Swainsonine biological activity

A variety of naturally occurring imino sugars presenting interesting biological activity, such as castanospermine, swainsonine or australine are bicyclic compounds (Fig. 44). 

One particular example of the early extraction of a chemical from a plant, a small tree found in the rainforests of eastern Queensland, would be that of acronycine 1 [1,2], an alkaloid currently undergoing clinical trials as an anticancer agent. More recently, a group in Perth at Murdoch University succeeded in extracting the alkaloid, swainsonine 2 from a desert shrub which causes poisoning in cattle [3]. Swainsonine has been found to exhibit an interesting spectrum of biological activity [4], especially as a potent, reversible inhibitor of various a-D-mannosidases [5]. 

It is regrettable that Australian chemists failed to discover another local alkaloid, namely castanospermine 3. It was left to an overseas group to collect and extract the seeds from a Queensland legume to yield this valuable alkaloid [6]. Castanospermine seems to display a broad biological activity which surpasses even that of swainsonine, being a particularly powerful competitive inhibitor of both a- and -o-glucosidases [7]. The alkaloid is plentiful enough in the... 

The first sources of swainsonine were the fiongus Rhizoctonia leguminicula and the loco-weed plants but the increasing interest in its biological activity lead to the search of alternative sources of this alkaloid. 

The pronounced and diverse biological activity of (- )-swainsonine (162) stems from its potency as an inhibitor of a-mannosidases, and its consequent ability to alter the course of glycoprotein processing. Mannosidases partially or wholly characterized during, or detected in, recent inhibition studies with the alkaloid include a-D-mannosidases in the parasite Trypanosoma cruzi 145,146) and in various insects 147,148), a murine lysosomal a-mannosidase 149), and a-mannosidases 1 and II from Vigna umbellata (rice beans) 150). The alkaloid was used to differentiate... 

Polyhydroxylated indolizidine alkaloids, due to their biological activity, have attracted considerable synthetic interest. The total synthesis of ( —)-l-qp/-swainsonine (250) from the chiral imine 238 (Scheme 58) and the parallel synthesis of (+ )-2,8,8a-tri-qp/-swainsonine (252) from the enantiomeric threose A-benzylimine 251, prepared from natural L-tartaric acid, provide further examples of the utility of tartaric acid in meeting the challenge of complex syntheses. A stereospecific 4 + 4 homologation utilizing 2-(trimethylsiloxy)furan (178) pro-... 

It is well known that alkyl azides also behave as 1,3-dipoles in intramolecular thermal cycloaddition reactions. The formation of two carbon-nitrogen bonds leads to triazolines, which are usually not stable. They decompose after the loss of nitrogen to aziridines, diazo compounds, and heterocyclic imines. There are a limited number of examples reported in which the triazoline was isolated [15]. The dipolar cycloaddition methodology has been extremely useful for the synthesis of many natural products with interesting biological activities [16], In recent years, the cycloaddition approach has allowed many successful syntheses of complex molecules which would be difficult to obtain by different routes. For instance, Cha and co-workers developed a general approach to functionalized indolizidine and pyrrolizidine alkaloids such as (-i-)-crotanecine [17] and (-)-slaframine [18]. The key step of the enantioselective synthesis of (-)-swainsonine (41), starting from 36, involves the construction of the bicyclic imine 38 by an intramolecular 1,3-dipolar cycloaddition of an azide derived from tosylate 36, as shown in Scheme 6 [ 19). 

Fellows, L. E., G. C. Kite, R. J. Nash, M. S. J. Simmonds, and A. M. Scofield, Castanospermine, swainsonine, and related polyhydroxyalkaloids Stracture, distribution, and biological activity, in Plant Nitrogen Metabolism (J. E. Poulton, J. T. Romeo, and E. E. Conn, eds.). Recent Advances in Phytochemistry Vol. 23, 395-427, Plenum Press, New York, 1989. 

A number of alkaloids are derived from perhydroindolizine (indolizidine). Among them, swainsonine (40, (lS)-8afS-octahydro-la,2p,8P-indolizine triol) shows remarkable biological activity as an inhibitor of some types of cancer and a promoter of the organism-specific cancer defence. Several syntheses of swainsonine are reported [227]. 

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