Synthesis and evaluation of iminocoumaryl and coumaryl derivatized glycosides as galectin antagonists

Article abstract of DOI:10.1016/j.bmcl.2014.05.063

A collection of iminocoumarylmethyl glycoside derivatives have been prepared by copper-catalyzed multi-component reaction of carbohydrate propargyl derivatives, sulfonyl azides, and salicylaldehyde or o-hydroxy acetophenone. The method is simple, versatile to all three components, and exceptionally high yielding. The carbohydrate N-sulfonyl iminocoumarine hybrid molecules were evaluated for binding galectin-1, -2, -3, -4 N, -4C, -7, -8 N, -9 N, and 9C using a competitive fluorescence polarization assay. Selective compounds were identified against galectin-3, 7, 8 N, and 9 N with up to 40-fold affinity enhancements relative to methyl α-d-galactopyranoside due to the coumarylmethyl moieties.

Full text of DOI:10.1016/j.bmcl.2014.05.063

Accepted Manuscript
Synthesis and evaluation of iminocoumaryl and coumarylderivatized glycosides
as galectin antagonists
Vishal Kumar Rajput, Hakon Leffler, Ulf J. Nilsson, Balaram Mukhopadhyay
PII:
S0960-894X(14)00563-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2014.05.063
BMCL 21677
Reference:
Bioorganic & Medicinal Chemistry Letters
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Accepted Date:
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3 May 2014
16 May 2014
Please cite this article as: Rajput, V.K., Leffler, H., Nilsson, U.J., Mukhopadhyay, B., Synthesis and evaluation of
iminocoumaryl and coumarylderivatized glycosides as galectin antagonists, Bioorganic & Medicinal Chemistry
Letters (2014), doi: http://dx.doi.org/10.1016/j.bmcl.2014.05.063
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Synthesis and evaluation of iminocoumaryl
and coumarylderivatized glycosides as
galectin antagonists
Vishal Kumar Rajput, Hakon Leffler, Ulf J. Nilsson, Balaram Mukhopadhyay∗

Bioorganic & Medicinal Chemistry Letters
jou rn al h om ep a ge : www .e ls e v ie r .c om
Synthesis and evaluation of iminocoumaryl and coumarylderivatized glycosides
as galectin antagonists
Vishal Kumar Rajputa,b, Hakon Lefflerc, Ulf J. Nilssona and Balaram Mukhopadhyayb∗
aCentre for Analysis and Synthesis, Department of Chemistry, Lund University, POB 124, SE-221 00 Lund, Sweden; bIndian Institute of Science Education and
ResearchKolkata, Mohanpur, Nadia 741252, India; cSection MIG, Department of Laboratory Medicine, Lund University, Sölvegatan 23, SE-223 62 Lund,
Sweden
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A collection of iminocoumarylmethyl glycoside derivatives have been prepared by copper-
catalyzed multi-component reaction of carbohydrate propargyl derivatives, sulfonyl azides, and
salicylaldehyde or o-hydroxy acetophenone. The method is simple, versatile to all three
components, and exceptionally high yielding. The carbohydrate N-sulfonyl iminocoumarine
hybrid molecules were evaluated for binding galectin-1, -2, -3, -4N, -4C, -7, -8N, -9N, and 9C
using a competitive fluorescence polarisation assay. Selective compounds were identified
against galectin-3, 7, 8N, and 9N with up to 40-fold affinity enhancements relative to methyl α-
Keywords:
D-galactopyranoside due to the coumarylmethyl moieties.
iminocoumarine
coumarine
2009 Elsevier Ltd. All rights reserved
.
galectin
antagonist
multicomponent reaction
———
∗ Corresponding author. Tel.: +91 9748 261742; fax: +91 33 2334 8092; e-mail: sugarnet73@hotmail.com

Coumarines, widely abundant in nature, are versatile in
applications as medicine, fluorescent indicators, dyes in laser
technology and perfumery.1-4 Many of them posses medicinally
relevant character including antifungal, anticancer and anti-HIV
activities.5-6Among the coumarin derivatives, iminocoumarins are
reported to be potential protein tyrosine kinase (PTK) inhibitors7
and therefore attractive compoundsfor the treatment of diseases
involving excess cell proliferation and antitumor processes.
