Inhibition of mammalian digestive disaccharidases by polyhydroxy alkaloids

Scofield, A. M.; Fellows, Linda E.; Nash, Robert J.; Fleet, George W. J.

doi:10.1016/0024-3205(86)90046-9

Cited by 138 publications

(59 citation statements)

References 22 publications

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“…In contrast to their sensitivity toward castanospermine, the hydrolyses ofsinigrin and PNPG were unaffected by swainsonine (250 AM) and deoxynojirimycin (100 gM). This agrees with earlier reports that swainsonine specifically inhibits a-mannosidases (5,21) and that the piperidine alkaloid deoxynojirimycin, an analogue of rglucose, was a potent inhibitor of a-glucosidases (16,20) but was much weaker or inactive against fl-glucosidases (16,17,21).…”

Section: Purification and Physical Properties Of Cress Myrosinasesupporting

confidence: 82%

Effect of Castanospermine and Related Polyhydroxyalkaloids on Purified Myrosinase from Lepidium sativum Seedlings

Durham

Poulton²

1989

Plant Physiol.

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Myrosinase (ft-thioglucoside glucohydrolase, EC 3.2.3.1) was purified to apparent homogeneity from light-grown cress (Lepidium sativum L.) seedlings. This enzyme, which catalyzes hydrolysis of the glucosinolate sinigrin (K,, 115 micromolar) at an optimum pH of 5.5 in sodium citrate buffer, had a native molecular weight of 130 ± 5 kilodaltons and an isoelectnc point of 4.7 to 4.9. SDS-PAGE revealed two polypeptides with molecular weights of 62 and 65 kilodaltons. values of 5 and 6 micromolar, respectively. In contrast, the related polyhydroxyalkaloids swainsonine and deoxynojirimycin were without effect upon these hydrolyses.

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Section: Purification and Physical Properties Of Cress Myrosinasesupporting

confidence: 82%

Effect of Castanospermine and Related Polyhydroxyalkaloids on Purified Myrosinase from Lepidium sativum Seedlings

Durham

Poulton²

1989

Plant Physiol.

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“…No Kj va lues were determined, the figures cited being relative values for the inhibitory effect in comparison to acarbose. These data differ in a few cases from so me results in the literature, which are also not always consistent (LEMBCKE et al 1985;SCOFIELD et al 1986;SAMULITIS et al 1987;YOSHIKUNI et al 1988;ROBINSON et al 1991ROBINSON et al , 1992. This is partly due to the fact that the disaccharidases used are not pure enzymes and originated from the sm all intestines of various mammalian sources (pig, rabbit, rat, mouse).…”

Section: -Deoxynojirimycincontrasting

confidence: 69%

“…It was also discovered in the culture broths of various species of Streptomyces lavendulae (MATSUMURA et al 1979c;MlTsuo and SAWAO 1980;MURAO and MIYATA 1980;EZURE et al 1985) and S. subrutilus (HARDICK et al 1991(HARDICK et al ,1992. Compared with nojirimycin, 1-deoxynojirimycin is a weaker inhibitor of nonmammalian and mammalian ß-glucosidases (NIWA et al 1970;see also: TRUSCHEIT et al 1981;MÜLLER 1985;SCOFIELD et al 1986;TRUSCHEIT 1987;ELBEIN 1987;TRUSCHEIT et al 1988;YOSHIKUNI et al 1988;LEGLER 1990;NISHIMURA 1991;YOSHIKUNI 1991;ROBINSON et al 1992;HUGHES and RUDGE 1994). However, the discovery of the inhibitory effect on mammalian a-glucosidases opened the possibility of a therapeutic application for 1-deoxynojirimycin.…”

