Glycosidases inhibitors

Three classes of oral therapeutic agent are available for treating patients with diabetes mellitiis (NIDDM) the arylsulfonylureas (known simply as sulfonylureas), biguanides, and a-glycosidase inhibitors. Since 1977, only the sulfonylureas have been approved for use in the United States, although the other classes are used elsewhere. 

Sinnlarly, f-i- -casuralme, a pentahydroxy pyrrolizidine alkaloid, is prepared by a tandem [4-i-3 /[3-i-3 cycloadchdon involving nitroalkene, chiral vinyl ether, and vinyl silane This process creates five of the six stereocenters present in this potent glycosidase inhibitor fScheme 8 35 ... 

Figure 10.31 Synthetic route to oxygenated pyrrolizidine alkaloids, and an aza-C-disaccharide as glycosidase inhibitors.

Triazoline imino sugar derivatives 297 that are prospective glycosidase inhibitors have been prepared as single diastereomers in high yield via an lAOC reaction of in situ generated azido alkene 296 (Eq. 32) [78]. m-CPBA oxidation of the dithioacetal groups in the 0-acetylated 5-azido-5-deoxydibenzyl dithio-acetal of o-xylose or D-ribose 294 to the bis-sulfone 295, followed by loss of HOAc between C-1 and C-2 provided the lAOC precursor 296. 

A case similar to the slow, practically irreversible inhibition of jack bean a-D-mannosidase by swainsonine is represented by the interaction of castanospermine with isomaltase and rat-intestinal sucrase. Whereas the association constants for the formation of the enzyme-inhibitor complex were similar to those of other slow-binding glycosidase inhibitors (6.5 10 and 0.3 10 M s for sucrase and isomaltase, respectively), the dissociation constant of the enzyme-inhibitor complex was extremely low (3.6 10 s for sucrase) or could not be measured at all (isomaltase), resulting in a virtually irreversible inhibition. Danzin and Ehrhard discussed the strong binding of castanospermine in terms of the similarity of the protonated inhibitor to a D-glucosyl oxocarbenium ion transition-state, but were unable to give an explanation for the extremely slow dissociation of the enzyme-inhibitor complex. 

In 1999, this methodology was applied to the synthesis of unnatural biologically active ( + )-5-epi-nojirimycin-5-lactam, a potent and selective glycosidase inhibitor.The key step of this synthesis was the asymmetric reduction of a cyclic triacetyloxy meso imide under the same conditions to those described above, which resulted in the formation of the corresponding hydroxy 5-lactam in good yield and enantioselectivity of 85% ee (Scheme 10.59). 

Martin has used this strategy for the preparation of (3-(l,6) and P,(3-(l,l) hnked C-disaccha-rides, as shown in Scheme 7.7.73 Such C-disaccharides are a class of nonhydrolyzable mimics of disaccharide and potential glycosidase inhibitors in the treatment of metabolic diseases (Scheme 7.7). 

The total syntheses of the potent glycosidase inhibitors (+)-castanospermine, (+)-6-epicas-tanosperimine, (+)-australine, and (+)-3-epiaustraline have been reported. These four natural products are derived from a single common intermediate, the nitroso acetal (as shown in Scheme 8.43), which is created in the key step by the asymmetric tandem [4+2]/[3+2] cycloaddition between silaketal nitroolefin and chiral vinyl ether.182 The strategy of the synthesis is outlined in Scheme 8.43. Scheme 8.44 presents a total synthesis of (+)-castanosperimine and (+)-6-epi-castanosperimine from the common intermediate prepared by tandem [4+2]/[3+2] cycloaddition. 

Many polyhydroxylated quinolizidines <1995CRV1677>, frequently designed as azasugars, are powerful glycosidase inhibitors and therefore have potential therapeutic application. The 7-oxa-l-azabicyclo[2.2.1]heptane derivative 191, obtained from 3-0-benzyl-l,2-0-isopropylidene-l,5-pentadialdo-a-D-xylofuranose with... 

The synthesis of a bridgehead sulfonium salt analogue 59, of the naturally occurring glycosidase inhibitor castanospermine, proceeded by a multistep procedure starting from 5-thio-d-glucopyranose pentaacetate <2000JA10769>. The desired bicyclic sulfonium salt 57 could not be obtained from the key bromide precursor... 

Intermolecular Reactions Intermolecular 1,3-dipolar cycloaddition reactions of nitrones to olefins seem to be the most studied. They are widely used for the synthesis of different enantiomerically pure compounds, including biologically active ones. For example, two new glycosidase inhibitors have been obtained by the nitrone cycloaddition strategy (Fig. 2.32) (733). 

The resulting derivatives (269) can be considered as strategically important intermediates in the synthesis of glycosidase inhibitors and carbocyclic nucleosides (150). A new approach to the stereoselective synthesis of the piperidine ring with the use of [4+ 2] [3+ 2]-cycloaddition from specially prepared substrates is also very interesting (431)b, c. In the context of this problem, the conditions for the formation of systems containing quaternary vicinal stereocenters were found. 

Recent research deals with stereoselective 1,3-dipolar cycloadditions of nitrones for the syntheses of alkaloids and aza heterocycles asymmetric synthesis of biologically active compounds such as glycosidase inhibitors, sugar mimetics, /3-lactams, and amino acids synthesis of peptido-mimetics and peptides chemistry of spirocyclopropane heterocycles synthesis of organic materials for molecular recognition and photochemical applications. 

Polyhydroxylated indolizidines have attracted considerable interest due to their potent activity as glycosidase inhibitors. Some analogues of these molecules bearing a sulfur instead of a carbon atom at the anomeric position such as 430-432 have been prepared (Scheme 112). Compound 431 was shown to give a 3/7 mixture of epimers at the anomeric position in DzO. 

Preparation of polyhydroxylated 6-oxanortropane glycomimetics (e.g. 32), structurally related to the glycosidase inhibitor family of the calystegines, was reported. The synthetic strategy involves the furanose/piperidine... 

In this context it is interesting to note that also glyconolactones, in which the anomeric carbon is hybridized sp2, are week glycosidase inhibitors.3... 

O. Lopez and M. Bols, Isofagomine, neouromycin and other 1-azasugars, imino sugars-related glycosidase inhibitors, in Imino sugars, from synthesis to therapeutic applications, ed. P. Compain and O. Martin, Wiley, 2007, pp. 131-151. 

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