α,α-Difluoro-β-ketophosphonates as potent inhibitors of protein tyrosine phosphatase 1B

Article abstract of DOI:10.1016/j.bmcl.2004.05.082

A novel series of inhibitors that contain an aryl α,α-difluoro- β-ketophosphonate group has been synthesized and evaluated against protein tyrosine phosphatase 1B. These compounds exhibit strong inhibitory activity, the best of which has a K_i value of 0.17μM. These results demonstrate that aryl α,α-difluoro-β-ketophosphonates are powerful phosphotyrosine mimetics for the development of potent PTP inhibitors.

Full text of DOI:10.1016/j.bmcl.2004.05.082

Bioorganic & Medicinal Chemistry Letters 14 (2004) 4301–4306
a,a-Difluoro-b-ketophosphonates as potent inhibitors of protein
tyrosine phosphatase 1B
Xianfeng Li,* Ashok Bhandari, Christopher P. Holmes and Anna K. Szardenings
Affymax, Inc., 4001 Miranda Avenue, Palo Alto, CA 94304, USA
Received 22 April 2004; accepted 27 May 2004
Available online 20 June 2004
Abstract—A novel series of inhibitors that contain an aryl a,a-difluoro-b-ketophosphonate group has been synthesized and eval-
uated against protein tyrosine phosphatase 1B. These compounds exhibit strong inhibitory activity, the best of which has a Ki value
of 0.17 lM. These results demonstrate that aryl a,a-difluoro-b-ketophosphonates are powerful phosphotyrosine mimetics for the
development of potent PTP inhibitors.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
nates,5a–c sulfotyrosines,5d fluoro-O-malonyltyrosines,5e
cinnamic acids,5f oxa-acetic acids,5g O-carboxymethyl
salicylic acids,5h 2-(oxalylamino)-benzoic acids,5i and
diaryloxamic acids.5j However, many of these pTyr mi-
metics are not quite effective or have very limited cell
permeability. Therefore, the discovery of new pTyr mi-
metics is needed and will greatly facilitate the develop-
ment of potent and selective PTP inhibitors in the field.
Protein tyrosine phosphatases (PTPs) are signal trans-
duction enzymes, which catalyze the hydrolysis of
phosphotyrosine residues (pTyr). These enzymes play a
critical role in regulating cell proliferation, differentia-
tion and metabolism. It has been shown that PTPs are
implicated in a number of human diseases such as dia-
betes, cancer, inflammation, and immune dysfunctions.1
In particular, PTP1B is a negative regulator of insulin
signaling and acts by dephosphorylation of the insulin
receptor.2 Recent knock-out studies in mice have dem-
onstrated that PTP1B is an attractive therapeutic target
for the treatment of Type II diabetes and obesity.3
Therefore, it would be highly desirable to develop PTP
inhibitors as therapeutic agents as well as valuable
probes for studying cellular signal transduction.
As part of our efforts to identify novel PTP inhibitors,
we have synthesized and evaluated aryl a,a-difluoro-b-
ketophosphonates as a new type of pTyr mimetics, and
explored their use in the development of small molecule
inhibitors for PTP1B. To the best of our knowledge,
inhibitory activity of this class against phosphatases has
not been reported in the literature. In an early study
Kluger has shown that acetonylphosphonate, a nonflu-
orinated b-ketophosphonate, is a competitive inhibitor
of acetoacetate decarboxylase.6 Recently, other com-
pounds containing b-ketophosphonate moiety have
been identified as inhibitors of serine protease cathepsin
G7 and glyceraldehyde-3-phosphate dehydrogenase.8
On the other hand, it has been shown that fluorinated
pTyr mimetics like a,a-difluoromethylphosphonates5a–c
and fluoro-O-malonyltyrosines5e are much more potent
PTP inhibitors than the corresponding nonfluorinated
analogues due to direct interactions of the fluorines with
the enzyme active site residues. Thus, aryl a,a-difluoro-
b-ketophosphonates (Fig. 1) are designed to stimulate
a variety of specific interactions with residues in the
active site of the phosphatase. While the difluoro-
methylphosphonate moiety targets the phosphate-binding
A common strategy in the development of PTP inhibi-
tors has been the incorporation of bioisosteric replace-
ments of the labile pTyr in appropriate peptide
substrates or small molecule scaffolds.4 These nonhy-
drolyzable pTyr mimetics serve as warheads to direct the
molecule to the catalytic phosphate-binding site of
phosphatases. A wide variety of pTyr mimetics have
been reported including a,a-difluoromethylphospho-
* Corresponding author at present address: Galileo Pharmaceuticals,
Inc., Santa Clara, CA 95054, USA. Tel.: +1-408-654-5830x228; fax:
+1-408-654-5832; e-mail: xli@galileopharma.com
Present address: Activx Biosciences, Inc., La Jolla, CA 92037, USA.
