Potent glucosidase inhibitors: De-o-suifonated ponkoranol and its stereoisomer

Article abstract of DOI:10.1021/ol1004005

(Figure Presented) Ponkoranol, a glucosidase inhibitor isolated from the plant Salacia reticulata, comprises a sulfonium ion with an internal sulfate counterion. An efficient synthetic route to de-O-sulfonated ponkoranol and its 5'-stereoisomer is reported, and it is shown that these compounds are potent glucosidase inhibitors that inhibit a key intestinal human glucosidase, the N-terminal catalytic domain of maltase glucoamylase, with K, values of 43 ± 3 and 15 ± 1 nM, respectively.

Full text of DOI:10.1021/ol1004005

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1632-1635
Potent Glucosidase Inhibitors:
De-O-sulfonated Ponkoranol and Its
Stereoisomer
Razieh Eskandari,† Douglas A. Kuntz,‡ David R. Rose,‡,§ and B. Mario Pinto*,†
Department of Chemistry, Simon Fraser UniVersity, Burnaby, British Columbia,
Canada V5A 1S6, Department of Medical Biophysics, UniVersity of Toronto and
DiVision of Molecular and Structural Biology, Ontario Cancer Institute, Toronto,
Ontario, Canada M5G 2M9, and Department of Biology, UniVersity of Waterloo,
Waterloo, Ontario, Canada N2L 3G1
bpinto@sfu.ca
Received February 16, 2010
ABSTRACT
Ponkoranol, a glucosidase inhibitor isolated from the plant Salacia reticulata, comprises a sulfonium ion with an internal sulfate counterion.
An efficient synthetic route to de-O-sulfonated ponkoranol and its 5′-stereoisomer is reported, and it is shown that these compounds are
potent glucosidase inhibitors that inhibit a key intestinal human glucosidase, the N-terminal catalytic domain of maltase glucoamylase, with
Ki values of 43 ( 3 and 15 ( 1 nM, respectively.
Compounds isolated from medicinal plants can provide the
lead structures for drug development programs.1,2 For
example, the aqueous extracts of the roots and stems of the
large woody climbing plant Salacia reticulata, known as
Kothalahimbutu in Singhalese, have been used in the
Ayurvedic system of Indian medicine in Sri Lanka and
Southern India for the treatment of Type-2 diabetes.3,4
Several glucosidase inhibitors have been isolated from the
water-soluble fraction of this plant extract and also other
plants that belong to the Salacia genus such as Salacia
chinensis, Salacia prinoides, and Salacia oblonga which
explain, at least in part, the antidiabetic property of the
aqueous extracts of these plants.5-7 Thus far, six components
have been isolated from the plant S. reticulata, namely
salaprinol (1),7 salacinol (2),6 ponkoranol (3),7 kotalanol (4),5
de-O-sulfonated kotalanol (5),8 and de-O-sulfonated salacinol
(6)9 (Figure 1), all of which possess a common structural
motif that comprises a 1,4-anhydro-4-thio-D-arabinitol and
† Simon Fraser University.
(5) Matsuda, H.; Li, Y. H.; Murakami, T.; Matsumura, N.; Yamahara,
‡ University of Toronto and Ontario Cancer Institute.
§ University of Waterloo.
J.; Yoshikawa, M. Chem. Pharm. Bull. 1998, 46, 1399–1403
(6) Yoshikawa, M.; Murakami, T.; Shimada, H.; Matsuda, H.; Yamahara,
J.; Tanabe, G.; Muraoka, O. Tetrahedron Lett. 1997, 38, 8367–8370
(7) Yoshikawa, M.; Xu, F. M.; Nakamura, S.; Wang, T.; Matsuda, H.;
Tanabe, G.; Muraoka, O. Heterocycles 2008, 75, 1397–1405
.
(1) Harvey, A. L. Natural products in drug discovery. Drug DiscoV.
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Today 2008, 13, 894–901
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(2) Butler, M. S. Natural products to drugs: natural product-derived
compounds in clinical trials. Nat. Prod. Rep. 2008, 25, 475–516
(3) Chandrasena, J. P. C. The Chemistry and Pharmacology of Ceylon
and Indian Medicinal Plants; H&C Press: Colombo, Sri Lanka, 1935
(4) Jayaweera, D. M. A. Medicinal Plants Used in Ceylon-Part 1;
National Science Council of Sri Lanka: Colombo, 1981
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(8) Muraoka, O.; Xie, W. J.; Tanabe, G.; Amer, M. F. A.; Minematsu,
T.; Yoshikawa, M. Tetrahedron Lett. 2008, 49, 7315–7317.
(9) Minami, Y.; Kurlyarna, C.; Ikeda, K.; Kato, A.; Takebayashi, K.;
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10.1021/ol1004005  2010 American Chemical Society
Published on Web 03/10/2010

