Of -castanospermine

The importance of a basic nitrogen atom for strong inhibition by the indolizine type of inhibitor is demonstrated by the finding that I for inhibition by castanospermine A -oxide of the ) -D-glucosidase from almonds is 500-fold larger than of castanospermine itself (760 fiM V5. 1.5 /lA/at pH... 

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. 

Stereoselective allylation of aldehydes is another preferred strategy for the synthesis of appropriate intermediates for the total synthesis and introduction of hydroxy functionalities. Park and co-workers <2003S2473> proposed a synthesis of castanospermine 228 through a key indium-mediated allylation in the presence of (+)-cinchonine of an a-amino aldehyde 247 derived from D-glucono-O-lactone (Scheme 53). 

As a matter of fact, the second cycle increases the conformational rigidity of the molecule sometime increasing the activity and selectivity of the inhibitor. In the case of castanospermine for example, it has been postulated that the increase of inhibitory activity on a-glucosidase with respect to nojirimicin, is due to the orientation of the hydroxyl group at C-6 (referred to glucose) that in the case of castanospermine is restricted (Fig. 45).76... 

Fig. 45 Restricted conformation of castanospermine with respect to deoxynojirimicin.

P. C. Tyler and B. G. Winchester, Synthesis and biological activity of castanospermine and close analogs, in A. E. Stiitz, (Ed.), Iminosugars as Glycosidase Inhibitors, Wiley-VCH, Weinheim, New York, 1999, pp. 125-156. 

The sialic acid aldolase-catalyzed condensation of D-mannose 8 and pyruvate led, in an excellent yield, to the synthesis of KDN 9 [33], a natural deaminated neuraminic acid first isolated from rainbow trout eggs [34] and then discovered in other species. The discovery that sialic acid aldolase accepts as substrates D-mannose substituted on the 2-position, even by bulky substituents such as phenyl, azido, or bromine, opened the route to novel unnatural sialic acid derivatives [35-39]. Pentoses also are substrates. N-Substituted neuraminic acids could be prepared either directly from the corresponding Af-substituted mannosamine, such as N-thioacyl derivatives [40], or after reduction and acylation of 5-azido-KDN [41]. Recently, AT-carbobenzyloxy-D-mannosamine was converted, in a good yield, into the N-carbobenzyloxy-neurarninic acid, further used as a precursor of a derivative of castanospermine [42]. 

Burgess K and Henderson I (1992) Synthetic approaches to stereoisomers and analogues of castanospermine. Tetrahedron 48, 4045-4066. 

Castanospermine is a polyhydroxylated alkaloid found in the plant Castanospermum australe.1 Its ability to function as a selective inhibitor of a and p glycosidases has made it the focal point of much synthetic activity in recent years.2 One particularly elegant synthesis of ( + )-castanospermine is that of Pandit and Overkleeft.3 It features a remarkable intramolecular olefin metathesis reaction for indolizidine ring assembly. We now analyse this interesting route, which showcases many important reagents and reactions used in contemporary organic synthesis. 

Pandit s synthesis of (+ )-castanospermine stands out for its seminal demonstration of the applicability of the Grubbs RCM reaction5 to dienes containing one electrophilic alkene and one nucleophilic alkene. When considered alongside Crowe and Goldberg s landmark work on the cross-metathesis of electron-deficient alkenes,6 Pandit s synthesis has... 

A search for analogues of Castanospermine as inhibitors for human immunodeficiency virus (HIV)627 illustrates the use of lipases in organic solvents pioneered in Klibanov s laboratory.62 Castanospermine [333.1, Scheme 4.333J underwent selective esterification of the Cl hydroxyl function using subtilisin in pyridine. A second selective acylation of the C7 hydroxyl in 333.2 was accomplished with the lipase isolated from Chromohacterium viscosum (CV) to give the 1,7-di-w-butanoyl derivative 333J from which the Cl acyl function was selectively removed using subtilisin in aqueous media. 

Castanospermine can be regarded as a bicyclic derivative of DNJ, with an ethylene bridge between the hydroxymethyl group and the ring nitrogen. However, owing to its toxicity, this compound was considered unsuitable for therapeutic use in diabetes mellitus. Unsuccessful attempts were made to synthesise derivatives of castanospermine that were better tolerated. ... 

Similarly, synthetic modification of castanospermine showed that the lipophilic 6-0-acyl derivatives were more potent inhibitors of HIV than the natural product. In particular, the 6-0-butanoyl derivative (MDL 28,574) was approximately twenty times more active than castanospermine and fifty times more active than A-butyl-DNJ. However, once inside cells, 6-0-butanoylcastanospermine appeared to be hydrolysed to release castanospermine and hence this compound can also be considered to be a pro-dmg. " Recently, this compound was reported to be tolerated well by patients during a phase II clinical trial. ° Studies in vitro have shown synergistic activity against HIV type 1 and 2 replication when castanospermine (and its 6-C>-butanoyI derivative) are combined with AZT and other similar dideoxynucleoside drags. ... 

Sunkara, P S, Bowlin, T L, Liu, P S, Sjoerdsma, A, Antiretroviral activity of castanospermine and deoxynojirimycin, specific inhibitors of glycoprotein processing, Biochem. Biophys. Res. Commun., 148, 206-210, 1987. 

Fig. (21). Glycoproteins trimming showing the action sites of castanospermine and swainsonine [43]...

The potenfijil activity of castanospermine as an anti-hyperglycemic agent was also studied using induced diabetic mice and a significant reduction of the blood s glucose level was seen for periods of 4-6 hours after castanospermine administration [186]. 

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