Planta Med 2014; 80 - P1L132
DOI: 10.1055/s-0034-1394789

Acronychia type acetophenones analogs inhibit 5-lipoxygenase

N Gaboriaud-Kolar 1, A Svouraki 1, C Pergola 2, U Garscha 2, M Halabalaki 1, O Werz 2, AL Skaltsounis 1
  • 1Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, University of Athens, Panepistimiopolis Zografou, Athens, Greece
  • 2Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University of Jena, Jena, Germany

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.

Fig. 1: Acrovestone natural heterodimer.

Fig. 2: General structure of synthetic homodimers.

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.