Design and synthesis of nonpeptidic, small molecule inhibitors for the Mycobacterium tuberculosis protein tyrosine phosphatase PtpB

Article abstract of DOI:10.1039/c0ob00182a

The design and synthesis of new inhibitor analogues for the Mycobacterium tuberculosis (Mtb) phosphatase PtpB is described. Analogues were synthesized by incorporation of two common and effective phosphate mimetics, the isothiazolidinone (IZD) and the difluoromethylphosphonic acid (DFMP). The basic scaffold of the inhibitor was identified from structure-activity relationships established for a previously published isoxazole inhibitor, while the phosphate mimetics were chosen based on their proven cell permeability and activity when incorporated into previously reported inhibitors for the phosphatase PTP1B. The inhibitory activity of each compound was evaluated, and each was found to have low or submicromolar affinity for PtpB.

Full text of DOI:10.1039/c0ob00182a

View Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/obc | Organic & Biomolecular Chemistry
Design and synthesis of nonpeptidic, small molecule inhibitors for the
Mycobacterium tuberculosis protein tyrosine phosphatase PtpB†‡
Katherine A. Rawls,a Christoph Grundnerb and Jonathan A. Ellman*c
Received 28th May 2010, Accepted 1st July 2010
First published as an Advance Article on the web 19th July 2010
DOI: 10.1039/c0ob00182a
The design and synthesis of new inhibitor analogues for
the Mycobacterium tuberculosis (Mtb) phosphatase PtpB is
described. Analogues were synthesized by incorporation of
two common and effective phosphate mimetics, the isoth-
iazolidinone (IZD) and the difluoromethylphosphonic acid
(DFMP). The basic scaffold of the inhibitor was identified
from structure–activity relationships established for a pre-
viously published isoxazole inhibitor, while the phosphate
mimetics were chosen based on their proven cell permeability
and activity when incorporated into previously reported
inhibitors for the phosphatase PTP1B. The inhibitory activity
of each compound was evaluated, and each was found to have
low or submicromolar affinity for PtpB.
Fig. 1 Previously reported isoxazole PtpB inhibitor 1.
Tuberculosis (TB) is a chronic, infectious disease caused by
Mycobacterium tuberculosis (Mtb). Each year, nearly 2 million
deaths occur out of over 13 million active cases of TB,1 and current
treatment of drug-sensitive strains requires 6–9 months to fully
eradicate the infection. New Mtb drugs that act on novel targets
are needed to shorten treatment time and address the emergence of
antibiotic resistance. Mtb PtpB is a secreted virulence factor that
functions within human macrophages, and chemical interference
with PtpB function has been shown to reduce bacterial loads
in an Mtb macrophage infection model.2 PtpB is attractive as
a therapeutic target due to its localization outside of the unusually
thick mycobacterial cell wall, which is difficult to penetrate and
leads to long treatment times for tuberculosis (TB).
We previously reported the development of isoxazole carboxylic
acid inhibitor 1 for PtpB, using the substrate activity screening
(SAS) method, a novel fragment-based approach for the identi-
fication of phosphatase inhibitors (Fig. 1).3 Development of the
isoxazole inhibitor revealed that ortho substituents are preferred
for optimal PtpB binding, with the cyclohexyl group providing the
most favorable enzyme interactions. In order to compare binding
affinity and cell activity, we desired a route to analogous inhibitors
incorporating other commonly used phosphate mimetics.
A variety of phosphate isosteres have been reported and could
be introduced in place of the isoxazole,4 but many contain at
least two acidic sites and lead to inhibitors with poor cellular
permeability.5 We therefore chose two phosphate mimetics that
have been effectively used in inhibitors of PTP1B, a human
phosphatase targeted for diabetes treatment, with good cell
permeability and activity, namely the isothiazolidinone (IZD)
and difluoromethylphosphonic acid (DFMP) mimetics (Fig. 2).
