Chamazulene Carboxylic Acid and Matricin:  A Natural Profen and Its Natural Prodrug, Identified through Similarity to Synthetic Drug Substances

Abstract

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.

Clinical efficacy of a 1% <i>Matricaria chamomile </i>L. mouthwash and 0.12% chlorhexidine for gingivitis control in patients undergoing orthodontic treatment with fixed appliances

“…Apigenin significantly inhibited the release of NO, prostaglandin E 2 , interleukin-1β, -6, and -12, and tumor necrosis factor-alpha (7). Chamazulene, another constituent of MTC, significantly protects against lipid peroxidation (25) and inhibits leukotriene B 4 formation (by 50%) (26), cyclooxygenase-2, and paw edema (27). Bisabolol, an essential oil found in MTC extract, was found to reduce edema, leukocyte migration, protein extravasation, tumor necrosis factor-alpha release, and neutrophil degranulation (28).…”

Natural sesquiterpenoids

“…Another compound of this type 385, a known bioactive chamazulene derivative, has been found to be formed from the lactone matricin by treatment with artificial gastric fluids. 349 The essential oil of Ajania fruticulosa contains the bisazulene 386, whose structure was determined by X-ray analysis. 350 …”

Variability of certain chemotypes in three accessions of German chamomile (Matricaria chamomilla L.)

“…Matricine, a basic sesquiterpenoid in the living plant, is rather instable and decomposes easily to the C14-body chamazulene by distillation (Ramadan et al 2006). As the presented investigations based on single plant examination of different components the chosen way of detection of matricine was via extracts and TLC rather than detecting chamazulene via distillation and GC analysis of the essential oil, which would have required a higher amount of dried starting material than available per plant (Fig.…”

“…The second component this research considered was matricine, the precursor of chamazulene, which gives the essential oil of chamomile its typical blue color. Both compounds are known to contribute significantly to the anti-inflammatory effects of chamomile preparations (Ramadan et al 2006;Ghassemi-Dehkordi and Hölzl 2011). Various reports exist about the health promoting, cytostatic and anti-cancer properties of the flavone apigenin and its glycosidic derivatives (Repčak and Krausová 2009;Mafuvadze et al 2013;Li and Zhang 2013;Wu et al 2014).…”