Considering the plethora of biological functions associated with
carbohydrates, it is a reasonable postulation that carbohydrate-
heterocycle hybrids can provide target-specific drug candidates.
In continuation to our recent research involving carbohydrate-
heterocycle hybrids,8 here we report an application of a facile
multicomponent protocol for the synthesis of glycosylated
iminocoumarins and coumarines. As an example of biomedical
use we tested the compounds as antagonists of galectins. The
galectins are a sub-class of lectins defined by having specific
affinity for β-galactosides having a wide variety of biologically
important functions including induction of apoptosis for T-cells,
anti-apoptotic and pro-inflammatory functions, modulation of
cell adhesion and migration.9-11 Hence, there is a clear demand of
molecules that would antagonize galectin activity and, therefore,
enable evaluation of galectin functions in more detail and lead to
the development of galectin blocking drugs.12-15
carbohydrate derivatives of various carbohydrates as the terminal
alkyne source for the synthesis of glycosylated N-
sulfonyliminocoumarins and coumarines as potential galectin
antagonists.
Initially, the scope and limitations of the method were
investigated with per-acetylated propargyl glucoside (1a), p-
toluenesulfonylazide (2a) and salicylaldehyde (3a), which were
subjected to the copper-catalyzed multi-component reaction
(Scheme 1). To optimize the reaction conditions, various bases,
solvents and copper catalysts (CuI or CuCl) were used (Table 1).
The best result (92% isolated yield) was obtained when the
reaction was carried out in THF in the presence of triethylamine
as base and CuI as catalyst at ambient temperature for 12h (Table
1, entry 3). Changing the solvent to CH2Cl2 or CH3CN resulted in
loss of yield and formation of inseparable by-products (Table 1,
entry 1 and 2). Use of other bases, such as pyridine (Table 1,
entry 5) or K2CO3 (Table 1, entry 6), also proved to be
detrimental to yields and purity. CuCl as catalyst failed to deliver
the desired product in good yield (Table 1, entry 4). Elevation of
the reaction temperature to 50 °C and shortening the reaction
time to 6h (Table 1, entry 7) led to a significant decrease in yield
(56%) of the desired product.
Table 1. Optimization of copper-catalyzed multi-component
reaction conditionsa of acetylated propargyl glucoside1a, p-
toluenesulfonylazide2a and salicylaldehyde3a.
Entry Base
Solvent Catalyst Time Yieldb
1
2
3
4
5
6
7
Et3N
Et3N
Et3N
Et3N
CH2Cl2
CuI
12h
12h
12h
12h
12h
12h
6hc
71%
44%
92%
≈20%
62%
38%
56%
CH3CN CuI
THF
THF
CuI
CuCl
CuI
CuI
CuI
Pyridine THF
K2CO3
Et3N
CH2Cl2
THF
aAlkyne (1 mmol), sulfonylazide (1 mmol), salicylaldehyde (1.1
mmol), base (2 mmol) and Cu-catalyst (0.1 mmol) in THF (10
b
c
mL) at RT. Isolated yield on the basis of the alkyne. Reaction
was performed at 50 °C.
Having the optimized conditions in hand, we next focused our
attention to investigate the generality of the reaction for different
carbohydrate alkynes. Thus, a series of propargyl glycosides (1a-
1g)25 including 6-deoxy, 2-deoxy-2-acetamido and disaccharide
were examined and to our satisfaction, excellent yield of the
corresponding iminocoumarin derivative was obtained in each
case (Scheme 2, Table 2). Propargyl ethers (1h) of carbohydrates
attached to positions other than anomeric also gave similar
results. In addition to p-toluenesulfonylazide (Table 2, entry 8),
the reaction is equally effective with other sulfonylazides
(Table2, entry 9, 11-12, and 14). Replacement of salicylaldehyde
to o-hydroxyacetophenone merely affects the outcome of the
reaction (Table 2, entries 13-14). Hence, the reaction is general
with respect to choice of all three substrates.