Section: I-deoxynojirimycinmentioning

confidence: 91%

“…DMDP has also been prepared from D-glucose (FLEET andSMITH 1985, 1987), from D-mannitol (DUREAULT et al 1991), and by an enzyme-catalyzed reaction of 2-azido-3-hydroxypropanal with dihydroxyacetone phosphate (DHAP), in which rabbit muscle aldolase (RAMA) was used as the catalytic enzyme (HuNG et al 1991). HO~~ HO OH HO DMDP is a distinctly weaker inhibitor of intestinal disaccharidases from mice (SCOFIELD et al 1986), rabbits (YOSHIKUNI 1988), and chickens (KITE et al 1990) than deoxynojirimycin or castanospermine (Table 16). This can undoubtedly be explained by the weaker structural similarity of DMDP to the transition state of the cleavage of a-glucosides.…”

Section: Monocyclic Pyrrolidine Derivativesmentioning

confidence: 99%

“…A comprehensive survey of the syntheses of castanospermine and its epimers and analogues has been published by BURGESS and HENDERsoN (1992). Castanospermine (222) is a strong inhibitor of various intl;:stinal glucosidases (SCOFIELD et al 1986;DANZIN and EHRHARD 1987;RHINEHART et al 1987b). In addition, 222 inhibits a wide range of a-and ß-glucosidases derived from plant as weil from animal and human sources PAN et al 1983;HORI et al 1984;SAUL et al 1984;SASAK et al 1985;GROSS et al 1986;CHAMBERS and ELBEIN 1986;TRUGNAN et al 1986;ELLMERS et al 1987;SUNKARA et al 1989).…”

Section: Castanosperminementioning

confidence: 99%

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Chemistry and Structure-Activity Relationships of Glucosidase Inhibitors

Junge¹,

Matzke²,

Stoltefuß³

1996

Oral Antidiabetics

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A. IntroductionWhen intestinal sucrase and pancreatic a-amylase were identified at Bayer as new targets for improved diabetes therapy (PULS et al. 1973), the problem remained of the best way to find a potent and selective inhibitor of these enzymes. The medicinal chemist today has two alternatives in the search for a first lead compound, firstly the screening of thousands of compounds with maximum structural diversity in a random screening approach, or secondly the rational design of a lead compound, when the biochemical mechanism and the structure of the enzyme are weIl known. In the late 1960s, when we started to look for such potent and selective inhibitors, we had to choose the random screening approach, relying mainly on testing of extracts of the culture broths of microorganisms.Today the mechanism of enzymatic splitting of sucrose by intestinal sucrase is fairly weIl understood. First the glucosidic oxygen atom of sucrose is protonated via a carboxyl group of the enzyme. The splitting of the glucosidic C-O bond is further facilitated by the glucosyl cation being stabilized by a second carboxylate group of the enzyme (COGOLI and SEMENZA 1975). FinaIly, the glucosyl cation reacts with water to give the products 0-glucose and o-fructose. The protonated sucrose molecule land the glucosyl cation 11 are two high-energy intermediates of the enzymatic reaction. Today we know that mimics of such high-energy intermediates are often potent inhibitors of the enzyme. Accordingly, compounds similar in structure to o-glucose but with an easily protonated basic N-atom either in the position of the anomeric oxygen atom (inhibitor type I) or in the position of the ring oxygen atom (inhibitor type 11) should be potent inhibitors of sucrase (Fig. 1). Interestingly, both types of inhibitors represented by either acarbose or I-deoxynojirimycin were found in our random screening. In the foIlowing sections these two types of inhibitors are not discussed in a historical order but under structural criteria. Not included in this discussion are the a-amylase inhibitors of protein nature because there is no evidence that they will find any therapeutic application.

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Localization and Catabolism of Cyanogenic Glycosides

Poulton

2007

Ciba Foundation Symposium 140 ‐ Cyanide Compounds in Biology

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Inhibition of mammalian digestive disaccharidases by polyhydroxy alkaloids

Cited by 138 publications

References 22 publications

Effect of Castanospermine and Related Polyhydroxyalkaloids on Purified Myrosinase from Lepidium sativum Seedlings

Effect of Castanospermine and Related Polyhydroxyalkaloids on Purified Myrosinase from Lepidium sativum Seedlings

Chemistry and Structure-Activity Relationships of Glucosidase Inhibitors

Localization and Catabolism of Cyanogenic Glycosides

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