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Hot Cuisine As a Source of Anti-Inflammatory Drugs

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Hot Cuisine As a Source of Anti-Inflammatory Drugs View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Springer - Publisher Connector Phytochem Reviews (2005) 4: 3–10 Ó Springer 2005 DOI 10.1007/s11101-004-1395-7 Hot cuisine as a source of anti-inflammatory drugs Giovanni Appendino*, Alberto Minassi & Nives Daddario Universita´ delPiemonte Orientale,Dipartimento diScienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Via Bovio 6, 28100 Novara, Italy. *Author for correspondence (Tel: +390321375744; Fax: +390321375631; E-mail: [email protected]) Key words: capsaicin, endovanilloids, neurogenic inflammation, nutraceuticals, vanilloids Abstract The shift in nutritional sciences from survival and safety to the promotion of well-being has led to sys- tematic investigations on the biological activity of natural products of dietary origin, questioning the assumption that food plants contain little if any secondary metabolites apart those revealed by our senses and responsible for their colour, taste, and flavour. With 25% of the human population consuming chilli pepper every day, capsaicin is the most important pharmacological agent we get from our diet, and the study of its pungency set in motion a multidisciplinary investigation that ultimately led to the discovery of vanilloid receptors (TRPVs), a class of ion channels involved in thermo-, chemo-, and mechanosensation, and whose malfunctioning is implicated in neurogenic inflammation and a host of other pathological conditions. A series of studies centred on the modification of capsaicin will be described, focusing on a) the preparation of a library of unnatural natural capsaicinoids and the identification of leads with the lipophilic C-moiety amenable to structure-activity study, and b) the reversal of the biological activity of capsaicin from a TRPV1 agonist into an antagonist by modification of its vanillyl moiety. Abbreviations: AE – Arachidonoylethanolamine (=Anandamide); COX-1 (2) – Cyclooxygenase-1 (2); CPS – Capsaicin; GRAS List – Generally Recognized as Safe List; NADA – N-Arachidonoyldopamine; NSAID – Non Steroid Anti-Inflammatory Drug; OLDA – N-Oleoyldopamine; PABA – para-Aminobenzoic Acid; PPAA – Prophyl Phosphonic Acid Anhydride; RTX – Resiniferatoxin; SERCA – Sarcoendoplasmatic Reticulum Ca(II) ATPase; TRPV – Transient Receptor Potential Vanilloid Introduction each other. Their divorce is essentially a modern artefact, since in all cultures a considerable share The modern clinical trial was first described in the of food plants have also been used in traditional Bible (Daniel, 1), but only carried out 2000 years medicine (Pieroni et al., 2002). Scouring the planet later by the navy surgeon James Lind as part of a for the most exotic and expensive remedies has study on the prevention of scurvy (Appendino and always been a sort of fashionable trend in natural Taglialatela- Scafati, 2003c). Several explanations products chemistry, even finding its way into the have been given as to why medicine was so slow to plot of a successful Hollywood movie (Medicine adopt the scientific method (Sneader, 1996). Nev- Man, directed by J. McTieman and starring Sean ertheless, edible- and not medicinal plants were Connery, 1992). Food plants are trivial, easily used in both cases (legumes and Citrus fruits, available, and generally contain low concentration respectively). This observation is hardly surprising, of secondary metabolites. Unsurprisingly, they since medicine and nutrition have long shaded into were long overlooked as a source of bioactive 4 compounds. However, over the past decades, there organisms, as is the occurrence of nonprenylated has been a growing awareness that food plants, oligomeric phloroglucinols like 3 in the leaves of apart from macronutrients (proteins, lipids, sug- myrtle (Appendino et al., 2002a). While no bio- ars) and essential micronutrients (vitamins, min- activity has so far been reported for pumpkin erals) also contain secondary metabolites that can p-aminobenzoates, the oligomeric phloroglucinols play a role in the maintenance of human health. from myrtle show a remarkable antibacterial This has led to a shift in nutritional sciences from activity, especially against super bugs (Appendino survival and safety to the promotion of well-being, et al., 2002a). Myrtle is just one of the over 150 challenging the long-held assumption that food plants included in the GRAS (Generally Recog- plants contain little if any secondary metabolites nized As Safe) list of herbal ingredient for liqueurs apart those revealed by our senses and responsible (Duke, 1987). Many of these plants have never for their colour, taste, and flavour. been investigated for their non-volatile constitu- There is currently no