STRUCTURE-ACTIVITY-RELATIONSHIPS OF THE NONREDOX-TYPE NONCOMPETITIVE LEUKOTRIENE BIOSYNTHESIS INHIBITOR ACETYL-11-KETO-BETA-BOSWELLIC ACID

Acetyl-11-keto-beta-boswellic acid (AKBA) from Boswellia serrata Roxb. and italics Boswellia carterii Birdw. is the first selective, direct, non-competitive and non-redox-type inhibitor of 5-lipoxygenase, the k ey enzyme for leukotriene biosynthesis (Safayhi et al., 1992). Previou sly, we showed that AKBA interacts with the 5-lipoxygenase via a penta cyclic triterpene selective effector site (Safayhi et al., 1995). In o rder to study the impact of AKBA's functional groups on enzyme inhibit ion, natural and synthetic analogues of this boswellic acid were teste d for 5-lipoxygenase inhibition in intact rat neutrophils (Sailer et a l., 1996a). The results reveal that the carboxylic group of AKBA combi ned with the 11-keto-group is essential for enzyme inhibition, whereas the acetoxy-group on position C-3 alpha increases the affinity of AKB A to its effector site. Furthermore, other experiments demonstrated th at minor structural modifications could cause a total loss of binding affinity and/or inhibitory activity of these compounds.