catalytic domain of human intestinal maltase glucoamylase
(ntMGAM) than kotalanol (4) itself (Ki ) 0.19 ( 0.03 µM)
(Table 1).17
Table 1. Experimentally Determined Ki Valuesa
Figure 1. Components isolated from Salacia species.
a polyhydroxylated side chain. We have carried out extensive
research on the synthesis of higher homologues of salacinol
(2) which has led to the stereochemical structure elucidation
of compounds 3-5.10-12 Interestingly, ponkoranol (3), the
recently isolated7 six-carbon-chain homologue of salacinol,
was synthesized by us several years earlier with the expecta-
tion that it would be an effective glucosidase inhibitor.13
Recently, Minami et al.9 reported the isolation of a
thiosugar sulfonium-alkoxide inner salt (7), neosalacinol
(Figure 2), from S. reticulata; however, Tanabe et al.14 have
a Analysis of ntMGAM inhibition was performed using maltose as the
substrate.
Figure 2. Proposed structure of neosalacinol.
In view of these findings, it was of interest to question
whether de-O-sulfonated ponkoranol 8 and its 5′-stereoisomer
9 (Figure 3) would be more potent inhibitors than ponkoranol
itself.
shown that this compound is de-O-sulfonated salacinol (6).
Comparison of the inhibitory activities of de-O-sulfonated
salacinol (6) vs salacinol (2) and de-O-sulfonated kotalanol
(5) vs kotalanol (4) against rat intestinal R-glucosidases
(maltase, sucrase, and isomaltase) revealed that the des-
ulfonated analogues were either equivalent or better inhibitors
than the parent compounds.7,15,16 Furthermore, we have
shown recently that de-O-sulfonated kotalanol (5) (Ki ) 0.03
( 0.01 µM) is more potent an inhibitor of the N-terminal
(10) Jayakanthan, K.; Mohan, S.; Pinto, B. M. J. Am. Chem. Soc. 2009,
131, 5621–5626
.
(11) Mohan, S.; Pinto, B. M. Carbohydr. Res. 2007, 342, 1551–1580
(12) Mohan, S.; Pinto, B. M. Collect. Czech. Chem. Commun. 2009,
74, 1117–1136
.
Figure 3. De-O-sulfonated ponkoranol and its 5′-stereoisomer.
.
(13) Johnston, B. D.; Jensen, H. H.; Pinto, B. M. J. Org. Chem. 2006,
71, 1111–1118.
(14) Tanabe, G.; Xie, W. J.; Ogawa, A.; Cao, C. N.; Minematsu, T.;
Yoshikawa, M.; Muraoka, O. Bioorg. Med. Chem. Lett. 2009, 19, 2195–
2198.
Our previous work with kotalanol analogues had suggested
that the configuration at C-5′ was not critical for inhibitory
(15) Matsuda, H.; Yoshikawa, M.; Murakami, T.; Tanabe, G.; Muraoka,
O. J. Trad. Med. 2005, 22, 145–153.
(17) Sim, L.; Jayakanthan, K.; Mohan, S.; Nasi, R.; Johnston, B. D.;
Pinto, B. M.; Rose, D. R. Biochemistry 2010, 49, 443–451.
(16) Ozaki, S.; Oae, H.; Kitamura, S. J. Nat. Prod. 2008, 71, 981–984
.
Org. Lett., Vol. 12, No. 7, 2010
1633

