Synthesis of Rhizobium sin-1 lipid-A derivatives as potential therapeutic agents against gram-negative septicemia
MetadataShow full item record
Several studies have shown that structurally novel Rhizobium sin-1 LPS do not stimulate human monocytes to produce cytokines. They can, however, act as an antagonist and can be of potential therapeutic value for the treatment of gram-negative sepsis. Due to microheterogeneity of R. sin- 1 LPS, it is difficult to identify which lipid A moiety makes it an antagonist rather than an agonist. In this thesis, the development of a highly convergent strategy for the synthesis of several R. sin-1 lipid A derivatives with varying fatty acid acylation pattern (2, 3, 4, and 5) is described. The approach employed the advanced intermediate 1, which is protected in such a way that the C-2 and C-2’ amino groups and C-3 and C-3’ hydroxyls can be selectively deprotected and acylated with varying chain lengths of ß-hydroxy and acyloxyacyl acids. Furthermore, it is not known whether the lipid A moiety of R. sin 1 exists as an aminogluconate or 2-aminogluconolactone and also a significant percentage of lipid A preparations lack a fatty acyl residue at the C-3 position. In order to address these issues, we also have developed highly convergent approach for the facile synthesis of 2-aminogluconate 6 and 2-aminogluconolactone 7, both lacking C-3 acylation. Also a general synthetic strategy for long chain ?-1 hydroxy fatty acids (27OHC28:0) that are present in the lipid A of many Rhizobial species including R. sin-1 has been developed. The approach employed a key reaction step of an olefin-cross metathesis between ?-unsaturated ester and 3-butene-2-ol. All the synthetic compounds lack the proinflammatory effects of E. coli LPS as indicated by the absence of the production of TNFa protein. In future these compounds can be potential candidates for the treatment of gram-negative sepsis.