The monoanionic IZD6 phosphate mimetic was developed by
Incyte through structure-based design,6g while the DFMP phar-
macophore is a commonly used phosphate mimetic that has been
investigated extensively in the literature.7 Despite being dianionic,
the DFMP isostere has recently been shown by Merck to be cell
permeable and orally bioavailable in animals when incorporated
into nonpeptidic inhibitors of PTP1B.8
aDepartment of Chemistry, University of California, Berkeley, California,
94720-1460, USA; Fax: +1 510.642.8369; Tel: +1 510.642.4488
bSeattle Biomedical Research Institute, Seattle, WA 98109-5219, and De-
partment of Global Health, University of Washington, Seattle, WA, 98195-
7660, USA. E-mail: christoph.grundner@sbri.org; Fax: +1 206.256.7229;
Tel: +1 206.256.7295
cDepartment of Chemistry, Yale University, New Haven, Connecticut, 06520-
8107, USA. E-mail: jonathan.ellman@yale.edu; Tel: +1 203.432.3647
† This paper is part of an Organic & Biomolecular Chemistry web theme
issue on chemical biology.
‡ Electronic supplementary information (ESI) available: Experimental
procedures, analytical data, and NMR spectra for all novel compounds;
procedure for enzyme assays. See DOI: 10.1039/c0ob00182a
Fig. 2 New PtpB inhibitor analogues incorporating the IZD and DFMP
phosphate mimetics.
Several syntheses have been reported for the IZD isostere.6a,6c–e
However, due to considerable steric interactions introduced by the
cyclohexyl group ortho to the IZD isostere in 2, implementation of
4066 | Org. Biomol. Chem., 2010, 8, 4066–4070
This journal is
The Royal Society of Chemistry 2010
©

View Online
Scheme 1 Synthesis of IZD inhibitor 2. Reagents and conditions: (a) Pd(OAc)2, KF, CyJohnPhos, THF, 50 ◦C; (b) Tf2O, Et3N, CH2Cl2, -78 ◦C; (c)
Pd2(dba)3·CHCl3, K3PO4, SPhos, B2pin2, toluene, 100 ◦C; (d) Pd(OAc)2, K3PO4, SPhos, cat. H2O, THF, 60 ◦C; (e) NaBH4, MeOH, 0 ◦C; (f) m-CPBA,
CH2Cl2, 0 ◦C to rt; (g) d-TFA, H2O, 80 ◦C.
successful cross-coupling methods for installing the isostere posed
a significant challenge (Scheme 1).
a successful cross-coupling the reaction parameters required
careful optimization, including choice of precatalyst, additive,
and reaction temperature. The cross-coupling conditions used
to prepare boronic ester 8 also afforded product 10, but in low
yield (15%), likely due to competitive formation of ring opened
byproducts from either heterocycle 9 or product 10, as determined
by NMR analysis (entry 1). We observed similar decomposition
byproducts when using an amination precatalyst developed by
Hartwig (entries 2–3), which was designed to increase the rate
of oxidative addition, a step that is often rate-limiting in the
Suzuki catalytic cycle.11 Ultimately, we found that use of Pd(OAc)2
as the precatalyst with inclusion of water enabled formation of
product at reduced temperatures, which minimized the formation
of undesired ring-opened byproducts (entry 4). Increasing the
amount of water and the reaction time ultimately gave the coupled
product in 69% yield (entry 5). Compound 10 was then reduced
with sodium borohydride, followed by oxidation to sulfone 12
with m-CPBA. Final TFA deprotection then gave the desired IZD
inhibitor 2 in racemic form (Scheme 1).
First, o-cyclohexyl phenol 4 was subjected to Suzuki coupling
with 4-fluoro-3-trifluoromethyl boronic acid 5 to afford the
biaryl phenol 6. Treatment with triflic anhydride under basic
conditions then afforded triflate 7, which was then coupled with
bis(pinacolato)diboron to provide boronic ester 8.9 This coupling
step required significant optimization due to the presence of the
sterically encumbered ortho cyclohexyl group, which has not been
previously reported as a partner in Suzuki couplings (Table 1).
To determine optimal conditions for boration of hindered triflate
7, we screened conditions using the biphenyl model substrate
13. Standard conditions for coupling with bis(pinacolato)diboron
failed to produce product (entry 1), as did standard Buchwald
conditions using cyclohexyl JohnPhos as the ligand (entry 2).
