Synthesis and evaluation of transition-state analogue inhibitors of α-1,3-fucosyltransferase

Article abstract of DOI:10.1002/1521-3773(20020816)41:16<3041::AID-ANIE3041>3.0.CO;2-V

Mimics of the geometry or charge of the fucose moiety of GDP-fucose in the transition state of fucosyltransferase-catalyzed reactions, compounds 1-3 are good competive inhibitors of α-1,3-fucosyltransferases V and VI with K_i values between 6 an

Full text of DOI:10.1002/1521-3773(20020816)41:16<3041::AID-ANIE3041>3.0.CO;2-V

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[26] L. Naldini, F. Demartin, M. Manassero, M. Sansoni, G. Rassu, M. A.
Zoroddu, J. Organomet. Chem. 1985, 279, C42.
[27] M. G. B. Drew, F. S. Esho, S. M. Nelson, J. Chem. Soc. Chem.
Commun. 1982, 1347.
Synthesis and Evaluation of
Transition-State Analogue Inhibitors of
a-1,3-Fucosyltransferase**
[28] a) Crystal structure analysis for [Cu26(hfac)11(1-pentynyl)15]: Crystals
were grown by slow cooling of a supersaturated solution of the
complex in hot n-hexane and were analyzed with a Bruker smart
APEX CCD area detector equipped with an Oxford Cryosystems LT
device operating at 150 K. C133H115Cu26F66O22, l ¼ 0.71073 ä, crystal
size ¼ 0.44 î 0.38 î 0.29 mm, cell determination: range 48 < 2q < 588,
no. reflections: 4764, monoclinic, space group Cc (checked with
MISSYM[28b-d]), Z ¼ 4, a ¼ 26.009(3), b ¼ 21.114(2), c ¼ 31.078(4) ä,
Michael L. Mitchell, Feng Tian, Lac V. Lee, and Chi-
Huey Wong*
Glycosidases and glycosyltransferases involved in the bio-
synthesis of glycoconjugates associated with intercellular
recognition, metastasis, and immune response represent
b ¼ 94.214(2)o, V¼ 17021(3) ä3, 1calcd ¼ 1.943 gcmÀ3, m ¼ 3.300 mmÀ1
.
7]
viable therapeutic targets.[1 Of particular interest are the
75941 reflections were collected in the range 1.318 < q < 28.948, of
which 38578 were unique and 33027 had Fo > 4s(Fo). A multiscan
absorption correction was applied using Sadabs[28e] (Tmax ¼ 0.862;
Tmin ¼ 0.679). The structure was solved by direct methods (SHELXS-
97),[28f] and refined by block-matrix least-squares against F2
(SHELXTL97).[28f] All non-hydrogen atoms were modeled with
anisotropic displacement parameters, except for one half-occupancy
hexane solvate molecule, and H atoms were included in ideal
positions. Numerous CF3 groups were disordered, a combination of
similarity and ADP equalization restraints were used to model this.
The conventional R1 factor (Fo > 4s(Fo)) was 0.0409 and wR2 was
0.0913. (w ¼ 1/[s2(Fo2) þ (0.0490P)2] where P ¼ (Fo2 þ 22c)/3). Largest
max/min residual electron density: þ 1.094/À0.917 eä3;b) Y. LePage,
J. Appl. Crystallogr. 1999, 20, 264; c) A. L. Spek, J. Appl. Cryst. 1987,
21, 578; d) L. J. Farrugia, J. Appl. Crystallogr. 1999, 32, 837; e) G. M.
Sheldrick, SADABS, Program for Empirical Correction of Area
Detector Data, University of Gˆttingen, Gˆttingen (Germany), 1998;
f) G. M. Sheldrick, SHELXTL97, Program for the refinement of
crystal structures, University of Gˆttingen, Gˆttingen (Germany),
1997. CCDC-186669 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge CB21EZ,
UK; fax: (þ 44)1223-336-033; or deposit@ccdc.cam.ac.uk).
[29] V. W. W. Yam, K. L. Yu, K. K. Cheung, J. Chem. Soc. Dalton Trans.
