Abstract:
The first isolation of hyrtiosulawesine (1) was from an Indonesian collection of the marine sponges Hyrtios erectus and H. reticulatus.1 The β-carboline alkaloid was subsequently re-isolated from a Red Sea collection of Hyrtios sp. and found to display anti-phospholipase A2 (PLA2) activity with an IC50 value of 14 μM. Phospholipase A2 catalyses the hydrolysis of membrane phospholipids at the sn-2 position to generate arachidonic acids (AA).3,4 AA are precursors to a large family of compounds known as the eicosanoids associated with inflammatory reactions.4 PLA2 inhibition by hyrtiosulawesine would lead to a decrease in AA and proinflammatory eicosanoids, with anti-inflammatory effect.4 In an effort to understand the structural attributes of the natural product (1) that cause PLA2 inhibition, hyrtiosulawesine and a series of related model compounds (2, 3) will be synthesised and evaluated for biological activity. Biomimetic nucleophiles will be used to probe hyrtiosulawesine and related compounds in order to determine their reactivity and possible site of reaction. Bioactive members of the library of compounds will subsequently be subjected to reaction with bee venom phospholipase A2 to identify the presence of any covalent adducts. Further studies may be directed to discovering the nature and location of the covalent linkage within the enzyme active site. The latest results will be presented. References 1. Salmoun, M.; Devijver, C.; Daloze, D.; Braekman, J.-C.; Van Soest, R. W. M. J. Nat. Prod. 2002, 65, 1173-1176. 2. Sauleau, P.; Martin, M.-T.; Dau, M.-E. T. H.; Youssef, D. T. A.; Bourguet-Kondracki, M.-L. J. Nat. Prod. 2006, 69, 1676-1679. 3. Balsinde, J.; Balboa, M. A.; Insel, P. A.; Dennis, E. A. Annu. Rev. Pharmacol. Toxicol. 1999, 39, 175-189. 4. Parente, L. J. Rheumatol. 2001, 28, 2375-2382.