Swainsonine effects

Like simple sugars, swainsonine is water-soluble and therefore distributed to many parts of the body. It is rapidly excreted, primarily in the urine, but in lactating animals a portion of it is transferred to the milk (James and Hartley, 1977). This fast excretion rate suggests that occasional consumption of locoweeds for short periods is unlikely to have serious effects, but continuous consumption, even at low levels, results in poisoning. Short intensive grazing episodes have been used as a management tool for grazing pastures heavily infested with locoweed (Ralphs et ah, 1984). 

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... 

As might be expected for a group of compounds that affect carbohydrate metabolism, the polyhydroxylated alkaloids have been reported to have a wide range of effects on a number of organisms and some cause serious livestock poisonings. In fact, it was the toxicity to livestock of the legumes Swainsona canescens and Castanospermum australe in Australia that first led to the isolation of the toxic principles swainsonine and castanospermine. ... 

Very few polyhydroxylated alkaloids are available commercially. Those which are available (principally DNJ, DMJ, castanospermine and swainsonine) have become standard reagents used to investigate the potential therapeutic and biochemical applications of this class of glycosidase inhibitor. So most of the following consideration of the therapeutic applications of polyhydroxylated alkaloids is based on a limited number of compounds that have been tested thoroughly, simply because these are the only ones which are readily available. It should also be noted that the doses required for beneficial effects in human disease states are generally below those causing the toxicides described in Section 1.4. 

Before swainsonine could be used clinically, the possible adverse effects of this agent had to be evaluated. As previously discussed, the systemic administration of high doses of swainsonine to sheep has been reported to induce a neural lysosomal mannoside storage disease.However, no evidence of an overt toxic reaction was observed when swainsonine was administered orally to rodents so it was considered that the mannosidosis induced by swainsonine could be a species- or tissue-specific... 

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... 

Swainsonine is water soluble and is rapidly absorbed from the gastrointestinal (GI) tract. It circulates through the body system, and is excreted in the urine, milk and fece after 5-6 days pratically no toxin remains in the serxun. Swainsonine is eliminated partially in milk and it can be fed to nursing calves and lambs, developing lesion, such as cats that feed milk from cows that consumed locoweed. Reversal of the effects of intoxications are slower, thus week or months may be required for recovery of cell function. Some CNS neurons are lost and cannot replaced [158]. 

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]. 

Swainsonine (162) continues to be a popular synthetic target owing to intense interest in its biological effects, and numerous synthetic stereoisomers, regioisomers and other analogs have also been reported. Only the syntheses of swainsonine itself are discussed below, but the interested reader is referred to the following post-1992 references for the synthesis of the swainsonine diastereomers illustrated in Fig. 3 (-)-l-episwainsonine (166) (112,113), (-)-8-episwainsonine (167, as the triacetate) (114), (- )-8a-episwainsonine (168) (775) and its acetonide (116), (+ )-l,8-diepiswainsonine (169) (113), (- )-8,8a-diepiswainsonine (170) (115, 117), (+ )-l,2,8-triepiswainsonine (171) (115), and (+ )-2,8,8a-triepi-swainsonine (172) (772). 

Rather few new studies on the immunomodulatory effects of swainsonine have appeared since 1992. Modification of cell membrane oligosaccharides by swainsonine was shown to inhibit T-cell-B-cell adhesion, thus blocking the maturation of the B-cells (163). The alkaloid increased the susceptibility of various CD4 human cell lines to infection by the LAV-2/B strain of human immunodeficiency virus type 2 (HfV-2), suggesting the existence of an alternative CD4-independent receptor for HIV-2 (164). Swainsonine was shown to lower the liposaccharide-induced humoral immune responses in mice (165). Low levels of swainsonine appeared not to affect the immune responses in sheep and cattle, but T-cell function was affected at higher concentrations (166). Perhaps the most significant recent finding is that swainsonine not only helped to boost the... 

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