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.05.082

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X. Li et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4301–4306
Scheme 1 shows the synthesis of target compounds 3a–e.
O
Although there are several reports on the preparation of
a,a-difluoro-b-ketophosphonate diesters,9 the method
by Blades et al. describing a cerium-mediated reaction of
benzoyl esters with lithium difluoromethylphosphonate
provides the most direct and reproducible approach.9d
The key intermediate esters 2 were prepared by the
reaction of benzoyl methyl esters 1 with lithium dif-
luoromethylphosphonate, generated by the addition of
diethyl difluoromethylphosphonate to LDA containing
cerium(III) chloride in THF. Subsequently, an aqueous
work-up with 1 N hydrochloric acid gave phosphonate
diethyl esters 2 in about 60% yields. Deprotection of 2
was achieved by treatment with excess TMSBr,10 fol-
lowed by hydrolysis, to give the desired phosphonic
acids 3 in quantitative yields.
CF2PO(OH)2
R
Figure 1. Aryl a,a-difluoro-b-ketophosphonates.
site through electrostatic interactions, the carbonyl
group adjacent to the aromatic would be able to form
additional hydrogen bonds with residues within the
pTyr binding pocket. Our approach to identify PTP
inhibitors was to begin with simple aryl a,a-difluoro-b-
ketophosphonates and then build up a series of ana-
logues based on small molecule scaffolds.
The inhibitory activity against PTP1B was measured
using O-methyl fluorescein monophosphate (OMFP) as
substrate,11 and IC50 values are shown in Table 1. For
representative compounds, inhibition kinetics were also
determined,11 and Ki values are given in Table 1. The
2. Results and discussion
Our first goal was to make simple aryl a,a-difluoro-b-
ketophosphonates and evaluate their biological activity.
O
O
O
OMe
CF2PO(OEt)2
CF2PO(OH)2
a,b
c,d
R
R
R
3a, R = H
1
2
3b, R = 4-CH
3
3c, R = 4-Ph
3d, R = 2-CH OH
2
3e, R = 3-Ph
Scheme 1. Reagents and conditions: (a) HF2PO(OEt)2, LDA, CeCl3, THF, ꢀ78 °C; (b) HCl, H2O; (c) TMSBr, DCM; (d) H2O.
Table 1. Inhibition of PTP1B by aryl a,a-difluoro-b-ketophosphonatesa
Compound
Structure
IC50 (lM)
Ki (lM)
O
3a
76
129
CF2PO(OH)2
O
3b
3c
62
50
71
CF2PO(OH)2
O
CF PO(OH)2
2
NDb
O
CF PO(OH)2
2
3d
3e
31
ND
ND
OH
O
CF PO(OH)2
2
180

X. Li et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4301–4306
4303
Table 1 (continued)
Compound
Structure
IC50 (lM)
Ki (lM)
NO2
O
O
S
N
CF2PO(OH)2
7
O
12
12
NH2
O
O
S
CF2PO(OH)2
8
8.8
1.3
ND
0.57
N
O
CF2PO(OH)2
O
O
S
10a
N
O
Br
CF PO(OH)2
2
O
CF2PO(OH)2
O
10b
10c
10d
10e
0.5
0.7
0.6
1.1
0.28
ND
0.17
ND
N
O
S
O
Br
F
O
CF2PO(OH)2
CF3
O
CF PO(OH)2
2
O
S
N
O
O
F
CF PO(OH)2
2
O
CF2PO(OH)2
O
S
N
O
O
CF2PO(OH)2
O
CF2PO(OH)2
O
S
O
N
O
CF2PO(OH)2
aValues are means of duplicate experiments, errors are usually within 10%.
b Not determined.
