Acetyl‐11‐keto‐β‐boswellic acid (AKBA): structure requirements for binding and 5‐lipoxygenase inhibitory activity

Abstract

1 5-Lipoxygenase (5-LOX) products from endogenous arachidonic acid in ionophore-stimulated peritoneal polymorphonuclear leukocytes (PMNL) and from exogenous substrate (20 gM) in 105,000 g supernatants were measured. 2 The effects of natural pentacyclic triterpenes and their derivatives on 5-LOX activity were compared with the inhibitory action of acetyl-l -keto-p-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 (ICs = 1.5 vs. 3 and 4.5 pM, respectively) and in the cell-free system (8 vs. 20 and 45 gM).5 fl-Boswellic acid (f-BA), lacking the 1 1-keto function, inhibited 5-LOX only partially and incompletely, whereas the corresponding alcohol from fl-BA, as well as amyrin, acetyl-ll-keto-amyrin, 1 l-keto-f-boswellic acid methyl ester had no 5-LOX inhibitory activity up to 50 pM in either system. 5 fl-BA only partially prevented the AKBA-induced 5-LOX inhibition, whereas the non-inhibitory compounds, amyrin and acetyl-1 l-keto-amyrin, almost totally antagonized the AKBA effect and shifted the concentration-inhibition curve for the incomplete inhibitor fl-BA to the right. In contrast, the noninhibitory 1 1-keto-fl-BA methyl ester exerted no antagonizing effect.6 The results demonstrate that the pentacyclic triterpene ring system is crucial for binding to the highly selective effector site, whereas functional groups (especially the 11 -keto function in addition to a hydrophilic group on C4 of ring A) are essential for 5-LOX inhibitory activity.

Evaluation of the Efficacy of Ginger, Arabic Gum, andBoswelliain Acute and Chronic Renal Failure

“…The antiinflammatory effect of Boswellia may be due to 3-Oacetyl-11-keto-β-boswellic acid, which is the most active component of Boswellia extract and has been demonstrated to be a potent inhibitor of 5-Lipoxygenase (5-LOX), which is a key enzyme in the biosynthesis of leukotrienes (LTs) from arachidonic acid in the cellular inflammatory cascade. 37 The second model used in this work is RIR injury. It is a major cause of acute renal failure and renal graft rejection and may lead to CRF if chronic.…”

Anti-Inflammatory Actions of Pentacyclic Triterpenes

“…Many PTs (including UA, OA, amyrin), but not 4-ring compounds, bind to 5-LO protein. However, only PTs from the BA series possessing an Il-keto group in addition to a hydrophilic function at C-4 exert potent 5-LO inhibitory activity (26)(27)(28). GA was reported to be active in ionophore-stimulated cells, although this action was attributed to inhibition of PLA2 (29).…”

Inhibition of 5-Lipoxygenase Product Synthesis by Natural Compounds of Plant Origin

“…It was suggested that AKBA 89 acts at a selective binding site of 5-LO for various PTs that is different from the AA-binding cleft [155], where certain functional groups (i. e., the 11-keto and C-4-carboxylic moiety) are essential for 5-LO inhibitory activity [166]. Although previous reports demonstrated a selectivity of BAs for 5-LO, we recently showed that AKBA 89 potently suppresses 12-LO product formation, with even higher potency in cell-free assays (IC 50 = 15 mM) as compared to 5-LO (IC 50 = 50 mM) [167].…”