New oligomers of conduritol-F and muco-inositol. Synthesis and biological evaluation as glycosidase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2003.12.050

Several oligomers possessing the configuration of conduritol-F and muco-inositol have been prepared and tested against six glycosidase enzymes. Electrochemical dehalogenation and reductive deprotection of cinnamyl ethers are featured in the reported syntheses. The synthesis, properties, and biological activities are investigated.

Full text of DOI:10.1016/j.bmcl.2003.12.050

Bioorganic & Medicinal Chemistry Letters 14 (2004) 1209–1212
New oligomers of conduritol-F and muco-inositol. Synthesis and
biological evaluation as glycosidase inhibitors
Stanley Freeman and Tomas Hudlicky*
Department of Chemistry, University of Florida, PO Box 117200, Gainesville, FL 32611, USA
Received 9 October 2003; revised 8 December 2003; accepted 12 December 2003
Abstract—Several oligomers possessing the configuration of conduritol-F and muco-inositol have been prepared and tested against
six glycosidase enzymes. Electrochemical dehalogenation and reductive deprotection of cinnamyl ethers are featured in the reported
syntheses. The synthesis, properties, and biological activities are investigated.
# 2003 Elsevier Ltd. All rights reserved.
Unnatural saccharides, including oligosaccharides, have
long been recognized as potential inhibitors of glycosi-
dic enzymes and hence show promise in the investiga-
tion of antiviral agents.1 Such compounds include
carbasugars,2 azasugars,3 and various analogues that
structurally and functionally resemble carbohydrates
but fail to enter the natural metabolic pathways follow-
ing their interaction with appropriate enzymes.4
(2). Both series of compounds were prepared in an
iterative fashion from the known epoxide 4,6,10 as
shown in Schemes 1 and 2.
A few years ago, we reported the synthesis of several
oligoinositols, a new class of compounds whose struc-
ture in solution resembles that of oligosaccharides but
which are not glycosidically labile. Consequently, these
compounds are ideal carbohydrate surrogates, espe-
cially in view of the fact that there are more combin-
atorial possibilities in the oligomeric inositol series than
for natural carbohydrates because of the presence of an
additional chiral center.5 Oligomers containing the ele-
ments of l-chiro- and neo-inositols6 as well as those
derived from naphthalene7 displayed remarkable struc-
tural and biological properties, including the ability to
sequester calcium ions from aqueous solutions.6 Results
in this area have been reviewed.8 Recently we synthe-
sized oxygen- and nitrogen-linked oligomers and tested
them against common glycosidase enzymes, with pro-
mising results.9 This paper describes the synthesis,
structure, and biological evaluation of oligomers based
on the motif of either conduritol-F (1) or muco-inositol
Epoxide 4 is available in two steps (75% overall yield)
from diol 3, obtained in a reproducible yield of 12 g/L,11
by the whole-cell fermentation of bromobenzene in a
15-L fermentor with Escherichia coli JM109 (pDTG601A),
an organism overexpressing toluene di-oxygenase.12 The
epoxide was opened in the presence of a Lewis acid
catalyst with cinnamyl alcohol and benzyl alcohol to
provide, respectively, 5a (73% yield) and 5b (75%
yield), which were used as nucleophilic partners in fur-
ther coupling to epoxide 4. Ether 6a was subjected to
dehalogenation, electrochemical deprotection of the
cinnamyl group,13 and hydrolysis to furnish conduritol-
F dimer 7. Another dimer 10, having C-2 symmetry,
was prepared via 9 by allowing trans diol 8 to open the
epoxide.
The corresponding muco-inositol oligomer was prepared
as shown in Scheme 2. Reduction of the halogen in 6b
gave 11, which was subjected to epoxidation with dioxi-
rane.16 After much experimentation, treatment of 11
with methyl-(trifluoromethyl)dioxirane generated in situ
Keywords: Inositol; Conduritol glycosidase inhibitor.
* Corresponding author at present address: Department of Chemistry,
Brock University, St. Catharines, Ontario, Canada L2S 3Al. Tel.: 1-
905-688-5550x4956; fax: +1-905-984-4841; e-mail: thudlicky@
brocku.ca
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.12.050