Similarly, all attempts to couple with pinacol borane gave no
reaction (entries 3–4). Finally, inclusion of the Buchwald ligand
SPhos9,10 afforded product, albeit in low yield (entry 5). Increasing
the temperature to 130 ◦C decreased the yield, likely due to
protodeborylation of the product (entry 6), but switching to the
precatalyst Pd2(dba)3 in addition to reversed-phase purification
of the somewhat unstable boronic ester improved the yield
significantly to 66% (entry 7). Upon applying the same conditions
to the desired triflate 7, the pinacol ester 8 was obtained in 69%
yield (Scheme 1).
Based on previous studies of IZD inhibitors for PTP1B,6a,6c–g
we reasoned that Mtb PtpB should bind one IZD enantiomer
preferentially, and we therefore prepared the two enantiomers
17 and 18 by subjecting compound 12 to chiral preparatory
chromatography (Scheme 2),12 followed by the same TFA treat-
ment described above to remove the tert-butyl protecting group
from compounds 15 and 16. Compounds 15 and 16 were
found to have >99% ee and >99% purity after separation and
isolation.
Upon developing conditions to successfully prepare the hin-
dered boronic ester 8, it was then necessary to carry out Suzuki
cross-coupling with heterocycle 9. As shown in Table 2, to achieve
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 4066–4070 | 4067
©

View Online
Table 1 Coupling of model biphenyl triflate 13 to afford model biphenyl boronic ester 14
Entry
R
[Pd] cat.
Ligand
Base
Solvent
T/◦C
Time/h
%Yielda
1
2
3
4
5
6
7
Bpin
Bpin
H
Pd(dppf)Cl2
Pd(OAc)2
Pd(PPh3)4
Pd(dppf)Cl2
Pd(OAc)2
Pd(OAc)2
—
KOAc
KF
Et3N
dioxane
toluene
dioxane
dioxane
toluene
toluene
toluene
80
100
80
26
17
4
27
15
16
17
0
0
0
CyJohnPhos
—
—
SPhos
SPhos
SPhos
H
Et3N
70
0
Bpin
Bpin
Bpin
K3PO4
K3PO4
K3PO4
100
130
110
28
14
66
Pd2(dba)3·CHCl3
a Yield was determined by mass balance after silica gel column chromatography.
Table 2 Coupling of biphenyl boronic ester 8 and heterocycle 9 to afford coupled product 10
Entry
[Pd] cat.
Solvent
T/◦C
Time/h
%Yielda
1
2
3
4
5
Pd2(dba)3·CHCl3
Pd[P(o-tol)3]2
Pd[P(o-tol)3]2
Pd(OAc)2
toluene
toluene
toluene
THF, 1 mol% H2O
THF, 10 mol% H2O
100
60
100
60
20
20
23
20
24
15
15
28
54
69
Pd(OAc)2
60
a Yield was determined by mass balance after silica gel column chromatography.
Scheme 2 Isolation of enantiomerically pure IZD inhibitors 17 and 18.
4068 | Org. Biomol. Chem., 2010, 8, 4066–4070
This journal is
The Royal Society of Chemistry 2010
©

View Online
Table 3 Assay of isoxazole inhibitor 1, IZD inhibitors 2, 17 and 18, and
DFMP inhibitor 3 versus PtpB
To complete the PtpB inhibitor panel and provide further
comparison of phosphate mimetics in terms of PtpB binding
affinity, we also developed a route to DFMP analogue 3. Several
synthetic approaches have been reported for installation of the
DFMP isostere and could be used in the synthesis of the DFMP
compound.13 We chose a relatively mild and straightforward cross
coupling approach between aryl iodide 20 and a commercially
available diethyl phosphonate,13c because this strategy is compat-
ible with a variety of functional groups and enables late stage
incorporation of the DFMP warhead (Scheme 3).
#
R
Ki/mMa
1
1.3 0.6b
2
3.7 0.6
17
18
3
2.4 0.0 or 8.0 0.4
2.4 0.0 or 8.0 0.4
0.69 0.21
Scheme
3
Synthesis of DFMP inhibitor 3. Reagents and condi-
tions: (a) bis(neoglycolato)diboron, K3PO4, SPhos, Pd2(dba)3·CHCl3,
toluene, 100 ◦C; (b) NaI, chloramine-T, 50% aq THF; (c) di-
ethyl(bromodifluoromethyl)phosphonate, Zn0, CuBr, DMA; (d) TMSI,
CHCl3.
a Compounds were assayed in duplicate and repeated in triplicate. b Assays
were run with a new batch of enzyme as compared to previous reports and
reproducibly gave a modestly higher Ki value.
