Castanospermine inhibitor

Castanospermine (6), isolated from Castanospermum australe by Ho-henschutz and coworkers and characterized as a strong inhibitor for )S-d-... 

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... 

The pH-dependence of the inhibition also indicated that unprotonated castanospermine is a better inhibitor than the protonated form. However, as essential carboxyl groups of the enzyme ionize in the same range of pH as castanospermine (pK, 6.09), it was not possible to estimate the inhibitory potency of protonated castanospermine. 

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. 

The total syntheses of the potent glycosidase inhibitors (+)-castanospermine, (+)-6-epicas-tanosperimine, (+)-australine, and (+)-3-epiaustraline have been reported. These four natural products are derived from a single common intermediate, the nitroso acetal (as shown in Scheme 8.43), which is created in the key step by the asymmetric tandem [4+2]/[3+2] cycloaddition between silaketal nitroolefin and chiral vinyl ether.182 The strategy of the synthesis is outlined in Scheme 8.43. Scheme 8.44 presents a total synthesis of (+)-castanosperimine and (+)-6-epi-castanosperimine from the common intermediate prepared by tandem [4+2]/[3+2] cycloaddition. 

The synthesis of a bridgehead sulfonium salt analogue 59, of the naturally occurring glycosidase inhibitor castanospermine, proceeded by a multistep procedure starting from 5-thio-d-glucopyranose pentaacetate <2000JA10769>. The desired bicyclic sulfonium salt 57 could not be obtained from the key bromide precursor... 

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... 

Castanospermine is a plant alkaloid isolated from the seeds of the Australian chestnut tree, Castanospermium australe. As with most anti-HIV inhibitors, the discovery of the compound predates the time of isolation of HIV-1. The compound inhibits a-glucosidase-1, and therefore normal processing of the glycopro-... 

Whitby K, Pierson TC, Geiss B, Lane K, Engle M, Zhou Y, Dorns RW, Diamond MS. (2005) Castanospermine, a potent inhibitor of dengue virus infection in vitro and in vivo. J Virol 79 8698-8706. 

Strongly lipophilic compounds, some closely resembling castanospermine (8), were introduced by Ortiz Mellet and Garcia Fernandez. Such compounds as 201 and 202 were found to be potent glycosidase inhibitors featuring interesting selectivities (Scheme 55).275,276,28° 374 375... 

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. 

A very powerful inhibitor, which is a bicyclic analogue of (33), is 6-acetamido-6-deoxycastanospermine (49), a compound synthesized from castanospermine and tested by Liu and co-workers [99]. This compound, amongst many other 6-modified castanospermine derivatives, was also prepared by the Furneaux team [100]. Furthermore, by controlled ring-contraction of suitably substituted castanospermine derivatives, these workers gained access to 8-acetamido-8-deoxyaustraline (50), a byciclic analogue of l-acetamido-l,2,5-trideoxy-2,5-imino-D-mannitol (44). This ring contraction reaction, which proceeds via a tricyclic aziridinium intermediate, is based on the same principle as the approach by Peter et al. to compound (45) [95]. 

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... 

Inhibitors can block the pathway at specific steps, causing the accumulation of biosynthetic intermediates. Castanospermine inhibits the a-glucosidase that removes the first glucose deoxymannojirimycin inhibits the a-mannosidase I that removes mannose from the Man8 intermediate, and swainsonine blocks the a-mannosidase II that removes mannose from the Man5 intermediate. In the presence of swainsonine, hybrid N-linked carbohydrates are synthesized. 

Addition of pyruvate to Cbz-protected D-mannosamine 194 under NeuA catalysis has furnished an JV-acyl derivative of neuraminic acid 5 from which internal reductive amination yielded an azasugar which could be further elaborated to 195, an analog of the bicyclic, indolizidine type glycosidase inhibitor castanospermine [91]. 

Bellenamine, (R)-3,6-diamino-V-(aminomethyl)hexanamide is a (very) small-molecular-weight (MW 174) antibiotic produced by Streptomyces nashvillensis. It has only weak antibacterial activity but inhibits HIV-1 infection at an IC50 of 0.62 pg/ml (3.6 iM). With a CC50 of > 2 mg/ml (11.5 mM), the selectivity index of bellenamine can be estimated at well above 2000. Similarl to the well-established glycosylation inhibitors castanospermine and 1-deoxynojirimycin, bellenamine inhibits the secondary spread of HIV, although, unlike the glycosylation inhibitors, bellenamine had no apparent inhibitory effect on the glycosylation process. Therefore, its antiviral mechanism remains to be elucidated. 

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. 

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