6-0-Butanoyl castanospermine

Castanospermine (67) Indolizine alkaloid MX-3253 (formerly MBI-3253 Celgosivir 6-0-butanoyl castanospermine) (68) Antiviral [Hepatitis C virus (HCV)] Inhibits a-glucosidase I Phase 11 MIGENIX (received license from Virogen Ltd., UK) 577-581... 

Whitby K, Taylor D, Patel D, Ahmed P, Tyms AS. (2004) Action of celgo-sivir (6-0-butanoyl castanospermine) against the pestivirus BVDV Implications for the treatment of hepatitis C. Antiviral Chem Chemother 15 141-151. 

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. 

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. ... 

The plant alkaloid [194] castanospermine 4 was discovered to inhibit HIV syncytium formation and virus replication [195]. Activity could be improved in vitro by a factor of 40, employing the corresponding 6-0-butanoyl derivative 73 [196]. Unfortunately, it turned out that the latter did not show any significant benefits in vivo [197], pointing to the fact that the beneficial butanoyl group is cleaved by nonspecific hydrolysis by esterases or lipases before the compound reaches the desired place of antiviral action. Castanospermine was also found to be active against the measles virus... 

Ruprecht, R M, Bernard, L D, Bronson, R, Gama Sosa, M A, Mullaney, S, Castanospermine vs. its 6-0-butanoyl analog a comparison of toxicity and antiviral activity in vitro and in vivo, J. Acquired Immune Defic. Syndr., 4, 48-55, 1991. 

Castanospermine has been screened for efficacy against simian immunodeficiency virus (265), and has been shown to prevent syncytium formation in feline astrocyte cultures infected with the feline immimodeficiency virus by modifying the viral cell envelope (266). It suppressed syncytium formation and hemolytic activity in baby hamster kidney cells infected with Newcastle disease virus however, synthesis and cell surface expression of the hemagglutinin-neuraminidase glycoprotein in the viral envelope were not affected, which strengthens the hypothesis that poor transport of the parent alkaloid across membrane barriers may limit its therapeutic use (267). Both 239 and its 6-0-butanoyl ester had comparable relative toxicities and antiviral effects on Rauscher murine leukemia virus (268), but the ester was more potent than the parent alkaloid in inhibiting replication of Moloney murine leukemia virus (258). The ester was also active against herpes simplex viruses types 1 and 2 (269,270). In the latter case, conclusive evidence was provided for intracellular hydrolysis to 239. 

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