Synthesis of DFMP analogue
3 began by coupling
bis(neoglycolato)diboron with triflate intermediate 7 used in
the synthesis of the IZD inhibitor (Scheme 3). This was fol-
lowed by iodination with in situ-generated ICl to form the aryl
iodide 20, then copper and zinc-mediated coupling with di-
ethyl(bromodifluoromethyl)phosphonate to afford the aryl phos-
phonate 21. Final deprotection then afforded the desired DFMP
inhibitor 3.
such as cell permeability, protein binding, oral bioavailability, and
clearance rates.
In conclusion, two new, nonpeptidic inhibitor analogues for
Mtb PtpB have been identified. Each of these compounds is
based on the optimal scaffold previously identified using the
SAS method,3 a novel fragment-based approach for phosphatase
inhibitor development. Inhibitors 2 and 3 incorporate the IZD
and DFMP phosphate mimetics, respectively, in place of the
isoxazole carboxylic acid warhead developed for compound 1.
These mimetics were chosen based on previous incorporation
into inhibitors of the phosphatase PTP1B, an enzyme targeted
for diabetes treatment. The IZD and DFMP analogues show
comparable inhibitory activity to isoxazole inhibitor 1 in terms
of binding affinity, and they are expected to vary in terms of cell
permeability and activity. The entire panel of inhibitor analogues is
therefore currently being evaluated in TB-infected cells and future
work will include evaluation in animal infection models.
Following isolation, each compound was assayed versus Mtb
PtpB (Table 3). To rule out non-specific aggregation-based enzyme
inhibition,14 the detergent Triton X-100 was included in all assays,
and Hill slopes were measured and found to be close to -1.0 for
all compounds (see ESI). Racemic IZD inhibitor 2 was found to
have a Ki of 3.7 mM versus PtpB, which is only modestly weaker
than isoxazole scaffold 1, while the enantiomerically pure IZD
compounds 17 and 18 were found to have Ki values of 2.4 and 8.0
mM, respectively.15 The chiral discrimination found for these IZD
enantiomers is more modest than for IZD inhibitors of PTP1B.6e,6g
DFMP compound 3 was found to have a Ki of 0.69 mM versus
PtpB, and represents the most potent inhibitor in the series.16
The results of this study demonstrate that the isoxazole,
IZD, and DFMP pharmacophores can each be incorporated
into effective inhibitors of Mtb PtpB. These inhibitors represent
a useful set of tool compounds for further dissection of the
biochemical role of PtpB in TB infection, because inhibitors are
expected to have different physicochemical properties, which will
impact important factors that contribute to compound efficacy
Acknowledgements
J.A.E. acknowledges the support of the NIH (GM054051). K.A.R.
was supported by an ACS Division of Medicinal Chemistry
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 4066–4070 | 4069
©

View Online
Pre-doctoral fellowship, sponsored by Eli Lilly. C.G. acknowledges
the support of the Paul G. Allen Family Foundation (grant 8999).
M. Hillman, L. Gonneville, B. G. Reid, M. Wei, M. Becker-Pasha, R.
Klabe, R. Huber, Y. Li, G. Hollis, T. C. Burn, R. Wynn, P. Liu and B.
Metcalf, J. Med. Chem., 2005, 48, 6544–6548.
7 (a) J.-P. Sun, A. A. Fedorov, S.-Y. Lee, X.-L. Guo, K. Shen, D. S.
Lawrence, S. C. Almo and Z.-Y. Zhang, J. Biol. Chem., 2003, 278,
12406–12414; (b) K. Shen, Y.-F. Keng, L. Wu, X.-L. Guo, D. S.
Lawrence and Z.-Y. Zhang, J. Biol. Chem., 2001, 276, 47311–47319;
(c) M. Sarmiento, L. Wu, Y.-F. Keng, L. Song, Z. Luo, Z. Huang, G.-
Z. Wu, A. K. Yuan and Z.-Y. Zhang, J. Med. Chem., 2000, 43, 146–155;
(d) M. Taing, Y.-F. Keng, K. Shen, L. Wu, D. S. Lawrence and Z.-Y.