Scheme 1. Copper-catalyzed multi-component reaction of acetylated
propargyl glucoside 1a, p-toluenesulfonylazide 2a and salicylaldehyde 3a
Literature methods for the synthesis of coumarins such as
Knoevenagel reaction and derivation of coumarins are often
troublesome and limited for a narrow range of substituents.16
Therefore, a practical synthesis of glycosylated iminocoumarins
will be timely and useful. Recent development of
multicomponent reactions (MCR) generated some excellent
routes towards the synthesis of complex molecules by forming
more than one covalent bonds in a single pot reaction.17 In
parallel to the extensive use of copper-catalysed Huisgen
cycloaddition reaction between alkyl/aryl azides and terminal
alkynes,18-19sulfonylazides are found to react in a different
fashion in similar conditions. By exploiting this difference in
reactivity, various MCR approaches have been reported in the
literature to form highly substituted and complex molecules.20-
21Recently, Wang et al22 reported an efficient route towards
formation of substituted iminocoumarines via copper-catalyzed
multi-component domino reaction with terminal alkyne,
sulfonylazide and salicylaldehyde or o-hydroxyacetophenone,
which recently was applied on propargyl glycosides.23-24 Taking
the cue from their observations, we opted for propargylated
In order to assess biological activity, it was essential to
deprotect the acetate groups. The initial concern associated with
the stability of the N-sulfonyls during NaOMe catalyzed de-O-
acetylation was proved to be safe with low NaOMe concentration
and controlled reaction time (Scheme 3). Completely de-O-
acetylated products 5 were obtained in good yields using 0.005M
NaOMe in MeOH (Table 3).

9
1a
1a
1h
1h
1h
1h
2b
2c
2b
2c
2a
2b
3a
3a
3a
3a
3b
3b
4aba
4aca
4hba
4hca
4hab
4hbb
84%
87%
88%
87%
88%
86%
10
11
12
13
14
aIsolated yields are calculated based on 1. bImino-coumarine4
numberingis accompanied with threeletter
combinationsdefining the source ofcarbohydrate propargyl
ether,sulfonylazide, and salicylaldehyde or o-
hydroxyacetophenone, respectively. See scheme 2 legend for
letter definitions.
Scheme 3. General de-O-acetylation of the carbohydrate-
iminocoumarines4 with NaOMe in MeOH.
Table 3.De-O-acetylation of the carbohydrate-iminocoumarines4
with NaOMe in MeOH.
Scheme 2. Copper-catalyzed multi-component reaction of panels of
propargyl derivatives 1a-h, sulfonylazides2a-c, and salicyaldehyde3a or
hydroxyacetophenone3b
Entry
4
5
Yielda
1
2
3
4
5
6
7
8
4aaa 5aaa 82%
4baa 5baa 77%
4caa 5caa 79%
4daa 5daa 80%
4eaa 5eaa 78%
Table 2.Synthesis of carbohydrate-iminocoumarin hybrids 4
by CuI-catalyzed multi-component reactions of carbohydrate
alkynes 1, sulfonylazides2, and salicylaldehyde or o-
hydroxyacetophenone3.
Entry
Alkyne 1
Sulfonylazid
Carbonyl
Imino-
Yield
a
4faa
5faa
81%
e2
3
coumarine4
4gaa 5gaa 74%
4aba 5aba 78%
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
2a
2a
2a
2a
2a
2a
2a
2a
3a
3a
3a
3a
3a
3a
3a
3a
4aaa
4baa
4caa
4daa
4eaa
4faa
4gaa
4haa
92%
90%
91%
86%
87%
89%
81%
91%
aYields after chromatographic purification.