simple phenyl a,a-difluoro-b-ketophosphonate 3a shows
competitive inhibition with an IC50 of 76 lM and a Ki of
129 lM, respectively. Introduction of a methyl group
(3b) or a phenyl group (3c) at the para position slightly
improved inhibitory potency. Compound 3d with a hy-
droxymethyl group at the ortho position also exhibit
good inhibitor activity. Interestingly, compound 3c
(IC50 ¼ 50 lM) with a phenyl group at the para position
is three-times more potent than 3e (IC50 ¼ 180 lM)
where the phenyl group is at the meta position, sug-
gesting that the interaction from the para-substituted
phenyl group with the enzyme is more favorable.
Encouraged by these results, we then explored the
method to incorporate para-substituted phenyl a,a-di-
fluoro-b-ketophosphonate in small molecule scaffolds.

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X. Li et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4301–4306
O
O
O
CF2PO(OEt)2
CF2PO(OEt)2
OMe
c
a,b
Br
4
1b
2b
Scheme 2. Reagents and conditions: (a) HF2PO(OEt)2, LDA, CeCl3, THF, ꢀ78 °C; (b) HCl, H2O; (c) NBS/CCl4, benzoyl peroxide, reflux.
Accordingly, we developed a building block approach,
which utilized 4-bromomethyl diethyl benzoyl-
inhibitory activity, as more favorable interactions of the
molecule with the active site residues are possible.13
More importantly, both carboxamides and benzothiaz-
epinones represent potential drug scaffolds for the
development of potent PTP1B inhibitors. One can
imagine designing more potent analogues by introduc-
ing various substituents around these scaffolds that
achieve favorable interactions within the enzyme active
site.
difluorophosphonate
4
as
a
useful intermediate
(Scheme 2). The reaction of 4-methyl benzoyl methyl
ester 1b with lithium difluoromethylphosphonate under
the above conditions gave the corresponding phospho-
nate diester 2b. Diester 2b was allowed to reflux with
NBS in carbon tetrachloride in the presence of benzoyl
peroxide to produce the desired benzyl bromide 4 in 87%
yield.
The recent discovery that PTP1B has a second pTyr
binding site adjacent to the catalytic pocket has led to
the development of bifunctional pTyr analogues against
PTP1B.14a;b Based on our results with the new pTyr
mimetics and sulfonamide scaffold, we synthesized
several bis(aryl a,a-difluoro-b-ketophosphonates) 10
according to Scheme 4. The reaction of sulfonamides 9
with 2 equiv of compound 4 in the presence of K2CO3
gave the corresponding bifunctional phosphonate esters.
After TMSBr treatment and hydrolysis, bis-phosphonic
acids 10 were isolated by preparative HPLC.
With bromide 4 in hand, we explored the reaction with
several molecular scaffolds such as carboxyamide or
sulfonamide, since they are known to function as a good
hydrogen bond acceptor in many biological systems. As
shown in Scheme 3, the reaction of 4 with 1 equiv of N-
benzyl-2-nitro-benzenesulfonamide 5 at 70 °C in the
presence of K2CO3 gave the corresponding phosphonate
diester. After TMSBr treatment and hydrolysis, phos-
phonic acid 7 was isolated by preparative HPLC. Under
similar conditions, the reaction of 4 with 3-Cbz-amino-
2,3-dihydro-1,5-benzothiazepin-4(5H)-one 612 followed
by TMSBr treatment resulted in phosphonic acid 8.
These bis(aryl a,a-difluoro-b-ketophosphonates) are
very potent inhibitors of PTP1B with IC50 values in the
range of 0.5–1.3 lM, as shown in Table 1. They are
reversible and competitive inhibitors, and kinetic
experiments show no evidence of time-dependent inhi-
bition. The best compound from this class, 10d, has an
IC50 of 0.6 lM and a Ki of 0.17 lM. Compared to 3a or
3b, compounds 10 exhibit a significant increase in po-
tency by 2 orders of magnitude. Presumably introduc-
tion of the second a,a-difluoro-b-ketophosphonate
As shown in Table 1, sulfonamide 7 inhibited PTP1B in
a competitive manner with an IC50 of 12 lM and Ki of
12 lM, respectively. Compared to simple aryl derivative
3a or 3b, compound 7 exhibits 5–6-fold improvement in
potency. Compound 8 containing a benzothiazepinone
scaffold was also 7-fold more potent than 3b, inhibiting
PTP1B with an IC50 of 8.8 lM. These results suggest
that additional recognition elements can lead to better
O
O
NO2
NO2
CF2PO(OEt)2
O
O
CF2PO(OH)2
a,b
+
S
S
Br
N
NH
O
O
Ph
Ph
4
5
7
NHCbz
O
NH2
N
O
O
CF2PO(OEt)2
S
O
N
a,b
+
S
CF2PO(OH)2
Br
6
Scheme 3. Reagents and conditions: (a) K2CO3, ACN, 70 °C; (b) TMSBr, DCM, then H2O.
