including difluoromethylenephosphonates,8 4′-O-[2-(2-
fluoromalonyl)]-tyrosine,9 2-(oxalylamino)-benzoic acids,10
difluoromethylenesulfonic acids,11 O-carboxylmethyl sali-
cylic acids,12 and R-ketocarboxylic acids.13 Although many
of these motifs can be used to develop potent inhibitors, one
of the current efforts in the field is to design effective mimics
of phosphotyrosine that have a reduced negative charge in
order to improve bioavailability. As part of our efforts in
this direction, we report on our discovery that derivatives of
squaric acid can serve as mimics of phosphate esters, and
that these compounds can be used to design effective
inhibitors of PTPases.
Figure 1 shows a comparison of the structures of 2-phenyl-
1-hydroxycyclobut-1-ene-3,4-dione and phenyl phosphate.
Figure 2. Structures of 2-aryl-1-hydroxycyclobut-1-ene-3,4-diones.
of glyoxylase I,16 and semisquaric acid (3-hydroxy-3-
cyclobutenedione) is an inhibitor of pyruvate dehydrogenase
and transketolase.17 Recently, Sekine and co-workers have
used a diamide of squaric acid as a replacement for one of
the phosphate diester linkages in an oligodeoxynucleotide.18
Beaulieu and co-workers have used squaric acid as a
replacement for phosphate in a peptide-based ligand for an
SH2 domain.19 Other derivatives of squaric acid serve as
high-affinity ligands for exitatory amino acid receptors20 and
antagonists of the NMDA (N-methyl-D-aspartate) receptor.21
In our current studies, we have examined eight simple 2-aryl-
1-hydroxycyclobut-1-ene-3,4-diones (Figure 2) and six mono-
amides of squaric acid (Figure 3) for their ability to inhibit
Figure 1. Comparison of the structure of a squaric acid derivative
with a phosphate ester.
The squaric acid derivative has a resonance structure that
places a negative charge on each of the two carbonyl oxygen
atoms and provides an aromatic cyclobutenyl ring system
that contains 2 π electrons. Therefore, this resonance
structure represents a good electrostatic mimic for the
phosphate group. Deprotonation of the hydroxycyclobutene-
dione gives a monoanion with an increased charge density
on the oxygen atoms.14,15
Squaric acids have found a variety of uses in bioorganic
and medicinal chemistry. Squaric acid itself is an inhibitor
(8) (a) Groves, M. R.; Yao, Z.-J.; Roller, P. P.; Burke, T. R., Jr.; Barford,
D. Biochemistry 1998, 37, 17773-17783. (b) Shen, K.; Keng, Y.-F.; Wu,
L.; Guo, X.-L.; Lawrence, D. S.; Zhang, Z.-Y. J. Biol. Chem. 2001, 276,
47311-47319.
Figure 3. Structures of amides of squaric acid.
(9) Burke, T. R., Jr.; Ye, B.; Akamatsu, M.; Ford, H., Jr.; Yan, X.; Kole,
H. K.; Wolf, G.; Shoelson, S. E.; Roller, P. P. J. Med. Chem. 1996, 39,
1021-1027.
(10) Andersen, H. S.; Iversen, L. F.; Jeppesen, C. B.; Branner, S.; Norris,
K.; Rasmussen, H. B.; Moller, K. B.; Moller, N. P. H. J. Biol. Chem. 2000,
275, 7101-7108.
the Yersinia PTPase (YopH) and PTP1B. We have used two
different methods to synthesize the 2-aryl-1-hydroxycyclobut-
(11) Leung, C.; Grzyb, J.; Lee, J.; Meyer, N.; Hum, G.; Jia, C.; Liu, S.;
Taylor, S. D. Bioorg. Med. Chem. 2002, 10, 2309-2323.
(12) Larsen, S. D.; Stevens, F. C.; Lindberg, T. J.; Bodnar, P. M.;
O’Sullivan, T. J.; Schostarez, H. J.; Palazuk, B. J.; Bleasdale, J. E. Bioorg.
Med. Chem. Lett. 2003, 13, 971-975.
(13) (a) Chen, Y. T.; Onaran, M. B.; Doss, C. J.; Seto, C. T. Bioorg.
Med. Chem. Lett. 2001, 11, 1935-1938. (b) Chen, Y. T.; Seto, C. T. J.
Med. Chem. 2002, 45, 3946-3952. (c) Chen, Y. T.; Xie, J.; Seto, C. T. J.
Org. Chem. 2003, 68, 4123-4125.
(14) See Supporting Information for a comparison of electron density
calculations of phenyl phosphate dianion and 2-phenyl-1-hydroxycyclobut-
1-ene-3,4-dione monoanion.
(16) Douglas, K. T.; Nadvi, I. N. FEBS Lett. 1979, 106, 393-396.
(17) Burka, L. T.; Doran, J.; Wilson, B. J. Biochem. Pharmacol. 1982,
31, 79-84.
(18) Sato, K.; Seio, K.; Sekine, M. J. Am. Chem. Soc. 2002, 124, 12715-
12724.
(19) Beaulieu, P. L.; Cameron, D. R.; Ferland, J.-M.; Gauthier, J.; Ghiro,
E.; Gillard, J.; Gorys, V.; Poirier, M.; Rancourt, J.; Wernic, D.; Llinas-
Brunet, M.; Betageri, R.; Cardozo, M.; Hickey, E. R.; Ingraham, R.; Jakes,
S.; Kabcenell, A.; Kirrane, T.; Lukas, S.; Patel, U.; Proudfoot, J.; Sharma,
R.; Tong, L.; Moss, N. J. Med. Chem. 1999, 42, 1757-1766.
(20) Chan, P. C. M.; Roon, R. J.; Koerner, J. F.; Taylor, N. J.; Honek,
J. F. J. Med. Chem. 1995, 38, 4433-4438.
(21) Kinney, W. A.; Abou-Gharbia, M.; Garrison, D. T.; Schmid, J.;
Kowal, D. M.; Bramlett, D. R.; Miller, T. L.; Tasse, R. P.; Zaleska, M. M.;
Moyer, J. A. J. Med. Chem. 1998, 41, 236-246.
(15) pKa of 2-phenyl-1-hydroxycyclobut-1-ene-3,4-dione has been re-
ported as 0.37 or -0.22. (a) Smutney, E. J.; Caserio, M. C.; Roberts, J. D.
J. Am. Chem. Soc. 1960, 82, 1793-1801. (b) Patton, E.; West, R. J. Am.
Chem. Soc. 1973, 95, 8703-8707.
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