comprehensive review or ents, and there is no shortage of interest for this book on the chemistry and biochemistry of sec- matter, as shown by the fascinating correlation ondary metabolites from food plants. This article, between the chromatic aberrations by van Gogh while highlighting the relevance of the subject, and the presence of santonin-like compounds in will essentially summarise recent results on a wormwood (Artemisia absinthium L.) (Arnold, single class of compounds (capsaicinoids). Though 1992). a-Santonin (4) was once used in medicine as undoubtedly limiting, the examples discussed are an anthelmintic drug, and can change the way nevertheless paradigmatic for the problems facing colours are perceived, turning vision to yellow. research in this field. Wormwood does not contain a-santonin, but the extremely bitter dimeric guaianolide absinthin (5), whose pharmacology is still totally unknown. Food plants as a source of drugs, drug leads, and Structurally unusual bitter sesquiterpene lactones unusual secondary metabolites are also contained in other plants used for the production of liqueurs, as exemplified by the per- Scouring the refrigerator or the cupboard for oxides 6 and 7 from mountain wormwood drugs leads might sound naı¨f in the age of -omic (A. umbelliformis Lam) (Appendino et al., 1983) sciences, but this is the origin of statins. With an- and from curly tansy (Tanacetum vulgare L. var. nual sales over 15 billion dollars, statins are the crispum Fiori) (Appendino et al., 1982), two plants commercially most successful drugs ever, and used for the production of alpine liqueurs (Genepy lovastatin (1) is their archetypal member. This and Chartreuse, respectively). compound was first isolated from the red yeast of rice, an ingredient of the oriental cuisine used to give the red colour and typical taste to the Peki- The kitchen connection. Vanilloid receptors as anti- nese duck, and this dietary origin has caused long inflammatory targets and bitter legal litigation between the pharma- ceutical- and the health food industries (Journoud No compound better than capsaicin (CPS, 8) and Jones, 2004). Statins are structurally unique exemplifies the blurred boundaries between food compounds. They belong to the rare class of nat- and medicine. With 25% of the human population urally occurring Diels-Alder adducts, and exem- consuming chilli pepper every day, 8 is the most plify how our diet can be a real treasure throve of important pharmacological agent we get from our structurally unique and biologically active sec- diet (Szallasi and Blumberg, 1999), and the study ondary metabolites. Another remarkable example of its pungency set in motion a multidisciplinary is the occurrence of triterpene p-aminobenzoates investigation that ultimately led to the discovery of (exemplified by 2) in the seeds of pumpkin and vanilloid receptors (TRPVs). These ion channels related plants (courgettes, cucumber, melon, water are involved in thermo-, chemo-, mechanosensa- melon) (Appendino et al., 2000). Nature is rather tion, and their malfunctioning is involved in neu- conservative in the use of key metabolites, and the rogenic inflammation, and, possibly, in other profligacy by which these plants accumulate esters pathological conditions as well (Szallasi and of PABA in their seeds is unprecedented in living Blumberg, 1999). 5 Capsaicin was first isolated in 1876, structurally ceptor specifically activated by CPS. Since 8 and 9 elucidated in 1919, and first synthesised in 1930 share a vanillyl moiety, this receptor was named (Szallasi & Blumberg, 1999). Despite all this the vanilloid receptor (VR1), but is now better chemical activity, it was ignored by pharmacolo- known as TRPV1 (for a recent review, see: gists for a long time, probably because too Appendino et al., 2003b). In 2000, knock-out mice obnoxious to handle. Things changed in 1989, for TRPV1 were created by genetic engineering. when an ultrapotent analogue was discovered, the This animals showed an impaired pain sensation, phorboid resiniferatoxin (RTX, 9a) (Szallasi and but were otherwise normal, an observation that Blumberg, 1989). By using radioactive RTX, it was validated TRPV1 as a pharmacological target. possible to demonstrate a specific binding of cap- Four further vanilloid receptors were cloned in the saicin to nerve membranes, and this set in motion years 2000–2003. Though structurally related to an intense research activity that culminated eight TRPV-1, these receptors (TRPV-2/TRPV-5) do years later in the characterisation of a thermore- not bind capsaicin, nor does the avian and version 6 of TRPV1 (Appendino et al., 2003). TRPV1 is a toid arthritis, migraine, asthma, psoriasis, allergic heat-sensitive ion channel whose activation rhinitis) whose current management is either threshold is lowered by an increase of temperature,
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