Studies on Glycan Processing Inhibitors: Synthesis of N-Acetylhexosamine Analogs and Cyclic Carbamate Derivatives of 1-Deoxynojirimycin

Kiso, Makoto; Kitagawa, Masayuki; Ishida, Hideyuki; Hasegawa, Akira

doi:10.1080/07328309108543888

Cited by 30 publications

(10 citation statements)

References 15 publications

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“…Activation of the 6-OH with a leaving group, for example, tosyl, followed by acetylation resulted in attack from the N-Boc protecting group leading to the cyclic carbamate 31. [31] However, when using activation with the bulky N,N,N',N',N'',N''-hexaA C H T U N G T R E N N U N G methylphosphinetriamine (HMPT) in tetrachloromethane and pyridine to give the intermediate 32, followed by treatment with sodium methoxide, the desired 3,6-anhydro compound with an intact Boc protection could be isolated in a modest yield. Due to rotamers from the Boc group in 33 a small amount was acetylated to confirm the structure.…”

Section: Resultsmentioning

confidence: 99%

“…Attempts to synthesize the all axial 3,6‐anhydro‐1‐deoxynojirimycin 34 from the standard procedures used for 3,6‐anhydro sugars were not successful (Scheme ). Activation of the 6‐OH with a leaving group, for example, tosyl, followed by acetylation resulted in attack from the N ‐Boc protecting group leading to the cyclic carbamate 31 31. However, when using activation with the bulky N,N,N',N',N'',N'' ‐hexamethylphosphinetriamine (HMPT) in tetrachloromethane and pyridine to give the intermediate 32 , followed by treatment with sodium methoxide, the desired 3,6‐anhydro compound with an intact Boc protection could be isolated in a modest yield.…”

Section: Resultsmentioning

confidence: 99%

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Quantifying Electronic Effects of Common Carbohydrate Protecting Groups in a Piperidine Model System

Heuckendorff

Pedersen

Bols

2010

Chemistry A European J

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A study of the substituent effects of protecting groups in hydroxypiperidines was carried out and compared with the electronic effects in glycosylation chemistry. 1-Deoxynojirimycin, the aza-sugar analogue of 1-deoxy-D-glucose, was used as a carbohydrate model, and protected with the most common carbohydrate protecting groups. The different stabilization of positive charge on the ring heteroatom was determined by pK(a) measurements. The protecting groups could be ranked in the following way after their destabilization of the piperidinium ion: benzoyl ≥ acetyl ≫ 4,6-O-benzylidine >benzyl ≈ methyl > H > 3,6-anhydro > tert-butyldimethylsilyl. The observed effects of having protecting groups with different electronic characteristics were found to be in agreement with the "armed-disarmed" concept. Comparison of the pK(a) of benzylated and benzoylated epimers of 3-hydroxy-6-hydroxymethyl piperidines showed increased stabilization of the piperidinium ion in the axial epimer. The difference between axial and equatorial epimers was larger in the benzylated than in the benzoylated piperidines.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Quantifying Electronic Effects of Common Carbohydrate Protecting Groups in a Piperidine Model System

Heuckendorff

Pedersen

Bols

2010

Chemistry A European J

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“…Although some 3-acetamido iminosugar derivatives have been reported we could not find precedents of evaluation of their properties as glycosidase inhibitors. 41,58,59 We thus considered it of interest to apply the above synthetic sequence to azido alcohol 20, i.e. benzylation (26), azide reduction and acetylation of the resulting amine (27), basic hydrolysis of the cyclic carbamate group (28) and final hydrogenolysis of the benzyl protecting groups.…”

Section: Resultsmentioning

confidence: 99%

“…[32][33][34] Most synthetic approaches to iminosugars are based on the chiral pool thus making these processes rather long. [35][36][37][38][39] This is also the case for acetamido iminosugars, 13,16,40,41 with a few exceptions limited to the stereoselective synthesis of 2-acetamido-1,2-dideoxyallonojirimycin (DAJNAc, 9) 42 and the manno diastereomer DMJNAc (5). 17 Herein, we report a new stereoselective total synthesis of the gluco counterpart DNJNAc (4) and its regioisomer 3-acetamido-1,3-dideoxyaltronojirimycin (29).…”

Section: Introductionmentioning

confidence: 93%

Stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc) and ureido-DNJNAc derivatives as new hexosaminidase inhibitors

et al. 2015

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2-Acetamido-1,2-dideoxyiminosugars are selective and potent inhibitors of hexosaminidases and therefore show high therapeutic potential for the treatment of various diseases, including several lysosomal storage disorders. A stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc), the iminosugar analog of N-acetylglucosamine, with high overall yield is here described. This novel procedure further allowed accessing ureidoDNJNAc conjugates through derivatization of the endocyclic amine on a key pivotal intermediate. Remarkably, some of the ureido-DNJNAc representatives behaved as potent and selective inhibitors of β-hexosaminidases, including the human enzyme, being the first examples of neutral sp 2 -iminosugar-type inhibitors reported for these enzymes. Moreover, the amphiphilic character of the new ureido-DNJNAc is expected to confer better drug-like properties.

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“…48). 4,6-Acetals 215a-c open access to various 1-deoxynojirimycin derivatives such as 1,2,3-trideoxynojirimycin (216) (JUNGE et al 1989), 4-amino-(218) and 2-acetylamino-deoxynojirimycins (217) (JUNGE et al 1989;KISO et al 1991), and fluoro derivatives such as 3-fluoro-1-deoxynojirimycin (219) OE CRESCENZO 1991, 1992a,b;cf. ARNONE et al 1993) (Fig.…”

Section: Deoxy Amino and Halogen Derivativesmentioning

confidence: 98%

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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Studies on Glycan Processing Inhibitors: Synthesis of N-Acetylhexosamine Analogs and Cyclic Carbamate Derivatives of 1-Deoxynojirimycin

Cited by 30 publications

References 15 publications

Quantifying Electronic Effects of Common Carbohydrate Protecting Groups in a Piperidine Model System

Quantifying Electronic Effects of Common Carbohydrate Protecting Groups in a Piperidine Model System

Stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc) and ureido-DNJNAc derivatives as new hexosaminidase inhibitors

Chemistry and Structure-Activity Relationships of Glucosidase Inhibitors

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