activity.17,18 We report here an efficient synthetic route to
de-O-sulfonated ponkoranol 8 and its 5′-stereoisomer 9 and
show that they are very potent inhibitors of the amino
terminal catalytic domain of human maltase glucoamylase
(ntMGAM).19
p-toluenesulfonyl ester 1324 in HFIP at 70 °C proceeded
smoothly and yielded the sulfonium ion 14 (Scheme 3). The
Scheme 3. Second Attempted Synthesis of 8
The sulfonium ions A could be synthesized by alkylation
of an appropriately protected 1,4-anhydro-4-thio-D-arabinitol
B at the ring sulfur atom with agent C. The desired
stereochemistry at C-5′ could be readily obtained by choice
of either D-glucose or D-mannose as starting material
(Scheme 1).
Scheme 1. Retrosynthetic Analysis
benzyl groups of compound 14 were removed by treatment
with boron trichloride at -78 °C in CH2Cl2. However,
attempts to hydrolyze the methyl glycoside 15 with 2 M HCl
were not successful, and decomposition of the product was
observed. Therefore, a benzyl glycoside was chosen as a
protecting group at the anomeric position to ensure its facile
removal after the coupling reaction. Thus, benzyl 6-O-p-
toluenesulfonyl-R-D-gluco 17 or mannopyranoside 20 were
readily prepared from D-glucose and D-Mannose, respec-
tively, according to literature procedures.25-27 The thioether
12 was reacted with 17 in HFIP containing K2CO323 to give
the protected sulfonium ion 18 in 52% yield (Scheme 4).
Initially, the S-alkylation of thioarabinitol 1220 with methyl
6-iodo-ꢀ-D-glucopyranoside 1121 in CH3CN using AgBF4 at
65 °C was examined, based on the procedure that has been
reported for S-alkylation with simple alkyl halides (Scheme
2).22 No product formation and decomposition of the starting
Scheme 2. First Attempted Synthesis of 8
Scheme 4. Synthesis of Compound 8
material were observed by TLC; the reaction in 1,1,1,3,3,3-
hexafluoroisopropyl alcohol (HFIP)23 as a solvent was also
unsuccessful. In contrast, the coupling reaction with the
The benzyl groups were then removed by treatment with
boron trichloride at -78 °C in CH2Cl2. During the course
of deprotection, the p-toluenesulfonate counterion was
(18) Nasi, R.; Patrick, B. O.; Sim, L.; Rose, D. R.; Pinto, B. M. J. Org.
Chem. 2008, 73, 6172–6181.
(19) Rossi, E. J.; Sim, L.; Kuntz, D. A.; Hahn, D.; Johnston, B. D.;
Ghavami, A.; Szczepina, M. G.; Kumar, N. S.; Sterchi, E. E.; Nichols, B. L.;
Pinto, B. M.; Rose, D. R. FEBS J. 2006, 273, 2673–2683.
(20) Satoh, H.; Yoshimura, Y.; Sakata, S.; Miura, S.; Machida, H.;
Matsuda, A. Bioorg. Med. Chem. Lett. 1998, 8, 989–992.
(21) Skaanderup, P. R.; Poulsen, C. S.; Hyldtoft, L.; Jorgensen, M. R.;
Madsen, R. Synthesis 2002, 1721–1727.
(24) Pellowska-Januszek, L.; Dmochowska, B.; Skorupa, E.; Chojnacki,
J.; Wojnowski, W.; Wis´niewski, A. P. Carbohydr. Res. 2004, 339, 1537–
1544.
(25) Andreana, P. R.; Sanders, T.; Janczuk, A.; Warrick, J. I.; Wang,
P. G. Tetrahedron Lett. 2002, 43, 6525–6528
.
(22) Sankar, M.; Sim, L.; David, R. R.; Pinto, B. M. Carbohydr. Res.
2007, 342, 901–912.
(26) Branchaud, B. P.; Meier, M. S. J. Org. Chem. 1989, 54, 1320–
1326
.
(23) Ghavami, A.; Sadalapure, K. S.; Johnston, B. D.; Lobera, M.;
Snider, B. B.; Pinto, B. M. Synlett 2003, 1259–1262.
(27) Koto, S.; Inada, S.; Yoshida, T.; Toyama, M.; Zen, S. Can. J. Chem.
1981, 59, 255–259
.
1634
Org. Lett., Vol. 12, No. 7, 2010

partially exchanged with chloride ion. Similar results were
observed in previous work from our laboratory.22 Hence,
after removal of the benzyl groups, the product was
subsequently treated with Amberlyst A-26 resin (chloride
form) to completely exchange the p-toluenesulfonate coun-
terion with chloride ion. Finally, the crude product was
reduced with NaBH4 to provide the desired de-O-sulfonated
ponkoranol 8 in 48% yield over three steps (Scheme 4). The
other diastereomer was obtained similarly. Thus, compound
20 was reacted with the thioether 12 to give the protected
sulfonium ion 21 in 47% yield which was converted, as
before, to the desired compound 9 in 41% yield over three
steps (Scheme 5).
Figure 4. 1D-NOESY correlations of selected protons in com-
pounds 18 and 21.
ranol 8 and its 5′-stereoisomer 9 inhibited ntMGAM with
Ki values of 43 ( 3 and 15 ( 1 nM, respectively, both
significantly lower than that (170 ( 3019) for ponkoranol
(3) itself (Table 1). Thus, it would appear that de-O-
sulfonation is beneficial. We have attributed this fact
previously to alleviation of steric compression of the sulfate
anion in a hydrophobic pocket within the active site of
ntMGAM.18 The Ki values for 8 and 9 compare to a Ki value
for de-O-sulfonated kotalanol of 30 ( 1 nM.17 It would
appear, therefore, that the configuration at C-5′ is not critical
for dictating enzyme inhibitory activity against ntMGAM
and, furthermore, that extension of the acyclic carbon chain
beyond six carbons is not essential. We note that 9 is the
most potent compound to date in this class of molecules.
Scheme 5. Synthesis of Compound 9
Acknowledgment. We are grateful to the Canadian
Institutes for Health Research (FRN79400) and the Heart
and Stroke Foundation of Ontario (NA-6305) for financial
support.
The absolute stereochemistry at the stereogenic sulfur
center in 18 and 21 was established by means of 1D-NOESY
experiments (Figure 4) which showed H-4 to H-6′ correla-
tions, implying that these atoms are syn-facial with respect
to the sulfonium salt ring.
Finally, we comment on the inhibitory activities of
compounds 8 and 9 against the N-terminus of recombinant
human maltase glucoamylase (ntMGAM),19 a critical intes-
tinal glucosidase for postamylase processing of starch-derived
oligosaccharides into glucose. The de-O-sulfonated ponko-
Supporting Information Available: Experimental pro-
1
cedures, characterization data, H and 13C NMR spectra of
compounds 8, 9, 14, 18, and 21, and 1D-NOESY spectra of
compounds 18 and 21. This material is available free of
charge via the Internet at http://pubs.acs.org.
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