Once the library of glycosylated-iminocoumarines 5 was in
hand, we focused our attention to evaluate their activities with
galectins. The deprotected glycosylated iminocoumarins 5 were
evaluated as antagonists against human galectin-1, -3, -7, -8N (N-
terminal domain), and -9N (N-terminal domain).This selection of
galectins to evaluate is based on their well-documented relevance
in immunity, inflammation and cancer. Galectin-4, -8 C-terminal
1g
1h

domain, -9 C-terminal domain, and -12 would also qualify as
galectins of interest to evaluate, however adequately accurate
assays for these galectins were not available. The data generated
from these experiments clearly revealed that galactose and
lactose-derived compounds 5baa and 5gaa posses binding
Scheme 4. Synthesis of 3-O-iminocoumarine and coumarine derivatives
10-11 of methyl α-D-galactopyranoside..
Next, we synthesized the 3-O-iminocoumarine derivatives of
galactose as an alternative strategy, because galectin:ligand X ray
structures30-36 reveal no clear contact between galactose 3-OH
and galectin CRDs. This suggests that galactose 3-O is ideal as
point of attaching putative affinity-enhancing coumaryl structures
pointing into an extended binding pocket, as has been
demonstrated with other structures in a series of publications.36-
42Hence, 3-O-propargylated galactopyranoside843was subjected
to the Cu-catalyzed three-component protocol to afford the
desired 3-O-iminocoumarine galactosides9a and 9b in good
yields. These derivatives were de-O-acetylated to afford
compounds 10aand 10’b, respectively, using the same controlled
de-O-acylation strategy with low sodium methoxide
concentration (Scheme 4). Interestingly, the 2-O- acetyl group
showed unexpectedly high stability and the partially de-O-
acetylated 10’a and10’b were isolated together with the fully de-
O-acetylated compounds 10a and 10b. As 2-O-substituted
galactopyranose derivatives have proven better antagonists, as
compared to parent galactosides, against galectin-344-48, it was of
interest to study the effect of 2-O-acetyl protecting group on
galectin binding. Alternatively, forcing the de-O-acetylation
conditions by using 0.05M in MeOH for 12h, followed by
addition of water yielded the corresponding coumarine
derivatives after an additional 12h. Hence, increasing the sodium
methoxide concentration, followed by addition of water, allowed
for simultaneous de-O-acetylation and de-N-sulfonylation to
yield the coumarine11.
Table 4.Kd-values (mM)a of binding compounds 5baa and
5gaaagainst human galectin-1, 3, 7, 8N, and 9N as measured
by a fluorescence polarization assay.26-28 Methyl β-D-
galactopyranoside6 and methyl β-lactoside7 are included as
references.
Compound
Galectin
1
3
7
8N
9N
5baa
5gaa
3.6 1.3
10 0.5
nbb
3.9 0.9
7.1 0.4
0.5 0.09 0.13 0.06 nb
0.14 0.01 0.080 0.010
Me β-D-
10
4.4
4.8
5.3
3.3
gal(6)26
Me β-
lac(7)29
0.19
0.22
0.11
0.062
0.023
aThe data are average and standard deviation of 4-8 single point
measurements. bNon-binding.
