Structure−Activity Relationships of Pentacyclic Triterpenoids as Inhibitors of Cyclooxygenase and Lipoxygenase Enzymes

Abstract

Pentacyclic triterpenes may be active agentsand provide a rich natural resource of promising compoundsfor drug development. The inhibitory activities of 29 naturaloleanane and ursane pentacyclic triterpenes were evaluatedagainst four major enzymes involved in the inflammatoryprocess: 5-LOX, 15-LOX-2, COX-1, and COX-2. It was foundthat 3-O-acetyl-β-boswellic acid potently inhibited human 15-LOX-2 (IC50= 12.2±0.47μM). Analysis of the structure−activity relationships revealed that the presence of a hydroxygroup at position 24 was beneficial in terms of both 5-LOXand COX-1 inhibition. Notably, the introduction of acarboxylic acid group at position 30 was important for dual5-LOX/COX inhibitory activity; furthermore, its combination with a carbonyl group at C-11 considerably increased 5-LOXinhibition. Also, the presence of anα-hydroxy group at C-2 or a carboxylic acid group at C-23 markedly suppressed the 5-LOXactivity. The presentfindings reveal that the types and configurations of polar moieties at positions C-2, -3, -11, -24, and -30 areimportant structural aspects of pentacyclic triterpenes for their potential as anti-inflammatory lead compounds.