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S. Freeman, T. Hudlicky / Bioorg. Med. Chem. Lett. 14 (2004) 1209–1212
bis epoxide 12 as a mixture of diastereoisomers (40%).
Hydrolysis of 12 proceeded as expected in a redundant
fashion17 providing a single isomer 13 via trans-diaxial
opening. Treatment of 13 with palladium on activated
carbon under a hydrogen atmosphere in acidic metha-
nol afforded the muco-di-inositol 14 in 97%.
duramines followed similar trends.9 The conduritol
motif resembles more closely the structure of the tran-
sition state assumed to operate in glycolysis,4 and this
may explain the higher inhibitory activity in comparison
with the fully hydroxylated inositols.
Three-dimensional representations of the oligomers
were obtained by modeling with the Spartan SGI soft-
ware, available from Wavefunction, Inc.18 The compo-
nents of muco-di-inositol (14) appear to position
themselves approximately ninety degrees from one
another in order to avoid steric interactions between a-
substituents. The structural arrangement of a higher
order oligomer, hypothetical muco-inositol octamer 16,
was also calculated, showing interesting intramolecular
To evaluate their potential as glycosidase inhibitors, all
compounds were screened against six commercially
available enzymes. The data presented in Table 1 reveal
promising inhibitory activity against some of the enzymes.
Compounds (7 and 10) that preserved the conduritol-F
motif proved to be stronger inhibitors compared to the
monomers or the muco-inositol oligomer. We have pre-
viously shown that nitrogen-linked inositols and con-
.
Scheme 1.ꢀReagents and conditions: (a) dimethoxypropane, acetone, pTsOH; (b) mCPBA, CH2Cl2; (c) cinnamyl or benzyl alcohol, BF3 OEt2,
ꢀ
.
CH2Cl2, 0 C; (d) 4, BF3 OEt2, CH2Cl2, 0 C; (e) À3.0 V, Et4NBr, MeCN; (f) trifluoroacetic acid:THF:H2O (4:1:1); (g) H2O.
Scheme 2. Reagents and conditions: (a) À3.0 V, Et4NBr, MeCN; (b) oxone, trifluoroacetone, NaHCO3, MeCN, 0 ꢀC; (c) Amberlyst A-27 resin
(basic), H2O; (d) H2, Pd/C, acidic MeOH.

S. Freeman, T. Hudlicky / Bioorg. Med. Chem. Lett. 14 (2004) 1209–1212
Table 1. Results of inhibition studiesa
1211
a-Glucosidase
b-Glucosidase
a-Galactocosidase
b-Galactocosidase
a-Mannosidase
b-Mannosidase
Conduritol-F14
I
I
I
I
I
I
I
I
I
600 mM
I
190 mM
250 mM
600 mM
I
I
I
I
I
I
I
I
muco-Inositol15
7
10
14
60 mM
I
800 mM
850 mM
275 mM
I
1.50 mM
I
a Each value shown is the average of two experiments; I=inactive.
hydrogen-bonding similar to that observed for the
octamer of l-chiro-inositol,9 which has been shown to
prefer a helical arrangement.
(PRF-38075-AC), and TDC Research, Inc., for support of
this project. The authors thank Merck Research Labora-
tories for a doctoral fellowshipfor Stanley Freeman.
All oligomers made upof inositol components contain a
trans linkage and therefore maintain a b-turn in their
secondary structure. The three dimensional shape is
defined by the stereochemistry of the monomeric units.
We describe these oligomers as ‘homogeneous’ as they
contain identical repeating units. Future endeavors will
examine ‘heterogeneous’ oligomers in which the shape is
‘programmed’ by rationally alternating different mono-
mers, for example, l-chiro, neo, muco. Such compounds
may find use as templates for asymmetric synthesis or in
the design of catalysts. The results of these endeavors
will be reported in due course.
References and notes
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Acknowledgements
The authors thank the National Science Foundation
(CHE-991412), the donors of the Petroleum Research
Fund administered by the American Chemical Society

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18. All results were calculated by means of Monte-Carlo
simulation to find the minimum energy conformations.
These structures were further optimized by semi-empirical
(AM1) methods. All calculations were performed with
parameters for gas phase medium.