activities against galectin-1, 3, 8N, and 9N in the same range as
reference methyl β-D-galactoside 6 and methyl β-lactoside7
(Table 4). On the contrary, galectin-7 did not bind by the
anomeric coumarines 5baa and 5gaa. The other carbohydrate
iminocoumarine compounds 5 as expected did not show any
significant binding as they do not posses the key galactose or
lactose moiety needed
Evaluation of 10a,10’a,10b, 10’b,and 11 as galectin
antagonists revealed only a marginal, but significant, affinity
enhancement for galectin-1. However, to our satisfaction, all five
compounds indeed showed binding(Table 5)to galectin-3, 8N,
and 9N with efficiencies approaching or even surpassing the
hitherto most promising galactose 3-C-modifications based on
aromatic amides and triazoles (e.g.methyl 3-deoxy-3-(4-
methylbenzamido)-1-thio-β-D-galactopyranoside 1246 and methyl
3-deoxy-3-(4-benzylaminocarbonyl-1H-[1,2,3]-triazol-1-yl)-1-
thio-β-D-galactopyranoside 13,40(Figure 1). For galectin-8N the
result was possibly even more intriguing because while the N-
sulfonylatediminocoumarines10a and 10b were more than20
Table 5.Kd-values (µM)a of 10a, 10’a, 10b, 10’b, 11, 12, 13,
and methyl α-D-galactoyranoside14against human galectin-1,
3,7, 8N, and 9N, as measured by a fluorescence polarization
assay.26-28
Galectin
1
3
7
8N
9N
10a
10’a
10b
10’b
11
1700 640
5100 590
650 110
4500 100
1900 290
980
120 25
97 22
81 13
130 49
78 15
220
1700 720
180 18
1100 270
230 50
850 130
250 55
170 46
390 46
270 70
180 17
>2000
140 13
36 13
76 16
45 5
180 27
1500
1240
>2000
2100
1339,40
14
n.b.b
150
>5000
>5000
>10000c
2700 42
0
11000 280
0
6300 97
0
2800 45
0

aThe data are average and standard deviation of 4-8 single point
measurements. bNon-binding. cNo inhibition observed at 10 mM
concentration.
derivatives showed greatly enhanced affinity over methyl α-D-
galactoside for galectin-3, 7, 8N, and 9N, but less so for galectin-
1. The affinity enhancements for galectin-3, 7, 8N, and 9N
surpasses those of earlier discovered 3-benzamido- and 3-
triazolyl galactosides, which clearly points to the 3-O-
iminocoumarylmethyl and 3-O-coumarylmethyl derivatization
being an attractive route towards efficient antagonists against
these galectins.
Acknowledgments
VKR thanks CSIR, New Delhi, India for Senior Research
Fellowship. The work wassupported by the Swedish Research
Council program Swedish Links sponsored by SIDA (Swedish
International Development Cooperation Agency), the Swedish
Research Council (Grant No. 621-2009-5326), and the
Department of Science and Technology, New Delhi, India (Grant
No. SR/S1/OC-67/2009).
References and notes
1. Venugopala, K. N.; Rashmi, V.; Odhav, B. BioMed Res. Int. 2013, 1.
2. Yu, D.; Suzuki, M.; Xie, L.; Morris-Natschke, S. L.; Lee, K.-H. Med.
Res. Rev. 2003, 23, 322.
3. O´Kennedy, R.; Thomas, R. D., Eds. Coumarins: Biology, Applications,
and Mode of Action; Wiley: Chichester, UK, 1997.
4. Brun, M. P.; Bischoff, L.; Garbay, C. Angew. Chem. Int. Ed. Engl.
2004, 43, 3432.
5. Hariprassad, V.; Talele, T. T.; Kulkarni, V. Pharm. Pharmacol. Comun.
1998, 4, 365.
6. Lacy, A.; Kennedy, R. Curr. Phar. Des. 2004, 10, 3797.
7. Burke, T. R.; Lim, B.; Marquez, V. E.; Li, Z.-H.; Bolen, J. B.; Bolen, J.
B.; Stefanova, I.; Horak, I. D. J. Med. Chem. 1993, 36, 425..
8. Mandal, S.; Gauniyal, H. M.; Kausikisankar, P.; Mukhopadhyay, B. J.
Org. Chem. 2007, 72, 9753.