4
8

X. Li et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4301–4306
4305
O
CF2PO(OH)2
O
O
O
NH2
CF2PO(OEt)2
S
N
S
+
O
R
O
O
R
Br
CF2PO(OH)2
10a, R = 2-Et, 4-Br
10b, R = 2-OCF3, 4-Br
9
4
10c, R = 2-F, 5-F
10d, R = 2-Me
10e, R = 4-Me
Scheme 4. Reagents and conditions: (a) K2CO3, ACN, 70 °C; (b) TMSBr, DCM, then H2O.
group provides additional binding interactions with the
second phosphate-binding site or nearby region in
PTP1B. The results also demonstrate that aryl a,a-di-
fluoro-b-ketophosphonates are powerful pTyr mimetic
for developing potent PTP inhibitors based on small
molecule scaffolds.
phosphonate group to bind to the enzyme active site.
The other known examples of pTyr mimetics with the
same atom spacing as a,a-difluoro-b-ketophosphonates
are aryloxymethylphosphonates,16 which have been re-
ported as relatively weak inhibitors against PTP1B. It
will be of interest to replace the carbonyl group of a,a-
difluoro-b-ketophosphonate with other bioisosteric
atoms or functional groups and explore the spatial and
structural requirements that are important for high
affinity binding to the active site of PTP1B.
One of the most effective pTyr mimetics that have been
developed to date is a,a-difluoromethylphospho-
nates.5a–c Our compounds, a,a-difluoro-b-ketophospho-
nates, exhibit comparable or even better inhibitory
activity against PTP1B than a,a-difluoromethyl-
phosphonates. For example, the simple phenyl
difluoromethylphosphonate has been reported to inhibit
PTP1B with an IC50 of 610 lM5c and a Ki of 2500 lM,5b
while the corresponding 3a is more active (IC50 ¼ 76 lM,
Ki ¼ 129 lM). 4-Biphenyl difluorometh-ylphosphonate
has an IC50 of 210 lM,5c and the corresponding 3c has
better activity with an IC50 of 50 lM against PTP1B.
There results indicate that the carbonyl group adjacent
to the aromatic can form effective interactions with
the active site residues similar to the phosphate oxy-
gen in pTyr or the difluoromethyl group in dif-
luoromethylphosphonates. Since the carbonyl group in
these compounds is highly activated and electrophilic,
and they can easily form hydrates in aqueous solution, it
is also possible that the hydrated form can effectively
mimic the water molecule in the active site15 and there-
fore exhibit high binding ability to the enzyme. In
addition, there is a potential for these compounds to
react with the active site Cys or nitrogen nucleophiles of
PTP1B in a reversible co-valent fashion to form hemi-
thioketals or enamines. Further biochemical studies are
required to elucidate detailed mechanism of inhibition
of this class of inhibitors.
In conclusion, we have synthesized and evaluated a new
class of PTP1B inhibitors, a,a-difluoro-b-ketophospho-
nates. The approach described here represents an
example of utilizing these pTyr mimetics to identify
potent inhibitors based on small molecules scaffolds,
which provide lead structures for further design and
development of novel PTP1B inhibitors as potential
therapeutic agents. Further studies with this class of
compounds should gain additional mechanistic and
structural insights into molecular recognition in signal
transduction processes.
Acknowledgements
We thank the drug discovery and biochemistry groups
at Affymax (especially Dr. Russ Grove, Larry Jang,
Lihong Shi, and Siqun Zhou) for inhibition and kinetics
studies. We also thank Prof. Ron Kluger at the Uni-
versity of Toronto for helpful discussions during the
preparation of this manuscript.
