PREPARATION OF NOVEL ANALOGS OF THE NONREDOX-TYPE NONCOMPETITIVE LEUKOTRIENE BIOSYNTHESIS INHIBITOR AKBA

AKBA (acetyl-11-keto-beta-boswellic acid, 1) and KBA (11-keto-beta-Ba, 2) from Boswellia serrata Roxb. and Boswellia carterii Birdw are dire ct, nonredox-type inhibitors of 5-lipoxygenase, the key enzyme for leu kotriene biosynthesis (IC50 = 1.5 and 3 mu M in intact neutrophils, re spectively). In order to study the impact of the carboxyl function for enzyme inhibition, we synthesized novel analogues of boswellic acids. The C-4 alcohol derivative of KBA (4) still exerted 5-lipoxygenase in hibitory activity (IC50=4.5 mu M), whereas (8), the C-4 alcohol analog ue of beta-boswellic acid (7), the methyl ester analogue of KBA (5), a nd acetyl-11-keto-amyrin (9) possessed no inhibitory potential in conc entrations up to 50 mu M. These findings reveal that a hydrophilic gro up at C4 in combination with an 11-keto-function is essential for 5-li poxygenase inhibition by boswellic acids.