Chamazulene carboxylic acid and matricin: a natural profen and its natural prodrug, identified through similarity to synthetic drug substances.
Chamazulene carboxylic acid (1) is a natural profen with anti-inflammatory activity and a degradation product of proazulenic sesquiterpene lactones, e.g., matricin. Both 1 and proazulenes occur in chamomile (Matricaria recutita), yarrow (Achillea millefolium), and a few other Asteraceae species. It was isolated in improved yields, characterized physicochemically, and found to be an inhibitor of cyclooxygenase-2, but not of cyclooxygenase-1. It had anti-inflammatory activity in several animal models with local and systemic application. When human volunteers were given matricin orally, plasma levels of 1 were found to be in the micromolar range. Matricin was converted to 1 in artificial gastric fluid, but not in artificial intestinal fluid. Matricin and the yarrow proazulenes are proposed to be anti-inflammatory through conversion to 1. Intriguingly, the biological activity of the natural compound 1 was found because of its similarity to fully synthetic drug substances. This is the reverse process of the common lead function of natural compounds in drug discovery.
Ramadan
Mai
M
Institut fuer Pharmazeutische Chemie, Philipps-Universitaet, 35032 Marburg, Germany.
Goeters
Susanne
S
Watzer
Bernhard
B
Krause
Eva
E
Lohmann
Klaus
K
Bauer
Rudolf
R
Hempel
Bernd
B
Imming
Peter
P
D031162:Achillea / Q000737:chemistry; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052176:Azulenes; D002264:Carboxylic Acids; D003508:Cycloheptanes; D051545:Cyclooxygenase 1 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors; D005858:Germany; D007783:Lactones; D031168:Matricaria / Q000737:chemistry; D015394:Molecular Structure; D004364:Pharmaceutical Preparations; D011355:Prodrugs / Q000737:chemistry; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052176:Azulenes; D002264:Carboxylic Acids; D003508:Cycloheptanes; D052246:Cyclooxygenase 2 Inhibitors; D007783:Lactones; D004364:Pharmaceutical Preparations; D011355:Prodrugs; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; C513457:chamazulene carboxylic acid; D051545:Cyclooxygenase 1; C039959:matricin