9. Leffler, H.; Carlsson, S.; Hedlund, M.; Qian, Y.; Poirier, F. Glycoconj.
J. 2004, 19, 433.
10. Rabinovich, G. A.; Croci, D. O. Immunity 2012, 36, 322.
11. Rabinovich, G. A.; Toscano, M. A. Nat. Rev. Immunol. 2009, 9, 338.
12. Ingrassia, L.; Camby, I.; Lefranc, F.; Mathieu, V.; Nshimyumukiza, P.;
Darro, F.; Kiss, R. Curr. Med. Chem. 2006, 13, 3513.
13. Leffler, H.; Nilsson, U. J., Eds. Galectins and Disease - Implications for
Targeted Therapies, 2013.
14. Oberg, C.; Leffler, H.; Nilsson, U. J. Chimia 2011, 65, 1.
15. Pieters, R. J. ChemBioChem 2006, 7, 721.
16. Volmajer, J.; Toplak, R.; Bittner, S.; Leban, I.; Le Marechal, A. M.
Tetrahedron Lett. 2003, 44, 2363.
Figure 1.Galectin-binding reference 3-C-modified galactosides12, 13 and 14.
17. Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. Engl. 2000, 39, 3168.
18. Kolb, H. C.; Sharpless, K. B. Drug Discovery Today 2013, 8, 1128.
19. Meldal, M.; Tornøe, W. Chem. Rev. 2008, 108, 2952.
20. Murugavel, G.; Punniyamurthy, T. Org. Lett. 2013, 15, 3828.
21. Whiting, M.; Fokin, V. V. Angew. Chem. Int. Ed. Engl. 2006, 45, 3157.
22. Cui, S.-L.; Lin, X.-F.; Wang, Y.-G. Org. Lett. 2006, 8, 4517.
23. Mandal, P. K. RSC Adv. 2014, 4, 5803.
24. Palanichamy, K.; Suravarapu, S. R.; Kaliappan, K. P. Synthesis, 2012,
2012, 1841.
25. Roy, B.; Mukhopadhyay, B. Tetrahedron Lett. 2007, 48, 3783.
26. Cumpstey, I.; Carlsson, S.; Leffler, H.; Nilsson, U. J. Org. Biomol.
Chem. 2005, 3, 1922.
27. Sörme, P.; Kahl-Knutsson, B.; Huflejt, M.; Nilsson, U. J.; Leffler, H.
Anal. Biochem. 2004, 334, 36.
28. Sörme, P.; Kahl-Knutsson, B.; Wellmar, U.; Nilsson, U. J.; Leffler, H.
Meth. Enzymol. 2003, 362, 504.
29. Cumpstey, I.; Salomonsson, E.; Sundin, A.; Leffler, H.; Nilsson, U. J.
ChemBioChem 2007, 8, 1389.
times better ligands than methyl α-D-galactopyranoside14, the
reference amide12 and triazole13 were virtually non-binding.
Surprisingly, the compounds with 2-O-acetyl protection 10’a
and10’b were proved better ligands against galectins-7 and 9N,
than de-protected iminosulfonyl-cumarines (10a and 10b). They
showed similar affinity as the coumarine11 for galectin-3 and
galectin-8N and considerably increased affinity against galectin-7
(10’aKd=180 µM and 10’bKd=230 µM), galectin-9 (10’aKd=36
µM and 10’bKd=45 µM), but rendered neutral or slightly adverse
effect against galectin-1 in comparison to compound 11,albeit in
no case did the substitution cause abolished binding. Taken
together, these results open up a promising avenue towards
exploiting galactose 3-C-coumarines as galectin antagonists.
30. Bianchet, M. A.; Ahmed, H.; Vasta, G. R.; Amzel, L. M. Proteins 2000,
40, 378.
31. Leonidas, D. D.; Vatzaki, E. H.; Vorum, H.; Celis, J. E.; Madsen, P.;
Acharya, K. R. Biochemistry 1998, 37, 13930.
32. López-Lucendo, M. F.; Solís, D.; André, S.; Hirabayashi, J.; Kasai, K.-
i.; Kaltner, H.; Gabius, H.-J.; Romero, A. J. Mol. Biol. 2004, 343, 957.
