Untersuchungen zur struktur des α-d-glucosidaseinhibitors acarbose

Junge, Bodo; Heiker, F. R.; Kurz, Jürgen; Müller, Lutz; Schmidt, Delf; Wünsche, Christian

doi:10.1016/0008-6215(84)85333-1

Cited by 96 publications

(41 citation statements)

References 16 publications

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“…Structurally it has two moieties: a maltose and a pseudodisaccharide acarviosine; acarviosine is composed of an unsaturated aminocyclitol, valienamine, which is connected via a nitrogen bridge to C-4 of a 6-deoxy-D-glucose (Bowers et al 2002;Degwert et al 1987;Mahmud 2003;Parenti and Coronelli 1979;Truscheit et al 1981). The valienamine moiety, which mimics the structure of glucose in an a configuration, is the active pharmacophore responsible for the inhibition of intestinal a-glucosidase and sucrase (Junge et al 1984;Mahmud et al 2001;Zheng et al 2005). In this way, a-glucosidases' capacity to digest saccharides is almost competitively blocked by acarbose, which has been developed as a powerful hypoglycemic agent to better control blood sugar levels in patients with NIDDM.…”

Section: Introductionmentioning

confidence: 99%

Optimization of media composition and culture conditions for acarbose production by Actinoplanes utahensis ZJB-08196

Wang

Liu

Feng

et al. 2011

World J Microbiol Biotechnol

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Acarbose is a clinically useful drug for the treatment of type II, insulin-independent diabetes as a hypoglycemic agent. An acarbose-overproducing strain ZJB-08196, indentified as Actinoplanes utahensis, was able to produce 4,210 mg l -1 of acarbose at 591 mOsm kg -1 with the optimized conditions at bench scale. Shake flask fermentation showed that maltose, glycerol and monosodium glutamate were supportive for acarbose production; soybean meal had higher bioavailability than corn steep liquor. Moreover, acarbose formation was not parallel with mycelial growth and the pattern of acarbose production by A. utahensis ZJB-08196 was the type of mixed-growth associated.

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Section: Introductionmentioning

confidence: 99%

Optimization of media composition and culture conditions for acarbose production by Actinoplanes utahensis ZJB-08196

Wang

Liu

Feng

et al. 2011

World J Microbiol Biotechnol

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“…However, treatment of the bromide 62, accessible from Ferrier's ketone, with the amino sugar derivative 63, accessible from maltose, gives the target molecule 64 in only 5% yield after a difficult separation (SAKAIRI and KUZUHARA 1982 The two D-glucose units of acarbose are of subordinated importance for the in vitro activity on sucrase (JUNGE et al 1984a). This is shown by the fact that a-methylacarviosin (33) is somewhat more effective than acarbose.…”

Section: Acarbosementioning

confidence: 98%

“…Acarbose provides the physician with the first new therapeutic principle for the treatment of diabetes in nearly 40 years. Determination of the structure of the pseudotetrasaccharide acarbose (44) is based partlyon spectroscopic studies and also on aseries of degradation reactions which break acarbose down into several sm all fragments with known structures (JUNGE et al 1984a The products of this cleavage are two small molecules, one of which, validatol (48), is known from the literature (HORII et al 1971b). The isolation of 48 gave important information on the stereochemistry of the cyclitol part of acarbose.…”

Section: Acarbosementioning

confidence: 99%

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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“…Acarbose (Figure 8, 46) [99,100] is one of the most clinically important compounds containing carbasugar units, since it is currently used for the treatment of type II insulinindependent diabetes. This disease is a metabolic disorder that is characterized by hyperglycemia in the context of insulin resistance and relative lack of insulin [101,102].…”

Section: Natural Carbapyranosesmentioning

confidence: 99%

Biosynthesis and Biological Activity of Carbasugars

Roscales

Plumet

2016

International Journal of Carbohydrate Chemistry

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The first synthesis of carbasugars, compounds in which the ring oxygen of a monosaccharide had been replaced by a methylene moiety, was described in 1966 by Professor G. E. McCasland's group. Seven years later, the first true natural carbasugar (5a-carba-R-D-galactopyranose) was isolated from a fermentation broth of Streptomyces sp. MA-4145. In the following decades, the chemistry and biology of carbasugars have been extensively studied. Most of these compounds show interesting biological properties, especially enzymatic inhibitory activities, and, in consequence, an important number of analogues have also been prepared in the search for improved biological activities. The aim of this review is to give coverage on the progress made in two important aspects of these compounds: the elucidation of their biosynthesis and the consideration of their biological properties, including the extensively studied carbapyranoses as well as the much less studied carbafuranoses.

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Untersuchungen zur struktur des α-d-glucosidaseinhibitors acarbose

Cited by 96 publications

References 16 publications

Optimization of media composition and culture conditions for acarbose production by Actinoplanes utahensis ZJB-08196

Optimization of media composition and culture conditions for acarbose production by Actinoplanes utahensis ZJB-08196

Chemistry and Structure-Activity Relationships of Glucosidase Inhibitors

Biosynthesis and Biological Activity of Carbasugars

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