References and notes
Compared to difluoromethylphosphonates, a,a-diflu-
oro-b-ketophosphonates have one extra atom spacing
between the aromatic and the phosphonate group. The
strong inhibitory activity of our compounds against
PTP1B suggests that the additional spacer derived from
the carbonyl group between the aromatic and phos-
phonate has no adverse effects on the ability of the
1. (a) For recent reviews see: Zhang, Z.-Y. Crit. Rev.
Biochem. Mol. Biol. 1998, 33, 1; (b) Evans, J. L.; Jallal,
B. Exp. Opin. Invest. Drugs 1999, 8, 139.
2. (a) Neel, B. G.; Tonks, N. K. Curr. Opin. Cell Biol. 1997,
9, 93; (b) Byon, J. C. H.; Kusari, A. B.; Kusari, J. Mol.
Cell. Biochem. 1998, 182, 101.

4306
X. Li et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4301–4306
3. Elchebly, M.; Payette, P.; Michaliszyn, E.; Cromlish, W.;
2002, 2640; (d) Blades, K.; Lequeux, T. P.; Percy, J. M.
Tetrahedron 1997, 53, 10623.
10. Salomon, C. J.; Breuer, E. Tetrahedron Lett. 1995, 36,
6759.
Collins, S.; Loy, A. L.; Normandin, D.; Cheng, A.;
Himms-Hagen, J.; Chan, C.-C.; Ramachandran, C.;
Gresser, M. J.; Tremblay, M. L.; Kennedy, B. P. Science
1999, 283, 1544.
11. The PTP1B assay was carried out at ambient temperature
using OMFP as a substrate in 62.5 mM MOPS buffer,
pH 7.0, containing 62.5 mM NaCl, 0.125 mg/mL BSA,
0.0125% Brij35, 1.25 mM EDTA and 1.25 mM DTT. The
reactions were initiated by the addition of enzyme and
quenched by the addition of stop solution (0.25 N NaOH).
Fluorescence emissions from the product o-methyl fluo-
rescein were measured using an appropriate plate reader
and converted to units of product formation. IC50 values
were calculated by nonlinear regression using the dose-
response equation in GraphPad Prism. For inhibitor
kinetics, best curve fit for Lineweaver–Burk plots and Ki
values was determined using the curve-fitting programs. 3-
Phenyl-a,a-difluorobenzylphosphonic acid (compd 12
from Ref. 5c) and a peptidic 2-carboxymethoxybenzoic
acid (compd VI from Ref. 15b) were routinely used as
reference compounds, which gave IC50 and Ki values that
were consistent with reported values. In some experiments,
PTP1B activity was also measured as the rate of hydrolysis
of p-nitrophenyl phosphate.
4. For recent reviews see: (a) Burke, T. R., Jr.; Yao, Z.-J.;
Liu, D.-G.; Voigt, J.; Gao, Y. Biopolymers 2001, 60, 32;
(b) Zhang, Z.-Y. Annu. Rev. Pharmacol. Toxicol. 2002, 42,
209; (c) Blaskovich, M. A.; Kim, H.-O. Exp. Opin. Ther.
Patents 2002, 12, 871; (d) Taylor, S. D. Curr. Top. Med.
Chem. 2003, 3, 759.
5. (a) Burke, T. R., Jr.; Kole, H. K.; Roller, P. P. Biochem.
Biophys. Res. Commun. 1994, 204, 129; (b) Yao, Z.-J.; Ye,
B.; Wu, X.-W.; Wang, S.; Wu, L.; Zhang, Z.-Y.; Burke, T.
R., Jr. Bioorg. Med. Chem. 1998, 6, 1799; (c) Taylor, S. D.;
Kotoris, C. C.; Dinaut, A. N.; Wang, Q.; Ramachandran,
C.; Huang, Z. Bioorg. Med. Chem. 1998, 6, 1457; (d)
Desmarais, S.; Jia, Z.; Ramachandran, C. Arch. Biochem.