Zhang, Biochemistry, 1999, 38, 3793–3803; (e) Z.-J. Yao, B. Ye, X.-W.
Wu, S. Wang, L. Wu, Z.-Y. Zhang and T. R. Burke, Jr., Bioorg. Med.
Chem., 1998, 6, 1799–1810; (f) Y. A. Puius, Y. Zhao, M. Sullivan, D. S.
Lawrence, S. C. Almo and Z.-Y. Zhang, Proc. Natl. Acad. Sci. U. S. A.,
1997, 94, 13420–13425.
8 Y. Han, M. Belley, C. I. Bayly, J. Colucci, C. Dufresne, A. Giroux, C. K.
Lau, Y. Leblanc, D. McKay, M. Therien, M.-C. Wilson, K. Skorey, C.-
C. Chan, G. Scapin and B. P. Kennedy, Bioorg. Med. Chem. Lett., 2008,
18, 3200–3205.
9 K. Billingsley and S. L. Buchwald, J. Am. Chem. Soc., 2007, 129, 3358–
3366.
Notes and references
1 World Health Organization, Global Tuberculosis Report 2009:
http://www.who.int/tb/publications/global_report/2009/pdf/full_
report.pdf.
2 (a) B. Zhou, Y. He, X. Zhang, J. Xu, Y. Luo, Y. Wang, S. Franzblau, Z.
Yang, R. Chan and Y. Liu, Proc. Natl. Acad. Sci. U. S. A., 2010; (b) N.
Beresford, S. Patel, J. Armstrong, B. Szoor, A. P. Fordham-Skelton and
L. Tabernero, Biochem. J., 2007, 406, 13–18; (c) C. Grundner, H.-L. Ng
and T. Alber, Structure, 2005, 13, 1625–1634; (d) R. Singh, V. Rao, H.
Shakila, R. Gupta, A. Khera, N. Dhar, A. Singh, A. Koul, Y. Singh, M.
Naseema, P. R. Narayanan, C. N. Paramasivan, V. D. Ramanathan and
A. K. Tyagi, Mol. Microbiol., 2003, 50, 751–762; (e) N. J. Beresford, D.
Mulhearn, B. Szczepankiewicz, G. Liu, M. E. Johnson, A. Fordham-
Skelton, C. Abad-Zapatero, J. S. Cavet and L. Tabernero, J. Antimicrob.
Chemother., 2009, 63, 928–36.
3 M. B. Soellner, K. A. Rawls, C. Grundner, T. Alber and J. A. Ellman,
J. Am. Chem. Soc., 2007, 129, 9613–9615.
10 (a) T. E. Barder, S. D. Walker, J. R. Martinelli and S. L. Buchwald,
J. Am. Chem. Soc., 2005, 127, 4685–4696; (b) T. E. Barder and S. L.
Buchwald, Org. Lett., 2004, 6, 2649–2652.
11 T. Ogata and J. F. Hartwig, J. Am. Chem. Soc., 2008, 130, 13848–9.
12 Chiral separation was performed by Lotus Separations, LLC, Wash-
ington Road, Frick Lab, Room 201, Princeton, NJ 08544-0000:
http://www.lotussep.com/.
4 (a) C. S. Rye and J. B. Baell, Curr. Med. Chem., 2005, 12, 3127–3141;
(b) Z.-Y. Zhang, Annu. Rev. Pharmacol. Toxicol., 2002, 42, 209–234;
(c) C. C. Kotoris, M.-J. Chen and S. D. Taylor, Bioorg. Med. Chem.
Lett., 1998, 8, 3275–3280.
5 X. Hu, Bioorg. Med. Chem. Lett., 2006, 16, 6321–6327.
6 (a) R. B. Sparks, P. Polam, W. Zhu, M. L. Crawley, A. Takvorian, E.
McLaughlin, M. Wei, P. J. Ala, L. Gonneville, N. Taylor, Y. Li, R.
Wynn, T. C. Burn, P. C. C. Liu and A. P. Combs, Bioorg. Med. Chem.
Lett., 2007, 17, 736–740; (b) P. Combs Andrew, B. Glass, G. Galya
Laurine and M. Li, Org. Lett., 2007, 9, 1279–82; (c) E. W. Yue, B.
Wayland, B. Douty, M. L. Crawley, E. McLaughlin, A. Takvorian, Z.