33. Nagae, M.; Nishi, N.; Nakamura-Tsuruta, S.; Hirabayashi, J.;
Wataksuki, S.; Kato, R. J. Mol. Biol. 2008, 375, 119.
In conclusion, we have employed a highly efficient multi-
component method for the synthesis of iminocoumarylmethyland
coumarylmehtylderivatised carbohydrates for evaluation as
galectin antagonists. While iminocoumarylmethylgalactosides
and lactosides derivativesshowedbinding activity against
galectin-1, 3, 7, 8N, and 9N in the same range as methyl β-D-
galactoside and β-lactoside, respectively,
iminocoumarylmethyl and coumarylmethyl
the 3-O-
galactoside

34. Saraboji, K.; Håkansson, M.; Genheden, S.; Diehl, C.; Qvist, J.;
Weininger, U.; Nilsson, U.; Leffler, H.; Ryde, U.; Akke, M.; Logan, D.
Biochemistry 2011, 51, 296.
35. Seetharaman, J.; Kanigsberg, A.; Slaaby, R.; Leffler, H.; Barondes, S.
H.; Rini, J. M. J. Biol.Chem. 1998, 273, 13047.
36. Sörme, P.; Arnoux, P.; Kahl-Knutsson, B.; Leffler, H.; Rini, J. M.;
Nilsson, U. J. J. Am. Chem. Soc. 2005, 127, 1737.
37. Cumpstey, I.; Salomonsson, E.; Sundin, A.; Leffler, H.; Nilsson, U. J.
Chem. Eur. J. 2008, 14, 4233.
38. Cumpstey, I.; Sundin, A.; Leffler, H.; Nilsson, U. J. Angew. Chem. Int.
Ed. 2005, 44, 5110.
39. Salameh, B. A.; Cumpstey, I.; Sundin, A.; Leffler, H.; Nilsson, U. J.
Bioorg. Med. Chem. 2010, 18, 5367.
40. Salameh, B. A.; Leffler, H.; Nilsson, U. J. Bioorg. Med. Chem. Lett.
2005, 15, 3344.
41. Salameh, B. A.; Sundin, A.; Leffler, H.; Nilsson, U. J. Bioorg. Med.
Chem. 2006, 14, 1215.
42. Sörme, P.; Qian, Y.; Nyholm, P.-G.; Leffler, H.; Nilsson, U. J.
ChemBioChem 2002, 3, 183.
43. Campo, V. L.; Sesti-Costa, R.; Carneiro, Z. A.; Silva, J. S.; Schenkman,
S.; Carvalho, I. Bioorganic & Medicinal Chemistry 2012, 20, 145.
44. Collins, P. M.; Oberg, C. T.; Leffler, H.; Nilsson, U. J.; Blanchard, H.
Chem. Biol. Drug Design 2012, 79, 339.
45. Öberg, C. T.; Blanchard, H.; Leffler, H.; Nilsson, U. J. Bioorg. Med.
Chem. Lett. 2008, 18, 3691.
46. Öberg, C. T.; Leffler, H.; Nilsson, U. J. J. Med. Chem. 2008, 51, 2297.
47. Öberg, C. T.; Noresson, A.-L.; Leffler, H.; Nilsson, U. J. Chem. Eur. J.
2011, 17, 8139.
48. Öberg, C. T.; Noresson, A.-L.; Leffler, H.; Nilsson, U. J. Tetrahedron
2011, 67, 9164.
Supplementary Material
Synthetic experimental procedures, NMR data, ms data, and
copies of NMR spectra.

HO
OH
O
OMe
HO
OH
6
HO
OH
OH
O
O
O
OMe
HO
HO
OH
OH
7
HO
OH
O
H
N
SMe
OH
O
12
O
HO
OH
BnHN
O
SMe
N
N
N
OH
13
HO
OH
O
HO
HO
OMe
14