Synthesis of a Nitrogen Analogue of Salacinol and Its .ALPHA.-Glucosidase Inhibitory Activity.

Abstract

A nitrogen analogue 4 of the naturally occurring sulfonium ion salacinol (1), a potent a a-glucosidase inhibitor isolated from the Ayruvedic medicine Salacia reticulata, was synthesized and its inhibitory activity against a a-glucosidase tested. Substitution of the sulfur atom in 1 with a nitrogen reduced the activity considerably. The solid-state stereostructure of the related compound (5) was determined on the basis of single crystal X-ray measurement.Key words cyclic sulfate; erythritol; salacinol; glycosidase inhibitor; glucosidase inhibitor; azasugar Salacinol (1) is a potent glycosidase inhibitor isolated from the aqueous extracts of the roots and stems of Salacia reticulata WIGHT (known as Kotala himbutu in Singhalese), which is traditionally used in Sri Lanka and India for the treatment of diabetes. The a-glucosidase inhibitory activity of 1 was confirmed to be as strong as that of acarbose, which is used clinically.1) The structure of 1 is unique in that the ring sulfonium ion is stabilized by a sulfate counteranion by forming a spirobicyclic-like configuration comprised of 1-deoxy-4-thioarabinofranosyl cation and 1-deoxyerythrosyl-3-sulfate anion, as shown in Chart 1. Due to both the extraordinary high glycosidase inhibitory activity and the intriguing structure, much attention has been focused on 1 and related compounds.2) Total synthesis of 1 was accomplished recently by two groups 3) independently on the basis of the same strategy. In both cases, the key step in the synthesis was the ring opening of the cyclic sulfate (2) by nucleophilic attack of 1,4-dideoxy-1,4-epitio-D-arabinitol (3a). Structure-activity relationships between some related sulfonium compounds and the glycosidase inhibitory activity have also been reported. 3b,4) On the other hand, polyhydroxylated pyrrolidines [azasugars, e.g. 1,4-dideoxy-1,4-imino-D-arabinitol (3b)] have been known to function as potent inhibitors of glycosidase because of their ability to mimic carbohydrates. 5) Structural modification of 1 represents a promising approach in the search for new antidiabetic agents. One strategy is to replace the thiosugar sulfur in 1 with a nitrogen, which gives the azacyclic version (4) of 1. The recent report by Ghavami et al. 6) on the synthesis of nitrogen analogues of 1 involving 4 and their evaluation as glycosidase inhibitors prompts us to report our own findings. This communication describes the synthesis of 4 and comparison of its a-glucosidase inhibitory activity with that of 1. The solid-state stereostructure of the related compound, 1Ј-(1-pyrrolidiniumyl)-2Ј,4Ј-O-isopropylidene-1Ј-deoxy-L-erythritol-3Ј-sulfate (5) is also presented.Synthesis of 4 was carried out by applying the ring-opening method developed by Yuasa 3a) and Ghavami 3b) for the synthesis of 1. The cyclic sulfate 2a, 3a) however, was synthesized starting from D-glucose (D-6), which is much less expensive than the L-isomer (L-6). Thus compound D-6 was first converted into 4,6-O-benzylidene-D-glucose (7) according to the protocol developed by Barili...

Punica granatum flower extract, a potent α-glucosidase inhibitor, improves postprandial hyperglycemia in Zucker diabetic fatty rats

“…As for most natural medicines, however, their action mechanisms need to be clarified. Although some herbal medicines have been reported to inhibit ␣-glucosidase activity, most of the experiments have been limited to in vitro studies or to normal or chemical-induced diabetic animal models only (Kim et al, 1999(Kim et al, , 2004Muraoka et al, 2001;Ye et al, 2002;Pan et al, 2003;Yoshikawa et al, 2003). In the present study, PGF extract markedly reduced plasma glucose levels in non-fasted ZDF rats, but affected neither the levels in fasted ZDF rats, nor interfered with plasma glucose levels in normal mice.…”

Leads from Indian medicinal plants with hypoglycemic potentials

“…Studies by Karunanayake et al (1984) and Yoshikawa et al (1998) suggested the hypoglycemic activity and possible mechanism behind the activity of the plant ( Table 1). The plant contains Salacinol, a potent alpha-glucosidase inhibitor (Muraoka et al, 2001), which may account for the glucose lowering effect of the plant. A clinical trial investigating the effects of Salacia reticulata Wight.…”

Absolute Stereostructures of Polypodane-Type Triterpenes, Myrrhanol A and Myrrhanone A, from Guggul-Gum Resin (the Resin of Balsamodendron mukul)

“…The sesquiterpene constituents isolated from myrrh, furanoeudesma-1,3-diene and curzarene, have analgesic effects that are blocked by naloxone, explaining the use of myrrh as a painkiller in ancient times. 6) However, because of its toxicity, myrrh is not used in medicines today, except as a mouthwash in India.In the course of our characterization studies on traditional Ayurvedic medicines, [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] we found that the 50% aqueous methanolic extract of guggul (the resin of B. mukul) showed an anti-inflammatory effect on adjuvant-induced air pouch granuloma in mice. From the extract, two new polypodanetype triterpenes, myrrhanol A (1) and myrrhanone A (2), were isolated as the active components.…”