmcl.2014.07.047
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

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C. Ballatore et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4171–4175
whereas the cyclopentane-1,3-dione is known to undergo rapid
exchange between enol-ketone tautomers, in the case of the corre-
sponding 1,2-dione, depending on the substitution pattern, one
tautomermay be considerably more stable than the other (Fig. 1B).12
Finally, given the structural differences, the two cyclic dione sys-
tems are likely to exhibit different geometries of hydrogen bonding.
COOEt
OK
O
Br
EtOOC
B
r
5
B
r
O
Conc. HCl/AcOH
100 oC, 5h
OK
Br
E
tO
C
DMF
C
O
E
t
100 oC, 3h
6
4
O
O
HO
Br
Br
OH
2 pka = 8.62
8 pka = 3.96
Mg
O
O
O
O
OH
Mg(OMe)2, MeOH
electrocyclization
O
3
7
Scheme 1. Synthesis of 1,2-dione model compounds 2 and 3 and structure of previously reported 1,3-dione 8; pKa determinations were conducted by Sirius analytical.
Figure 2. Rapid tautomeric exchange of 8 (top) results in weak 13C NMR signals of the 1,3-dione system, while 13C NMR spectrum of 2 (bottom) shows only one of the two
enol-ketone tautomers.

C. Ballatore et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4171–4175
4173
Thus, to characterize the cyclopentane-1,2-diones as potential
surrogates of the carboxylic acid functional group, we evaluated
the acidity, tautomerism, and geometry of hydrogen bonding of
representative model compounds
2
and 313 (Scheme 1), in
which the cyclopentane-1,2-dione is substituted either at C3 (2)
or C4 (3).The synthesis of was achieved starting from
2
Figure 3. X ray structure of compound 2 (CCDC 1009311), revealing inter-molecular H-bonding.
Scheme 2. Synthesis of 1,2-dione derivative 9.

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C. Ballatore et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4171–4175
Scheme 3. Synthesis of 1,2-dione derivative 10.
4-bromobenzylbromide (4) and the di-potassium salt 5,14 which
reacts to form the di-benzylated intermediate 6. Next, following
reported procedures,15 treatment of 6 with concentrated hydro-
chloric acid at 100 °C led to simultaneous decarboxylation and
hydrolysis of the benzyl ether, resulting in the formation of 1,2-
dione 2. Compound 313 was synthesized via magnesium methoxide
antagonist 17 (Fig. 1C), in which the carboxylic acid moiety is
replaced with cyclopentane-1,2-dione linked at C3 or C4
a
(respectively 9, Scheme 2; and 10, Scheme 3), were designed and
synthesized to be evaluated in a TP receptor functional assay.
The synthesis of 1,2-diones 9 and 10 followed similar strategies
employed for the synthesis of model compounds 2 and 3. Thus,
central to the synthesis of dione 9 was the acid-mediated decom-
position of intermediate 11 that could be obtained by reacting ben-
zyl iodide 12 with the di-potassium salt 514 (Scheme 2), while
dione 10 was obtained via magnesium methoxide promoted cycli-
induced cyclization of
ously (Scheme 1).
a,b-unsaturated dione 7, as described previ-
After synthesis, potentiometric titrations determined that the
pKa value of 2 is approximately 8.6, thus significantly higher than
the pKa of carboxylic acids and that of the corresponding 1,3-dione
88 (i.e., pKa ꢀ4.0; see Scheme 1 and Supporting information). Also
of notice, comparison of infrared (IR) and NMR spectra of com-
zation of a,b-unsaturated dione 13 (Scheme 3).
Test compounds were evaluated in a human TP (hTP) receptor
functional assay, which measures receptor-stimulated production
of the inositol triphosphate (IP3) metabolite, inositol monophos-
phate (IP1),8 in comparison with reference compound 1 and/or tet-
rahydronaphthalene derivative 1416 (Fig. 4), one of the most potent
TP receptor antagonists reported to date. As shown in Table 1 and
in Figure 4, both 1,2-dione derivatives were found to be active in
the functional assay, with 9 exhibiting an IC50 value comparable
to that of carboxylic acid 1. The results from the functional assay
also suggest that the orientation of the 1,2-dione fragment within
the receptor may be important for biological activity, as suggested
by the fact that 10 was found to be approximately 20 times less
potent than 9 (Table 1). A similar observation had been made with
the corresponding 1,3-diones derivatives.8
pound
2 and 8 clearly highlights the significant differences
between the cyclic 1,2-dione and the corresponding 1,3-dione sys-
tem in terms of rate of tautomeric exchange and relative stability
of the tautomers (see Fig. 2 and Fig. S1, Supporting information).
Finally, single crystal X-ray analysis of model compounds 2 and 3
revealed that, unlike the 1,3-diones and similar to the carboxylic
acids, the 1,2-diones can form dimers characterized by two-point
interactions (see Fig. 3 and Fig. S2, Supporting information), indi-
cating that the 1,2-dione system may in fact provide hydrogen
bond geometry that more closely mimics that of the carboxylic
acids. By comparison, X-ray structure of the corresponding 1,3-
dione system (8) did not show dimer formation but rather multi-
meric structures characterized by linear head-to-tail H-bond
interactions.8
Finally, to evaluate whether the cyclopentane-1,2-dione frag-
ment might be a chemically reactive system that could lead to
non-specific alkylation of proteins under physiological conditions,
the stability of derivative 9 was determined in vitro by monitoring
the disappearance of the compound, by LC/MS/MS, upon
Having established that the cyclopentane-1,3-diones can be
effective bio-isosteres of the carboxylic acid moiety in the context
of TP receptor antagonists,8 derivatives of the known TP receptor

C. Ballatore et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4171–4175
4175
incubation in plasma at 37 °C. As shown in Figure 5, compound 9
was found be essentially stable in plasma after 1 h incubation.
Collectively, our data indicate that the cyclopentane-1,2-dione
fragment, which is characterized by a relatively low intrinsic acid-
ity and a geometry of hydrogen bonding that resembles that of
carboxylic acids, holds promise as a potential carboxylic acid bio-
isostere.
Acknowledgments
Financial support for this work has been provided by NIH/NIA
Grant AG034140, NSF Grant CHE-0840438 (X-ray facility), and
the Marian S. Ware Alzheimer Program.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.07.
047.
Figure 4. Dose–response curves of test compounds in the hTP receptor IP1
functional assay.
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IC50 (lM)
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14
9
0.190 0.060
0.0026 0.001
0.054 0.016
1.140 0.820
10
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Figure 5. In vitro plasma stability of 9.