Biophys. 1998, 354, 225; (e) 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; (f) Moran, E. J.; Sarshar, S.; Cargill, J. F.; Shahbaz,
M. M.; Lio, A.; Mjalli, A. M. M.; Armstrong, R. W. J.
Am. Chem. Soc. 1995, 117, 10787; (g) Malamas, M. S.;
Sredy, J.; Moxham, C.; Katz, A.; Xu, W.; McDevitt, R.;
Adebayo, F. O.; Sawicki, D. R.; Seestaller, L.; Sullivan,
D.; Taylor, J. R. J. Med. Chem. 2000, 43, 1293; (h) Larsen,
S. D.; Barf, T.; Liljebris, C.; May, P. D.; Ogg, D.;
O’Sullivan, T. J.; Palazuk, B. J.; Schostarez, H. J.; Stevens,
F. C.; Bleasdale, J. E. J. Med. Chem. 2002, 45, 598; (i)
Andersen, H. S.; Iversen, L. F.; Jeppesen, C. B.; Branner,
S.; Norris, K.; Rasmussen, H. B.; Moller, K. B. J. Biol.
Chem. 2000, 275, 7101; (j) Szczepankiewicz, B. G.; Liu, G.;
Hajduk, P. J.; Abad-Zapatero, C.; Pei, Z.; Xin, Z.;
Lubben, T. H.; Trevillyan, J. M.; Stashko, M. A.;
Ballaron, S. J.; Liang, H.; Huang, F.; Hutchins, C. W.;
Fesik, S. W.; Jirousek, M. R. J. Am. Chem. Soc. 2003, 125,
4087.
6. Kluger, R.; Nakaoka, K. Biochemistry 1974, 13, 910.
7. Greco, M. N.; Hawkins, M. J.; Powell, E. T.; Almond, H.
R., Jr.; Corcoran, T. W.; Garavilla, L. D.; Kauffman, J. A.;
Recacha, R.; Chattopadhyay, D.; Andrade-Gordon, P.;
Maryanoff, B. E. J. Am. Chem. Soc. 2002, 124, 3810.
8. Ladame, S.; Bardet, M.; Perie, J.; Willson, M. Bioorg.
Med. Chem. 2001, 9, 773.
9. (a) Obayashi, M.; Ito, E.; Matsui, K.; Kondo, K.
Tetrahedron Lett. 1982, 23, 2323; (b) Burton, D. J.;
Ishihara, T.; Maruta, M. Chem. Lett. 1982, 755; (c)
Ladame, S.; Willson, M.; Perie, J. Eur. J. Org. Chem.
12. See, for example: Schwarz, M. K.; Tumelty, D.; Gallop,
M. A. J. Org. Chem. 1999, 64, 2219.
13. From a different class of compounds, we found that a,a-
difluoro-b-ketophosphonates based on tetrahydro-b-carbo-
line scaffold showed poorer activity against PTP1B
compared to 3b, presumably due to unfavorable interac-
tions of the scaffold with the enzyme.
14. (a) Puius, Y. A.; Zhao, Y.; Sullivan, M.; Lawrence, D. S.;
Almo, S. C.; Zhang, Z.-Y. Proc. Natl. Acad. Sci. U.S.A.
1997, 94, 13420; (b) Jia, Z.; Ye, Q.; Dinaut, A. N.; Wang,
Q.; Waddleton, D.; Payette, P.; Ramachandran, C.;
Kennedy, B.; Hum, G.; Taylor, S. D. J. Med. Chem.
2001, 44, 4584.
15. For the active site water molecule in X-ray structures see:
(a) Burke, T. R., Jr.; Ye, B.; Yan, X. J.; Wang, S. M.; Jia,
Z. C.; Chen, L.; Zhang, Z. Y.; Barford, D. Biochemistry
1996, 35, 15989; (b) Bleasdale, J. E.; Ogg, D.; Palazuk, B.
J.; Jacob, C. S.; Swanson, M. L.; Wang, X. Y.; Thompson,
D. P.; Conradi, R. A.; Mathews, W. R.; Laborde, A. L.;
Stuchly, C. W.; Heijbel, A.; Bergdahl, K.; Bannow, C. A.;
Smith, C. W.; Svensson, C.; Liljebris, C.; Schostarez, H. J.;
May, P. D.; Stevens, F. C.; Larsen, S. D. Biochemistry
2001, 40, 5642.
16. Ibrahimi, O. A.; Wu, L.; Zhao, K.; Zhang, Z.-Y. Bioorg.
Med. Chem. Lett. 2000, 10, 457.