D-Swainsonine

Inhibition of D-Mannosidases and D-Glucosidases by Swainsonine and Castanospermine, Respectively... 

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. 

Swainsonine is a trihydroxylated bicyclic indolizidine alkaloid with four chiral centres, whose relative stereochemistry was determined by X-ray crystallographic analysis and the absolute configuration was deduced on the basis of biosynthetic and asymmetric induction studies, and then confirmed by an enantiospecific synthesis from D-mannose [2a]. 

Figure 1 Chemical structures of some amphipathic weak bases that have been loaded and stabilized in liposomes using trialkylammonium salts of polyanionic trapping agents in our lab. (A) Doxorubicin, (B) epirubicin, (C) vinorelbine, (D) vincristine, (E) vinblastine, (E) topotecan, (G) irinotecan, (H) swainsonine, (I) 2-diethylami-noethyl-ellipticinium, (J) 6-(3-aminopropyl)ellipticine, and (K) LAQ824.

Dennis, J.W., White, S.L., Freer, A.M. and Dime, D. (1993). Carbonoyloxy analogs of the anitmetastatic drug swainsonine. Activation in tumor cells by esterases, Biochem. Pharmacol., 46, 1459-1466. 

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]. 

Pearson and Lin (52) developed an elegant approach to the synthesis of optically active ( )-swainsonine (247) from isopropylidene-D-erythrose (242) (Scheme 9.52). Wittig reaction of the acetonide 242 led to the (Z) alkene 252 in 86% yield. The chloro alcohol 252 was converted to the azide 253 in 76% yield, which subsequently underwent 1,3-dipolar cycloaddition, isomerization and hydroboration-oxidation to give the indolizidine 255 in 70% overall yield. Cleavage of the acetonide unit in 255 using 6 N HCl gave the target molecule 247 in 85% yield. 

Dreyer, D. L., Jones, . C. and Molyneux, R. L. (1985). Feeding deterrency of some pyrrolizidine, indolizidine, and quinolizidine alkaloids towards pea aphid (Acryrthosiphon pisum) and evidence of phloem transport of indolizidine alkaloid swainsonine. Journal of Chemical Ecology 11 1045-1051. 

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 /3-D-glucosidases [7]. The alkaloid is plentiful enough in the... 

Since mannosido.se results from a genetically derrved absence of lysosomal a-mannosidase that leads to an accumulation of mannose-rich oligosaccharides, the effects of swainsonine (1) on this enzyme were investigated. The alkaloid, which bears a structural resemblance to the open-chain form of D-man nose (2), was in fact shown to be a reversible inhibitor of lysosomal a-mannosidase.8... 

Acylamino cyclization.l0 The indolizidine alkaloid (- )-swainsonine (3) has been synthesized by radical cyclization of the acylamine 1, derived from D-tartaric acid, to provide the indolizidinones 2 in 71% yield. Conversion to the alkaloid (3) included removal of the keto group by conversion to the thiolactam by Lawesson s reagent (97%) followed by desulfurization with Raney nickel (96% yield). 

Ralphs, M.H., Creamer, R., Baucom, D., Gardner, D.R., Welsh, S.L., Graham, J.D., Hart, C., Cook, D. and Stegelmeier, B.L. (2008) Relationship between the endophyte Em-bellisia spp. and the toxic alkalod swainsonine in major locoweed species (Astragalus and Oxytropis). ]. Chem. EcoL, 34, 32-8. 

Figure 6 Chemical tools can be used to interfere with cellular glycosylation. Tools to interfere with mucin-type 0-linked glycosylation include (a) a-benzyl GalNAc (b) Galpl-4GlcNAcp-0-naphthalenemethanol (c) Galpl-3GlcNAcp-0-naphthalenemethanol (d) 1-68A and (e) 2-68A. Molecules used to disrupt N-linked glycosylation at different steps include (f) 1-deoxymannojirimycin (g) deoxynojirimycin (h) tunicamycin and (i) swainsonine.

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