1999, 2913.
fucosyltransferases (FucTs), which play a key role in the
biosynthesis of many important fucose-containing oligosac-
charides such as sialyl Lewis x (sLex), a determinant in
numerous cell cell interactions, for example, in inflamma-
tion[8,9] and tumor metastasis.[10,11] The terminal step in the
biosynthetic pathway of these fucose-containing saccharides is
the transfer of l-fucose from guanosine diphosphate b-l-
fucose (GDP Fuc) to the corresponding glycoconjugate
acceptors,[12,13] which is catalyzed by a-1,3-fucosyltransferase
(a-1,3-FucT).[14,15] Since inhibitors of fucosyltransferase may
disrupt the biosynthesis of these saccharides, they have
potential medicinal applications as anti-inflammatory or
antitumor agents.
In the proposed transition state of a-1,3-FucT V,[16] the
pyrophosphate chelates a divalent manganese and the fucose
ring adopts a flattened half-chair conformation with substan-
tial oxocarbenium ion character (Scheme 1). Recognition of
these salient features of the transition state guided our design
of potential inhibitors 1 3 for fucosyltransferase.
In the present study, analogues of fucose, which incorporate
the geometry or charge of the fucose moiety in the transition
state, were linked to GDP, thereby retaining the contribution
of GDP to binding. The cyclohexene ring of 1 was designed to
mimic the flattened half-chair conformation of the fucose
moiety. In addition, the carbocyclic ring is chemically more
stable than its pyranose counterpart and may be more stable
in vivo.
Triazoles also resemble the flattened conformation of the
fucose moiety in the transition state.[17] Previous work based
on fucose-derived triazoles lacking the negative charge
normally present in the GDP-fucose substrate only weakly
inhibited fucosyltransferase.[18] Therefore, a triazole was
attached to GDP providing 2, which allowed us to exploit
the electrostatic interactions of the pyrophosphate and
residues in the active s9ite.
[30] V. W. W. Yam, S. H. F. Chong, K. M. C. Wong, K. K. Cheung, Chem.
Commun. 1999, 1013.
[31] C.-M. Che, Z. Mao, V. M. Miskowski, M.-C. Tse, C.-K. Chan, K.-K.
Cheung, D. L. Phillips, K.-H. Leung, Angew. Chem. 2000, 112, 4250;
Angew. Chem. Int. Ed. 2000, 39, 4084.
[32] J. M. Zuo, M. Kim, M. O©Keeffe, J. C. H. Spence, Nature 1999, 401, 49.
[33] H. L. Hermann, G. Boche, P. Schwerdtfeger, Chem. Eur. J. 2001, 7,
5333.
[34] L. Magnko, M. Schweizer, G. Rauhut, M. Schutz, H. Stoll, H. J.
Werner, Phys. Chem. Chem. Phys. 2002, 4, 1006.
[35] J. C. Slater, J. Chem. Phys. 1964, 41, 3199.
[36] Pairs of atoms in the second annulus defining the parallel sides of the
pseudotrigonal prism make contact with the same pair of atoms in the
third annulus, namely Cu(2) and Cu(3) with Cu(9) and Cu(10); Cu(4)
and Cu(5) with Cu(11) and Cu(12); and Cu(6) and Cu(7) with Cu(8)
and Cu(13).
[37] The closest Cu¥¥¥Cu contacts formed by atoms in the ™bud unit∫
(Figure 1) are either longer than the sum of van der Waals radii of two
CuI atoms or, for Cu(24)¥¥¥Cu(11) and Cu(24)¥¥¥Cu(25), close to this
value (2.7401(9) ä and 2.7057(10) ä respectively).
[38] K. M. Chi, H. K. Shin, M. J. Hampden-Smith, T. T. Kodas, E. N.
Duesler, Inorg. Chem. 1991, 30, 4293.
[39] P. Doppelt, T. H. Baum, J. Organomet. Chem. 1996, 517, 53.
[40] R. B. Grossman, Tetrahedron 1999, 55, 919.
[41] I. A. Koppel, J. Koppel, V. Pihl, I. Leito, M. Mishima, V. M. Vlasov,
L. M. Yagupolskii, R. W. Taft, J. Chem. Soc. Perkin Trans. 2 2000, 6,
1125.
[*] Prof. C.-H. Wong, Dr. M. L. Mitchell, Dr. F. Tian, Dr. L. V. Lee
Department of Chemistry and the Skaggs Institute
for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax : (þ 1)858-784-2409
E-mail: wong@scripps.edu
[42] J. Vicente, M.-T. Chicote, Inorg. Synth. 1998, 32, 172.