Wasserman, M. J. Bower, M. Wei, Y. Li, P. J. Ala, L. Gonneville, R.
Wynn, T. C. Burn, P. C. C. Liu and A. P. Combs, Bioorg. Med. Chem.,
2006, 14, 5833–5849; (d) A. P. Combs, W. Zhu, M. L. Crawley, B. Glass,
P. Polam, R. B. Sparks, D. Modi, A. Takvorian, E. McLaughlin, E. W.
Yue, Z. Wasserman, M. Bower, M. Wei, M. Rupar, P. J. Ala, B. M. Reid,
D. Ellis, L. Gonneville, T. Emm, N. Taylor, S. Yeleswaram, Y. Li, R.
Wynn, T. C. Burn, G. Hollis, P. C. C. Liu and B. Metcalf, J. Med. Chem.,
2006, 49, 3774–3789; (e) P. J. Ala, L. Gonneville, M. C. Hillman, M.
Becker-Pasha, M. Wei, B. G. Reid, R. Klabe, E. W. Yue, B. Wayland, B.
Douty, P. Polam, Z. Wasserman, M. Bower, A. P. Combs, T. C. Burn,
G. F. Hollis and R. Wynn, J. Biol. Chem., 2006, 281, 32784–32795;
(f) P. J. Ala, L. Gonneville, M. Hillman, M. Becker-Pasha, E. W. Yue,
B. Douty, B. Wayland, P. Polam, M. L. Crawley, E. McLaughlin, R. B.
Sparks, B. Glass, A. Takvorian, A. P. Combs, T. C. Burn, G. F. Hollis
and R. Wynn, J. Biol. Chem., 2006, 281, 38013–38021; (g) A. P. Combs,
E. W. Yue, M. Bower, P. J. Ala, B. Wayland, B. Douty, A. Takvorian, P.
Polam, Z. Wasserman, W. Zhu, M. L. Crawley, J. Pruitt, R. Sparks, B.
Glass, D. Modi, E. McLaughlin, L. Bostrom, M. Li, L. Galya, K. Blom,
13 (a) M. Hussain, V. Ahmed, B. Hill, Z. Ahmed and S. Taylor, Bioorg.
Med. Chem., 2008, 16, 6764–6777; (b) O. A. Ibrahimi, L. Wu, K. Zhao
and Z.-Y. Zhang, Bioorg. Med. Chem. Lett., 2000, 10, 457–460; (c) T.
Yokomatsu, T. Murano, K. Suemune and S. Shibuya, Tetrahedron,
1997, 53, 815–822; (d) D. Solas, R. Hale and D. Patel, J. Org. Chem.,
1996, 61, 1537–1539.
14 (a) K. Coan, D. Maltby, A. Burlingame and B. Shoichet, J. Med. Chem.,
2009, 52, 2067–2075; (b) B. Shoichet, Drug Discovery Today, 2006, 11,
607–615; (c) J. Seidler, S. McGovern, T. Doman and B. Shoichet, J. Med.
Chem., 2003, 46, 4477–4486; (d) S. McGovern, B. Helfand, B. Feng and
B. Shoichet, J. Med. Chem., 2003, 46, 4265–4272.
15 Note that the absolute configuration of each compound has not
been established; repeated attempts at crystallization failed to produce
crystals sufficient for X-ray analysis, likely due to the inability of these
compounds to pack with the necessary co-solvents.
16 For examples of other previously reported PtpB inhibitors, see: (a) L.
Tan, H. Wu, P. Yang, K. Kalesh, X. Zhang, M. Hu, R. Srinivasan
and S. Yao, Org. Lett., 2009, 11, 5102–5105; (b) A. Noeren-Mueller,
W. Wilk, K. Saxena, H. Schwalbe, M. Kaiser and H. Waldmann,
Angew. Chem., Int. Ed. Engl., 2008, 47, 5973–5977; (c) I. R. Correa,
Jr., A. Noeren-Mueller, H.-D. Ambrosi, S. Jakupovic, K. Saxena, H.
Schwalbe, M. Kaiser and H. Waldmann, Chem.–Asian J., 2007, 2, 1109–
1126.
4070 | Org. Biomol. Chem., 2010, 8, 4066–4070
This journal is
The Royal Society of Chemistry 2010
©