Workup-dependent formation of 5-lipoxygenase inhibitory boswellic acid analogues.
Pentacyclic triterpenes from the 11-keto-boswellic acid series were identified as the active principal ingredients of Boswellia resin, inhibiting the key enzyme of leukotriene biosynthesis, 5-lipoxygenase (5-LO). Of the genuine boswellic acids hitherto characterized, 3-O-acetyl-11-keto-beta-boswellic acid, AKBA (1), proved to be the most potent inhibitor of 5-LO. In the course of purification of further boswellic acid derivatives from Boswellia resin, we observed the degradation of the natural compound 3-O-acetyl-11-hydroxy-beta-boswellic acid (2) to the thermodynamically more stable product 3-O-acetyl-9, 11-dehydro-beta-boswellic acid (4). The metastable intermediate of this conversion, under moderate conditions of workup in methanolic solutions, was identified as 3-O-acetyl-11-methoxy-beta-boswellic acid (3). The novel artifactual boswellic acid derivatives inhibited 5-LO product formation in intact cells with different characteristics: 4 almost totally abolished 5-LO activity, with an IC(50) of 0.75 microM, whereas 3 and 9,11-dehydro-beta-boswellic acid (5), the deacetylated analogue of 4, were incomplete inhibitors. The data suggest that the conditions chosen for the workup of Boswellia extracts could significantly influence the potency of their biological actions and their potential therapeutic effectiveness.
Schweizer
S
S
Department of Pharmacology, Institute of Pharmaceutical Sciences, Auf der Morgenstelle 8, D-72076 Tübingen, Germany.
von Brocke
A F
AF
Boden
S E
SE
Bayer
E
E
Ammon
H P
HP
Safayhi
H
H
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D008401:Gas Chromatography-Mass Spectrometry; D015289:Leukotrienes / Q000032:analysis / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors; D009682:Magnetic Resonance Spectroscopy; D008519:Medicine, Traditional; D009504:Neutrophils / Q000201:enzymology; D010946:Plants, Medicinal / Q000737:chemistry*; D012116:Resins, Plant / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet; D014315:Triterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D012116:Resins, Plant; D014315:Triterpenes; C054625:boswellic acid; D001094:Arachidonate 5-Lipoxygenase