[**] This work was supported by the NIH and the Skaggs Institute. M.L.M.
acknowledges fellowships from UNCF¥Merck Science Initiative and
Skaggs Predoctoral Fellows Program.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
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compounds 1 3, which are designed to mimic the transition
state of the GDP fucose moiety of fucosyltransferase-cata-
lyzed reactions.
Since three contiguous secondary alcohols of d-mannose
and l-fucose share the same configuration, d-mannose was
chosen as the starting material for the construction of 1.
Synthesis began with differential protection of the hydroxy
groups of a-4-methoxyphenyl d-mannopyranoside (4)[23]
(Scheme 2). The C6 primary alcohol was protected as a tert-
butyldiphenylsilyl (TBDPS) ether and the remaining secon-
dary alcohols were masked as methoxymethyl (MOM) ethers
to give mannopyranoside 5. Treatment with ceric ammonium
nitrate (CAN)[24,25] revealed the anomeric hydroxy group, and
subsequent Albright Goldman oxidation[26] afforded lactone
6. Nucleophilic addition of lithium dimethyl methylphosph-
onate to the carbonyl group of 6 then provided tertiary
alcohol 7. Reductive ring opening with sodium borohydride to
generate a diol, subsequent Swern oxidation,[27] and intra-
molecular Horner Emmons olefination[28] yielded the enone
8. Stereoselective 1,2-reduction of 8 by Luche reduction[29]
gave exclusively the pseudo-equatorial alcohol that was
converted to a methyl ether with sodium hydride and
iodomethane to furnish 9. The tert-butyldimethylsilyl ether
was removed with tetrabutylammonium fluoride (TBAF) to
give the corresponding alcohol that was phosphorylated by
using dibenzyl diisopropylphosphoramidite and subsequently
oxidized with 3-chloroperoxybenzoic acid (mCPBA) to give
10.[30] Global deprotection with trifluoroacetic acid and
thiophenol[31] gave the intermediate phosphate, which was
coupled to GMP using GMP-morpholidate and 1H-tetra-
Scheme 1. Proposed transition state of a-1,3-FucT V.[16]
O
HO
N
N
OH
NH
O–
O–
OH
CH3O
O
O
O
P
P
N
NH2
O
O
O
OMOM
O
OH
O
TBDPSO
MOMO
MOMO
HO
1
a, b
c, d
HO
HO
OH
HO
OC6H4OCH3
OC6H4OMe
O
N
4
5
7
HO
OH
N
N
NH
O–
O–
OH
O
O
O
N
P
P
OMOM
O
NH2
TBDPSO
MOMO
MOMO
O
OMOM
O
O
TBDPSO
MOMO
MOMO
H3C
f-h
O
O
e
N
N
P(OMe)2
O
OH
HO
OH
6
2
O
MOMO
MOMO
HO
OMOM
OMOM
N
N
i, j
OH
k, l
NH
O–
O–
OMOM
OMOM
H3CO
OH
H3C
N
H
O
O
O
OTBDPS
OTBDPS
O
P
P
N
NH2
O
O
O
8
9
3
HO
OH
MOMO
H3CO
HO
OMOM
OH
m, n
O
OMOM
OP(OBn)2
OH
H3CO
While the cyclohexene and triazole motifs mimic the
conformation of the fucose moiety in the transition
state, iminocyclitols mimic the partial positive charge
developed in the transition state. Iminocyclitols are
good inhibitors of glycosidases,[19,20] but are only modest
inhibitors of glycosyltransferases.[21,22] Covalently link-
ing the negatively charged GDP to the six-membered
iminocyclitol may provide a more potent inhibitor (3).
