Polyhydroxylated glycosidase, inhibitors

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... 

Hydroxylated nitrones 321 and 322 afford, by subsequent thermal rearrangement of the adducts, a straightforward approach to polyhydroxylated indolizidines, inhibitors of glycosidases. The total synthesis of (+ )-Len-tiginosine is representative of the process (Scheme 47) [82]. 

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... 

FIG. 2. Polyhydroxylated azepanes 9-13 that have been assayed as glycosidase inhibitors. These structures were inspired by the natural-product glycosidase inhibitors nojirimycin (14) and fagomine (15). 

Related imino alditols such as azepanes or lactam derivatives have been obtained and have shown to be glycosidase inhibitors [96, 100]. Both d- and l-gulonolactone have been converted into polyhydroxylated 1,6-aldonolactams of type 79 in a sequence of straightforward functional transformations, including sulfinylation of the corresponding aldonolactone-derived acetonides 76 that gave 5,6-cyclic sulfites 77 (Scheme 23) [101]. The latter reacted with sodium azide... 

Very few polyhydroxylated alkaloids are available commercially. Those which are available (principally DNJ, DMJ, castanospermine and swainsonine) have become standard reagents used to investigate the potential therapeutic and biochemical applications of this class of glycosidase inhibitor. So most of the following consideration of the therapeutic applications of polyhydroxylated alkaloids is based on a limited number of compounds that have been tested thoroughly, simply because these are the only ones which are readily available. It should also be noted that the doses required for beneficial effects in human disease states are generally below those causing the toxicides described in Section 1.4. 

In the preparation of polyhydroxylated azepane as potential glycosidase inhibitors, Dha-vale [28] described a short synthetic route utilizing the Henry approach. The nitroaldol reaction of l,2-0-isopropylidene-3-0-benzyl-a-D-xylo-pentodialdose 36 and nitromethane in the presence of triethylamine at room temperature afforded a-D-gluco- and /3-L-ido- nitroal-dose 37, the precursors to (2S, 3R, 4R, 5R) and (2S, 3R, 4R, 55) tetrahydroxyazepanes 38 and 39, in a 88 12 ratio in 95% yield (O Scheme 13). 

Two new types of polyhydroxylated alkaloids containing dihydroxypyrrolidine moieties as glycosidase inhibitors from higher plants 02H(57)1539. 

Polyhydroxylated alkaloids have been of great interest due to their activity as glycosidase inhibitors. These alkaloids, including 247, 250, and 251, were described in Volume five of this series [542]. A molecular modeling study has attempted to explain the inhibitory properties of these compounds [543]. Several reviews of these alkaloids are available [544-546]. 

The plant alkaloid castanospermine 155 and the related piperidine alkaloid 1-deox-ynojirimicin 160, like several other polyhydroxylated octahydroindolizidines, piperidines and pyrrolidines, are potent glycosidase inhibitors. These nitrogen bases are of considerable interest for the study of biosynthetic processes and, in addition, castanospermine and some of its derivatives may be of clinical value as antineo-plastic agents and as drugs in the treatment of AIDS. 

Polyhydroxylated piperidines from natural sources, which have structures and shapes resembling monosaccharides have been found as a -glycosidase inhibitors. They competitively inhibit glycosidases whose substrates they most closely resemble. 1-Deoxynojirimycin (moranoline) (98 1), was isolated from Mori Cortex (root bark of the mulberry tree, Morus bombycis (Moraceae)), leaves of Jacobinia suberecta (Acanthaceae)... 

A series of polyhydroxylated tropane alkaloids have been isolated from the leaves of Solanum tuberosum and from both a sphingid moth and an ithomiine butterfly, the larvae of which feed on Solanum species (Nash et al., 1993). These alkaloids are potent glycosidase inhibitors, in a manner similar to certain hydrox3q)yrrolidine and indolizidine alkaloids see Chapter 30). 

The products presented in scheme 5 show that it should be possible by subsequent introduction of amino groups through halogen or oxirane functionalities, to get an efficient entry into a series of polyhydroxylated piperidines (azasugars) [6,7,30] by intramolecular reductive amination. This class of compounds gained much interest recently because of its biological activity as potential glycosidase inhibitors [31-33]. In scheme 8 novel substitution patterns of polyhydroxy piperidines (boxed), which we synthesized stereoselectively by our own new procedures [34], are compared with known compounds derived from natural sources. 

Scheme 8. Novel polyhydroxylated piperidines (azasugars) as potential glycosidase inhibitors [34]...

Reviews on the calystegines were compiled previously, or were included in reviews on glycosidase inhibitors and polyhydroxylated alkaloids (4,9-13). In this review, emphasis will be placed on the following ... 

Cycloaddition reaction of nitrone (—)-(394) with dimethyl maleate D14 has been used for the synthesis of two new polyhydroxyl pyrrolizidines (687) and (688) (Schemes 2.293, 2.294). These compounds are analogs of alkaloids ros-marinecine and crotanecine, which were assayed for their inhibitory activities toward 22 commercially available glycosidase enzymes. One of them ((-)- a-epi-crotanecine) (—)-(688) is a potent and selective inhibitor of a-mannosidases (310). The reaction of (—)-(394) with dimethyl maleate gave a 9.6 6 1 mixture of cycloadducts (—)-(680), (+ )-(680), and (—)-(681), which arise from anti-exo,... 

Similar strategies have been used for the synthesis (286) of the tetrahydro-pyrrolizidine 323 from 2,3 5,6-di-O-isopropylidene-D-g/yccroD-ta/o-hep-tono-1,4-lactone (322). These polyhydroxylated pyrrolidines and pyrrolizi-dines are potential specific inhibitors of glycosidases. The stereochemistry of the hydroxyl groups have a profound effect on the selectivity of the inhibition (286-288). 

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