Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.
Design, synthesis and evaluation of potential glycoside hydrolase inhibitors based on castanospermine and swainsonine.
Diss Abstr Int [B]; 55(3):1051 1994. Unique Identifier : AIDSLINE ICDB/95607537 Tan P; State Univ. of New York at Buffalo
Abstract:
A family of new analogues of polyhydroxylated indolizidine alkaloids swainsonine and castanospermine was synthesized and evaluated as potential inhibitors of alpha-mannosidase or alpha-glucosidase, the enzymes required in the secondary processing of glycoprotein biosynthesis in HIV virus and tumor cells. N-swainsonine [(1S,2R,8R,8aR)-1,2,8-trihydroxy-1,2,3,7,8,8a-hexahydropyrrolo-(1- ,2-c)pyrimidine], an amidine analogue of swainsonine synthesized in 12 steps from stereochemically defined D-mannose via a hydrogenolysis-reductive-amination key step, was a specific, time-dependent inhibitor of jack bean alpha-mannosidase with a Ki of 5.2 mM, a k(inact) of 0.20/min and half-life (t1/2) of 3.5 min. Swainsonine and N-swainsonine showed cooperative inhibition, the presence of the known competitive inhibitor swainsonine (1.0 uM) in the assay media enhanced the binding of N-swainsonine to alpha-mannosidase 29-fold (Ki = 0.18 mM) in accordance with the proposed kinetic model, which suggests that swainsonine and N-swainsonine bind to different sites of alpha-mannosidase. A binding model for enzyme-inhibitor interaction and the possible covalent modification of alpha-mannosidase by N-swainsonine were proposed. All the other 5-substituted N-swainsonines (5-methyl-, 5-amino-, 5-alkylamino-N-swainsonine, N-swainsonine-5-one and 5-thione) did not show any activity against both jack bean alpha-mannosidase or baker's yeast alpha-glucosidase. O-swainsonine [(1S,2R,8S,8aR)-1,2,8-trihydroxy-2H (1,2,3,7,8,8a)hexahydro-pyrrolo(1,2-c)(1,3)oxazine], which incorporated an oxygen atom into the 6-position of swainsonine, was equally as active as swainsonine against alpha-mannosidase. 6-Amino-1,4,6-trideoxy-1,4-imino-D-mannitol, an analogue of the known inhibitor DIM, was 22-fold less potent than swainsonine. The 2-substituted (2-alpha- and 2-beta-aminomethyl, 2-alpha- and 2-beta-cyano)3-alpha,4-beta-dihydroxy-1,2,3,4-tetrahydroquinoline derivatives, which possess the basic structural feature of castanospermine and were synthesized from the Reissert compounds, were found no activity against these two enzymes. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD94-20218)
Keywords: alpha-Glucosidases/METABOLISM HIV/METABOLISM Indolizines/*METABOLISM Mannosidases/*METABOLISM Neoplasms/*METABOLISM Swainsonine/*METABOLISM THESIS 950830
M9581002
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Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.