Reported here is the synthesis and evaluation of
OGDP
10
1
Scheme 2. Reagents and conditions: a) TBDPSCl, DMAP, pyridine, 86%;
b) MOMCl, DIPEA, DMAP, CH2Cl2, 88%; c) CAN, CH3CN/H2O; d) DMSO,
Ac2O, 77%; e) CH3P(O)(OCH3)2, nBuLi, THF, 82%; f) NaBH4, THF; g) DMSO,
TFAA, CH2Cl2, À788C; h) NaH, diglyme, 658C, 70% for three steps; i) NaBH4,
CeCl3, MeOH, 95%; j) NaH, MeI, THF, 100%; k) TBAF, THF, 92%; l) (iPr)2N-
P(OBn)2, 1H-tetrazole, CH2Cl2; mCPBA, 77%; m) 95% aq. TFA, thiophenol, 86%;
n) GMP-morpholidate, 1H-tetrazole, pyridine, 25%. DMAP ¼ 4-dimethylamino-
pyridine, DIPEA ¼ diisopropylethylamine, TFAA ¼ trifluoroacetic anhydride.
3042
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zole[32] to provide target 1. These named reactions were also
used by Marquez and Lim[33a] and Vasella and co-workers[33b]
for the synthesis of other carbocycles.
BnO
TBSO
OTBS
OBn
c-e
OBn
a, b
OTBS
CO2Me
N
N
N
CO2Me
N
Beginning from the known triazole 11,[18] catalytic hydro-
genolysis generated the hydroxy groups, which were then
protected as tert-butyldimetylsilyl ethers to give 12
(Scheme 3). Reduction of the carboxylic ester with lithium
aluminum hydride (LAH), followed by phosphorylation of
the resulting hydroxy group with dibenzyl diisopropylphos-
phoramidite and subsequent oxidation with mCPBA furnish-
ed intermediate 13.[30] Treatment with TBAF, followed by
catalytic hydrogenolysis gave phosphate 14, which underwent
1H-tetrazole-catalyzed coupling with GMP morpholidate to
give target 2.
N
N
11
12
TBSO
HO
OTBS
OH
O
OP(OBn)2
f, g
h
OTBS
OH
OPO3H2
N
N
N
N
N
N
13
14
HO
OH
OH
OGDP
N
N
Scheme 4 illustrates the chemoenzymatic synthesis of 3.
Regiospecific epoxide opening of 15[34] with sodium azide,
followed by acetylation provided acetate 16. Resolution of the
diastereomers was accomplished with Pseudomonas lipase
(PSL)[35] to give products 17a and 17b, which were separable
by chromatography. Treatment of 17b with 0.1n HCl un-
masked the aldehyde, which underwent an FDP aldolase-
catatlyzed aldol reaction[34] with dihydroxyacetone phosphate
(DHAP)[36] to give phosphate 18. The azido-sugar 18 was then
hydrogenated in the presence of platinum oxide under a
hydrogen atmosphere to give the iminocyclitol phosphate 19.
Whereas reductive amination using palladium catalysts re-
ductively cleaved the phosphate group as a side reaction, no
corresponding side product was observed with platinum
oxide. Coupling with GMP morpholidate and 1H-tetrazole[32]
then provided the desired iminocyclitol 3.
N
2
Scheme 3. Reagents and conditions: a) H2, Pd/C, MeOH/AcOH, 85%;
b) TBSOTf, 2,6-lutidine, CH2Cl2, 93%; c) LAH, THF, 97%; d) (iPr)2N-
P(OBn)2, 1H-tetrazole, CH2Cl2; e) mCPBA, CH2Cl2, 94% for two steps;
f) TBAF, THF; g) H2, Pd/C, EtOH, 88% for two steps; h) GMP
morpholidate, 1H-tetrazole, pyridine, 39%.
EtO
EtO
N3
EtO
EtO
a, b
c
CH3
CH3
O
OAc
15
16
EtO
EtO
N3
EtO
EtO
N3
d, e
+
CH3
CH3
OAc
OH
The transition-state analogues were evaluated by using a
fluorescence-based assay that couples the production of GDP
to the consumption of NADH with pyruvate kinase (Sigma)
and lactate dehydrogenase (Sigma).[16] Compounds 1 3 ex-
hibited good competitive inhibition of both FucT V and VI,
with Ki values between 6 and 13 mm (Table 1), although no
general trend of inhibition was clearly discernable. Also
included in Table 1 are published inhibition data for FucT
inhibitors known in the literature. The fluorinated GDP
fucose analogues (e.g. 20) are the most potent inhibitors of
FucTs known to date.[37] GDP fucose analogue 23 is a good
competitive inhibitor,[38] but inhibition activity for C-fucopyr-
anosyl analogue 22[39] could not be found. Transition-state
analogues such as the five-membered GDP iminocyclitol
21[40] show competitive inhibition against FucT V, whereas the
cyclohexene 24 has an affinity constant similar to that of
GDP fucose (8-34 mm).[38] No significant inhibition of 1 3 was
observed with other commercially available glycosyltransfer-
ases such as sialyltransferases.
