Piperidine glycosidase inhibitors

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. 

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... 

The simple piperidine pelletierine from Punica granatum (pomegranate) (Punicaceae) and Duboisia myoporoides (Solanaceae) is an anthelmintic. The simple piperidine derivatives deoxy-mannojirimycin (DMJ) and deoxynojirimycin (DNJ) from Lonchocarpus species (Fabaceae) are glycosidase inhibitors because they are structurally similar to the pyranose (six-membered ring) sugar moieties of the glycosidase disaccharide substrates. 

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)... 

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]...

A variety of aza-sugars have been prepared and tested as glycosidase inhibitors. These include l,4,5-trideoxy-l,4-imino-L-lyxitol as an a-fucosidase inhibitor as well as the piperidines 35 and nucleoside analogues 36. ... 

Elbein and Molyneux (36) in an earlier review emphasized that three structural features are common in all alkaloid glycosidase inhibitors (AGI) which are toxic to mammals they have a secondary or tertiary nitrogen atom in a pyrrolidine, piperidine or indolizidine ring they have at least three hydroxyl groups in a jS-position relative to the nitrogen and they have fixed stereochemical relationships between the hydroxyl groups, which likely accounts for the specificity of the enzyme inhibition observed. Data from insect studies suggest that these same structural constraints may apply. Clearly there is much yet to be learned empirically about specificity of these compounds. 

Aspidiaceae (Fellows et al., 1986 Janzen et al., 1990). These compounds are similar in some regards to coniine (48), a nonhydroxylated piperidine alkaloid. In some legumes, polyhydroxy piperidine alkaloids make up as much as 2% of the dry weight of the plant. These compounds are similar structurally to sugars and are potent inhibitors of glycosidase activity. Specificity varies and some compounds of this series inhibit mannosidases, others fucosidases, and so forth. No glucosidase inhibitor has been reported to present (Fellows et al., 1986) (also see Chapter 15). 

All these advances allowed the preparation of a collection of polyhydroxy-lated piperidine, pyrrolidine, pyrrolizidines, indolizidine, and quinolizidine type iminocyclitols (e.g.. Scheme 16.9) which were widely investigated against a panel of commercial glycosidases as well as inhibitors of intestinal rat disaccharidases [16, 19, 21]. 

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