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DOI: 10.1055/s-0034-1394789
Acronychia type acetophenones analogs inhibit 5-lipoxygenase
Asthma is a chronic inflammatory disease of the airways characterized by reversible airflow obstruction, bronchospasm, coughing and shortness of breath. Its development has been correlated with the overproduction of leukotrienes (LTs). 5-Lipoxygenase (5-LO) is an iron-containing enzyme responsible for the biosynthesis of LTB4, LTCs and other cysteinyl-LTs (cys-LTs), the latter playing a prominent role in asthma [1]. 5-LO has thus been proposed as a potential therapeutic target to treat the symptoms of asthma and Zileuton is actually the only 5-LO inhibitor marketed for this purpose. Interestingly, the traditional medicine in South-Eastern Asia countries recommends the use of Acronychia penduculata (Rutaceae) notably for the treatment of asthma [2]. The phytochemical exploration of the plant revealed the presence of several prenylated acetophenone dimers and monomers, acrovestone (1) being the main representative [2,3,4]. We therefore undertook the synthesis of several dimers and monomers derivatives and assess their inhibitory potency towards 5-LO along with the natural products. Our study revealed good inhibition of 5-LO by both natural (IC50 Acrovestone = 2.7µM) and synthetic molecules highlighting 5-LO as the potential biological target of Acronychia extracts traditionally used for the treatment of asthma. A synthetic monomer bearing a geranyl substitution (IC50= 0.9µM) is currently under in vivo evaluation.
Keywords: Prenylated acetophenones, synthesis, 5-LO, asthma
References:
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[4] C.-R. Su, P.-C. Kuo, M.-L. Wang, M.-J. Liou, A.G. Damu, T.-S. Wu (2003)J. Nat. Prod. 66: 990 – 993.