In summary, aspects of the transition state of GDP fucose
in fucosyltransferase-catalyzed reactions were investigated
through the use of transition-state analogues. The importance
of charge and conformation appear to be roughly equivalent
as evident by the similar inhibition constants of transition-
state analogues 1 3. The procedures described for the syn-
thesis of 1 3 are relatively straightforward and efficient. Of
particular interest in the reductive amination of the aldolase
product azido-sugar phosphate 18 provides iminocyclitol
phosphate 19 for subsequent coupling to give iminocyclitol
17a
17b
N3
H2O3PO
HO
HO
O
OH
f
g
CH3
OH
H3C
N
H
OPO3H2
HO
OH
18
19
HO
OH
OH
H3C
N
H
OGDP
3
Scheme 4. Reagents and conditions:a) NaN3, NH4Cl, EtOH/H2O, reflux,
44%; b) Ac2O, pyridine, 95%; c) PSL 800, pH 7.0 phosphate buffer, 51%
conversion; d) 0.1n HCl, 508C; e) DHAP, FDP aldolase, pH 6.7, 70% for
two steps; f) H2, PtO2, MeOH/H2O, 60%; g) GMP morpholidate, 1H-
tetrazole, pyridine, 40%.
Table 1. The inhibition constants were determined for FucT V and VI at
2 Km LacNAc (70 and 10 mm, respectively), pH 7.4, and 10 mm MnCl2.
FucT V and VI were from CalBiochem. NA ¼ data not available.
FucT V
FucT VI
[mm]
Ref.
FucT V
[mm]
FucT VI
[mm]
Ref.
[mm]
[40]
[39]
[38]
[38]
1
8
6
21
22
23
24
45
NA
NA
2
8
13
11
10
NA
3
20
13
4
< GDP[a]
~ GDP Fuc[b]
[37a]
[a] Inhibitory activity described as better than that of GDP (Ki for GDP ¼
29 mm). [b] Inhibitory activity described as comparable to that of GDP
fucose (Km for GDP-Fuc ¼ 8 34 mm).
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nucleotide 3. This new chemoenzymatic strategy should find
use in the synthesis of other iminocyclitol nucleotides. We
believe that compounds 1 3 should be useful as general
inhibitors of fucosyltransferases.
Cyanoethynylethenes: A Class of
Powerful Electron Acceptors for
Molecular Scaffolding**
Nicolle N. P. Moonen, Corinne Boudon, Jean-
Paul Gisselbrecht, Paul Seiler, Maurice Gross, and
FranÁois Diederich*
Received: May 8, 2002 [Z19273]
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N
N
N
N
N
1
5
2
6
3
7
4
N
N
N
N
N
N
N
[18] T. Flessner, C.-H. Wong, Tetrahedron Lett. 2000, 41, 7805.
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N
N
Scheme 1. Progression from tetraethynylethene (TEE, 1) to tetracyanoe-
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Cyanoethynylethenes (2 6, CEEs) are an interesting class
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which is one of the strongest organic electron acceptors
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We have now extended the family of CEEs and report
herein the synthesis of 9 11a (Scheme 2), silylated derivatives
[*] Prof. Dr. F. Diederich, N. N. P. Moonen, P. Seiler
Laboratorium f¸r Organische Chemie
ETH-Hˆnggerberg, HCI, 8093 Z¸rich (Switzerland)
Fax : (þ 41)1-632-1109
E-mail: diederich@org.chem.ethz.ch
Dr. C. Boudon, Dr. J.-P. Gisselbrecht, Prof. Dr. M. Gross
Laboratoire d’Electrochimie et de Chimie Physique du Corps Solide
UMR 7512, C.N.R.S.
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Universitÿ Louis Pasteur
4, rue Blaise Pascal, 67000 Strasbourg (France)
[**] We thank the ETH Research Council and the Fonds der Chemischen
Industrie for their support of this work. Robin Gist is acknowledged
for the supply of starting materials.
3044
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Angew. Chem. Int. Ed. 2002, 41, No. 16