Current Medicinal Chemistry, 2006, 13, 199-222 199 Chemistry and Biological Activity of Natural and Synthetic Prenyloxycoumarins † Massimo Curini *,1 , Giancarlo Cravotto 2 , Francesco Epifano 1 and Giovanni Giannone 2 1 Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Via del Liceo, 06123 Perugia, Italy 2 Dipartimento di Scienza e Tecnologia del Farmaco, Via P. Giuria 9, 10125 Torino, Italy Abstract: Prenyloxycoumarins and prenyloxyfuranocoumarins (isopentenyloxy-, geranyloxy-, linear and cyclic sesquiterpenyloxy compounds and their biosynthetic derivatives) represent a family of secondary metabolites that have been considered for years just as intermediates of other coumarin-based compounds. Only in the last two decades these secondary metabolites have been recognized as interesting and valuable biologically active natural products. Up to now more than 160 compounds have been isolated from plants mainly belonging to the families of Rutaceae and Umbelliferae, comprising common edible vegetables and fruits like lemons, oranges and grapefruits. In view of the biological activity of some natural prenyloxycoumarins, very recently syntheses of structurally related analogs aimed to establish detailed structure-activity relationships have also been carried out. Many of the isolated prenyloxy- and prenyloxy- furanocoumarins and their semisynthetic derivatives were shown to exert in vitro and in vivo remarkable anti- tumoral, anti-inflammatory and anti-viral effects. The object of this review is to examine in detail the different types of prenyloxycoumarins and prenyloxyfuranocoumarins from the chemical, phytochemical and biological point of view. Keywords: Biological activity, Prenyloxycoumarins, Prenyloxyfuranocoumarins, Rutaceae, Umbelliferae. INTRODUCTION exerting interesting biological activities. Considering the length of the carbon chain, three types of prenyloxy skeletons can be identified in this class of coumarins: C 5 (isopentenyl), C 10 (geranyl) and C 15 (linear, mono- or bicyclic sesquiterpenyl). Isoprenyl and geranyloxy chains are abundant in nature, while sesquiterpenyloxy chains are less common, being found mostly in umbelliprenine (7- farnesyloxycoumarin), in bicyclic sesquiterpenyloxycouma- rins related to farnesiferol and its derivatives, and in some monocyclic sesquiterpenyloxycoumarins. The skeleton may consist only of carbon and hydrogen or may contain heteroatoms, usually oxygen (alcohol groups, free or in form of glycosides, epoxide and less frequently keto, aldehyde and ether groups) but sometimes chlorine. Furano- and pyranocoumarins may also carry a prenyloxy side chain; as an example we shall quote auraptene (7-geranylo- xycoumarin), the best known prenyloxycoumarin. First isolated from Citrus aurantium and structurally characterized in 1930 by Komatsu and Tanaka [4], it has subsequently been found to be the most common component of fruits from Citrus spp. Although it has been known so long, the first study describing a pharmacological effect of auraptene appeared only in 1991 [5]. In the last fifteen years more than 160 prenyloxycoumarins have been isolated (in particular from common edible vegetables and fruits), synthesized and shown by biologically tests to possess a variety of promising pharmacological activities. In this review we shall deal with the chemistry and the pharmacology of various prenyloxycoumarins and prenyloxyfuranocoumarins, most of them obtained from plants that were long used for proven or supposed medical properties according to some ancient ethnomedical tradition. Coumarins are a large class of natural compounds mainly found in the families of Rutaceae and Umbelliferae, but also in fungi and bacteria. Although more than 1300 natural coumarins have been identified to date [1], most chemical and pharmacological studies have been carried out on coumarin itself or structurally simple derivatives such as umbelliferone (7-hydroxycoumarin), esculetin (6,7- dihydroxycoumarin), scopoletin (7-hydroxy-6-methoxy- coumarin), scoparone (6,7-dimethoxycoumarin), citropten (5,7-dimethoxycoumarin) [2]. Among synthetic or semi- synthetic compounds containing the coumarin moiety, warfarin and dicumarol rank as major anticoagulant drugs. Among ring-fused coumarins such as furano- and pyranocoumarins we find phytochemicals (e.g. psoralens and aflatoxins) that are endowed with powerful biological activities [2]. A third group of coumarins comprises compounds in which a terpenyl chain is linked to the benzopyrone ring directly or through one or more phenoxy groups via an ethereal bond. These derivatives are respectively called prenyl and prenyloxycoumarins. While the first have been well studied both form the chemical and the pharmacological point of view [3], prenyloxycoumarins, considered for decades merely as biosynthetic intermediates of linear-, furano- and pyranocoumarins, have only in the last decade been characterized as secondary metabolites *Address correspondence to this author at the Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Via del Liceo, 06123 Perugia, Italy; Tel: +390755855106; Fax: +390755855116, E-mail: curmax@unipg.it † Dedicated to the Memory of Prof. Nano Morelli 0929-8673/06 $50.00+.00 © 2006 Bentham Science Publishers Ltd.