Isolation, structure identification and SAR studies on thiosugar sulfonium salts, neosalaprinol and neoponkoranol, as potent α-glucosidase inhibitors

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Abstract

Two hitherto missing members of sulfonium salts family in Salacia genus plants as a new class of α-glucosidase inhibitors, neoponkoranol (7) and neosalaprinol (8), were isolated from the water extracts, and their structures were unambiguously identified. For further SAR studies on this series of sulfonium salts, several epimers of 7 and 8 were synthesized, and their inhibitory activities against rat small intestinal α-glucosidases were evaluated. Among them, 3′-epimer of 7 was found most potent in this class of molecules, and revealed as potent as currently used antidiabetics, voglibose and acarbose.

Introduction

Glucosidases are largely involved in the human metabolic system. Thus, the inhibition of glucosidases is considered to be an efficient way to treat diseases such as diabetes,1 cancers,2 viral infections3 and Gaucher’s disease.4 Many naturally occurring and synthesized azasugars, which are believed to carry a positive charge at physiological pH and hence are postulated to bind in the active sites of glucosidase enzymes, are effective inhibitors of various glucosidases.5 These evidences indicated that a potent glucosidase inhibitor might include an atom that carries a permanent positive charge at a suitable position that mimic the oxacarbenium ion-like transition state of the enzyme-catalyzed reaction.6

In late 1990s, salacinol (1) was isolated by us as a potent α-glucosidases inhibitor from an Ayurvedic medicinal plant Salacia reticulata,7 which have been traditionally used for the treatment of diabetes in Sri Lanka and south region of India. The structure of 1 was quite unique, bearing the permanent positive charge as the thiosugar sulfonium sulfate inner salt comprised of 1-deoxy-4-thio-d-arabinofranosyl cation and 3′-sulfate anion as shown in Figure 1.7 Its α-glucosidase inhibitory activity was revealed to be as potent as those of voglibose and acarbose which are widely used clinically these days.7 The mode of action of salacinol (1) was also proved to be the competitive inhibition against α-glucosidase, and Ki values against rat intestinal α-glucosidases, that is, maltase, sucrase, and isomaltase were revealed as 0.31, 0.32, and 0.47 μg/mL, respectively.7b Since the discovery of 1, related sulfonium sulfates, kotalanol8 (2), ponkoranol9 (3) and salaprinol9 (4) were subsequently isolated, and the stereostructure of these sulfonium sulfates (2, 3, 4) were elucidated by the total synthesis or other means10 (Fig. 1).

Other than 4, all these sulfonium sulfates showed potent α-glucosidase inhibitory activities, composing a new class of naturally occurring α-glycosidase inhibitors. Because of both the intriguing structure and high α-glucosidase inhibitory activities, much attention has been focused on 1, and intensive studies on the structure–activity relationships (SAR) have been reported.11

In 2008, another two compounds termed neosalacinol12 (5′) and 13-membered cyclic sulfoxide13 (6′) were reported, by Minami and Ozaki, respectively, as the constituents responsible for the α-glucosidase inhibitory activities of Salacia genus plants (Fig. 2). Shortly thereafter, these two compounds were revised to be de-O-sulfonates (514 and 615) of 1 and 2, respectively, as shown in Figure 1. It was interesting to note that desulfonated kotalanol (6) showed higher α-glucosidase inhibitory activities than the original sulfate (2).9 Ever since the discovery of the existence of 5 and 6 in Salacia genus plants, intensive exploratory study on water extracts of Salacia chinensis originated from Thailand have been conducted by us in order to isolate other minor sulfoniums. In this paper, full details of isolation and identification of desulfonates of 3 and 4, neoponkoranol (7) and neosalaprinol (8), respectively, the existence of which in the plants has been strongly expected, are described. In addition, syntheses of their epimers (3′-epi-7, 5′-epi-7, and 2′-epi-8) and SAR studies on this neo-series of compounds against rat small intestinal α-glucosidases are also presented.16

Section snippets

Isolation and Identification of Neoponkolanol (7) and Neosalaprinol (8)

A water extract was prepared in 9.87% yield in a usual manner from dried stems of S. chinensis originated from Thailand. The extract was then dissolved in water, and centrifuged. The supernatant was subjected to Diaion HP-20 column chromatography to give a water-eluted fraction (4.00%) and a MeOH-eluted fraction (1.95%). An aliquot of the H2O-eluted fraction was dissolved in MeCN/H2O (50:50, v/v) and centrifuged one more time, then the supernatant was subjected to column chromatography

Conclusions

In conclusion, by intensive exploratory studies on Salacia extracts, two prognosticated constituents, neoponkoranol (7) and neosalaprinol (8), have been isolated. The structures of 7 and 8 were unambiguously identified by comparison of their physical and spectral data with those reported or with authentic specimens alternatively synthesized. Thus, all the predicted or speculated neo-type members of the sulfonium salt so far were finally extracted out successively. One of the two newly isolated

General experimental procedures

IR spectra were measured on either a Shimadzu IR-435 grating spectrophotometer or a Shimadzu FTIR-8600PC spectrophotometer. NMR spectra were recorded on a JEOL JNM-ECA 500 (500 MHz 1H, 125 MHz 13C) or a JEOL JNM-ECA 600 (600 MHz 1H, 150 MHz 13C) or a JEOL JNM-ECA 700 (700 MHz 1H, 175 MHz 13C) spectrometers. Chemical shifts (δ) and coupling constants (J) are given in ppm and Hz, respectively. DSS was used as an internal standard in the measurement of NMR spectra in D2O, and TMS was used otherwise

Acknowledgment

This work was supported by ‘High-Tech Research Center’ Project for Private Universities: matching fund subsidy from MEXT (Ministry of Education, Culture, Sports, Science and Technology), 2007-2011.

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