epidermal growth factor receptor Ac-DADEpYL-NH2
(EGFR988-993).9 A number of investigators have shown
that the Ac-DADE-X-L-NH2 peptide, where X denotes a
non-hydrolyzable pTyr analogue, is a useful template for
designing PTPase inhibitors.10 One of the most effective
pTyr mimics that has been inserted into this peptide is
difluoromethylphosphonophenylalanine (F2Pmp).11 The
difluoromethylenephosphonic acid (DFMP) group has
also been used as the basis for a number of other
nonpeptidic PTPase inhibitors.12 Despite the potency of
the DFMP group, the efficacy of phosphonates is ham-
pered by their inability to penetrate into cells. This low
permeability is likely to be due to their high charge at
physiological pH.13
To improve bioavailability, efforts have been directed
toward the development of less-charged, non-phosphorus-
containing inhibitors. These efforts have resulted in pTyr
mimics that include L-O-(2-malonyl)tyrosine (OMT),14 its
fluorinated counterpart 4′-O-[2-(2-fluoromalonyl)]-L-ty-
rosine (FOMT),15 and 2-(oxalylamino)benzoic acids.16
Recently, we reported that R-ketoacids such as phenyl-
glyoxylic acid (1) can serve as a new class of pTyr
mimic.17,18 While several pTyr mimics that contain a
single carboxylic acid group have been found to be
moderately good ligands of src homology (SH2) domains,
few have shown good affinity for PTPases.19
During our investigations of new phosphate analogues
that can be used for PTPase inhibition, we also became
interested in sulfonamides. Sulfonamides are a common
functional group in medicinal chemistry, and they have
served in a variety of applications such as carbonic an-
hydrase inhibitors20 and bacteriostatic agents.21 Com-
pounds such as benzylsulfonamide 2 may possess a si-
milar geometry to that of aryl phosphates and aryl-
methylenephosphonates. As a result, investigation of
sulfonamides may to lead to noncharged PTPase inhibi-
tors that have improved bioavailability. Here, we report
the synthesis of pTyr analogues that incorporate an
R-ketoacid or sulfonamide group that are then used in
the synthesis of Ac-DADE-X-L-NH2-based inhibitors
Peptidic r-Ketocarboxylic Acids and
Sulfonamides as Inhibitors of Protein
Tyrosine Phosphatases
Yen Ting Chen,† Jian Xie,† and Christopher T. Seto*
Department of Chemistry, Brown University, 324 Brook St.
Box H, Providence, Rhode Island 02912
Received January 28, 2003
Abstract: One common approach for designing protein
tyrosine phosphatase (PTPase) inhibitors is to incorporate
a nonhydrolyzable phosphotyrosine (pTyr) mimic into a
peptide substrate for PTPases. This report describes the
synthesis of three such nonhydrolyzable pTyr mimics that
contain R-ketoacid, R-hydroxyacid, and methylenesulfona-
mide functional groups in place of the phosphate. These pTyr
mimics were incorporated into the peptide sequence Ac-Asp-
Ala-Asp-Glu-X-Leu-NH2, where X is the pTyr mimic, and
analyzed for activity against the Yersinia PTPase and
PTP1B.
There is considerable interest in the development of
inhibitors for protein tyrosine phosphatases (PTPases)
because PTPases are associated with a variety of human
diseases.1,2 For example, overexpression of the human
PTPases PTP1B, LAR, and PTPR leads to abnormal
insulin resistance that is often associated with type II
diabetes.3 As a consequence, several studies have shown
that inhibitors of PTP1B are potential therapeutic agents
for the treatment of both diabetes and obesity.4,5 In a
second example, the Yersinia pestis bacterium, the
causative agent of the bubonic plague, employs the
PTPase YopH that is essential for its virulence.6 Thus,
inhibitors of YopH are potential antibacterial agents that
can be targeted for this organism.
The active site of PTPases selectively binds phospho-
tyrosine (pTyr),7 but the amino acids that flank a pTyr
residue are also crucial for recognition of substrates by
PTPases.8,9 One peptide that is a good substrate for a
variety of PTPases is the sequence derived from the
(10) Burke, T. R., Jr.; Yao, Z.-J.; Liu, D.-G.; Voigt, J.; Gao, Y.
Biopolymers 2001, 60, 32.
(11) Burke, T. R., Jr.; Kole, H. K.; Roller, P. P. Biochem. Biophys.
Res. Commun. 1994, 204, 129.
† These authors contributed equally to this work.
* Corresponding author.
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10.1021/jo034113n CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/22/2003
J. Org. Chem. 2003, 68, 4123-4125
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