Anti castanospermine

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-... 

In addition to swainsonine, some of the other naturally-occurring polyhydroxylated alkaloids listed in Table 1 also show various anti-cancer properties. However, none of these compounds have been exploited to nearly the same extent as swainsonine. For example, the potent a-glucosidase inhibitor castanospermine (also an indolizidine alkaloid) has been reported to inhibit experimental metastasis in mice. ... 

Another therapeutic application of polyhydroxylated alkaloids is as anti-viral agents. Inhibitors of processing a-glucosidases, such as castanospermine and DNJ, have been shown to decrease the infectivity of human immunodeficiency virus (HIV) in vitro at concentrations which are not cytotoxic to lymphocytes, whereas specific inhibitors of processing a-mannosidases (swainsonine and 1-deoxymannojirimycin) have no effect on Castanospermine and DNJ also reduce the infectivity of other retroviruses... 

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]. 

Nectrisine also has anti-viral activity and inhibits the retrovirus Friend leukaemia virus in vivo in mice and can potentiate the activity of AZT (zidovudine) [103]. Synergistic activity has also been shown when castanospermine and AZT are used in combination therapy in vitro [104], In vivo combination studies with V-butyl-deoxynojirimycin and AZT in human patients mdicated anti-viral activity but caused diarrhoea, abdominal pain and weight loss [103], Chemical modification of V-butyl-deoxynojirimycin to make it better tolerated was suggested. 

Castanospermine, swainsonine and nectrisine have been shown to have anti-cancer activity. Castanospermine inhibits experimental metastasis in mice [106], Nectrisine (FR-900483) has been reported to induce la antigen and restore the immune response of immunosuppressed mice and these effects were assumed to be due to a-mannosidase inhibition [107]. 

Castanospermine also has been shown to have anti-inflammatory activity, modifies the expression of adhesion molecules and prolongs allograft survival in a dose dependent manner [117]. 

Much of the current interest in making simple derivatives of (+ )-castanospermine (239) can be traced to a seminal publication in 1989, which showed that the alkaloid s anti-HIV activity could be increased by as much as twenty times upon esterification (216). Positionally selective acylation procedures usually involve sequential protection, acylation, and deprotection steps e.g. the preparation of esters at the C-6 and C-7 (217) or the C-8 hydroxy groups (218). Also of interest are procedures that take advantage of enzyme-catalyzed transesterification with activated esters, e.g. the use of subtilisin for ester formation at C-1, pancreatic porcine lipase for preferential reaction at C-6 and C-7 (219-221), and cross-linked enzyme crystals (CLECs) of subtilisin for making the potentially valuable antitumor agent 1-0-butanoylcastanospermine (222). A cautionary note was sounded, however, when it was observed that 6-0-acyl castanospermine esters could equilibrate to a mixture of... 

Burgess et al. developed a novel approach for the synthesis of polyhydroxylated compounds such as castanospermine 87 and swainsonine 89 ° utilizing alkoxyallylboration of as one of the key steps (Eigure 25.12). Similarly, Jadhav and Woerner were able to convert the octose derivative 90 into the polyhydroxyindolizidine 91 in seven further transformations (Figure 25.12). Several of these indolizidines exhibit potent anti-cancer, anti-viral, and anti-AIDS activities. 

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