ACETYL-11-KETO-BETA-BOSWELLIC ACID (AKBA) - STRUCTURE REQUIREMENTS FOR BINDING AND 5-LIPOXYGENASE INHIBITORY ACTIVITY

1 5-Lipoxygenase (5-LOX) products from endogenous arachidonic acid in ionophore-stimulated peritoneal polymorphonuclear leukocytes (PMNL) an d from exogenous substrate (20 mu M) in 105,000 g supernatants were me asured. 2 The effects of natural pentacyclic triterpenes and their der ivatives on 5-LOX activity were compared with the inhibitory action of acetyl-11-keto-beta-boswellic acid (AKBA), which has been previously shown to inhibit the 5-LOX by a selective, enzyme-directed, non-redox and non-competitive mechanism. 3 The 5-LOX inhibitory potency of AKBA was only slightly diminished by deacetylation of the acetoxy group or reduction of the carboxyl function to alcohol in intact cells (IC50 = 1.5 vs. 3 and 4.5 mu M, respectively) and in the cell-free system (8 v s. 20 and 45 mu M). 5 beta-Boswellic acid (beta-BA), lacking the 11-ke to function, inhibited 5-LOX only partially and incompletely, whereas the corresponding alcohol from beta-BA, as well as amyrin, acetyl-11-k eto-amyrin, 11-keto-beta-boswellic acid methyl ester had no 5-LOX inhi bitory activity up to 50 mu M in either system. 5 beta-BA only partial ly prevented the AKBA-induced 5-LOX inhibition, whereas the non-inhibi tory compounds, amyrin and acetyl-11-keto-amyrin, almost totally antag onized the AKBA effect and shifted the concentration-inhibition curve for the incomplete inhibitor beta-BA to the right. In contrast, the no ninhibitory 11-keto-beta-BA methyl ester exerted no antagonizing effec t. 6 The results demonstrate that the pentacyclic triterpene ring syst em is crucial for binding to the highly selective effector site, where as functional groups (especially the Il-keto function in addition to a hydrophilic group on C4 of ring A) are essential for 5-LOX inhibitory activity.