Helenalin - a Sesquiterpene Lactone with Multidirectional Activity

Send Orders for Reprints to [email protected] Current Drug Targets, 2018, 19, 000-000 1 REVIEW ARTICLE Helenalin - A Sesquiterpene Lactone with Multidirectional Activity Joanna Drogosz and Anna Janecka* Department of Biomolecular Chemistry, Medical University of Lodz, Poland Abstract: Sesquiterpene lactones, secondary metabolites of plants, present in a large number of species mostly from the Asteracea family, are used in the traditional medicine of many countries for the treatment of various pathological conditions. They exert a broad range of activities, including anti- inflammatory, anti-bacterial and anti-cancer properties. The best-known sesquiterpene lactones which A R T I C L E H I S T O R Y are already used as drugs or are used in clinical trials are artemisinin, thapsigargin and parthenolide. Received: June 07, 2018 Yet another sesquiterpene lactone, helenalin, an active component of Arnica montana, known for its Revised: October 05, 2018 Accepted: October 08, 2018 strong anti-inflammatory activity, has been used for centuries in folk medicine to treat minor injuries. Unfortunately, helenalin’s ability to cause allergic reactions and its toxicity to healthy tissues prevent- DOI: ed so far the development of this sesquiterpene lactone as an anticancer or anti-inflammatory drug. 10.2174/1389450119666181012125230 Recently, the new interest in the biological properties, as well as in the synthesis of helenalin analogs has been observed. This review describes helenalin's major biological activities, molecular mechanisms of action, its toxicity and potential for further research. Keywords: Natural products, NF-κB, telomerase, apoptosis, synthetic analogs, cancer, protozoa. 1. INTRODUCTION (Fig. 1). Depending on this skeleton, which can be mono-, di- or tricyclic, SLs can be divided into seven major groups: ger- For centuries medicinal plants have served humanas a macranolides, eudesmanolides, eremophilanolides, guaiano- source of various curative substances. A large number of lides, pseudoguaianolides, xanthanolides and carabranolides important drugs, including aspirin, morphine, quinine, and [12, 13]. taxol are of plant origin. The active component can be either extracted and used directly or, more often, serves as a parent compound for chemical modifications, in the search for analogs with improved pharmacological properties. R R A large group of active plant constituents, comprising over 5000 known compounds, are sesquiterpene lactones R O R O (SLs) occurring in several angiosperm plant families, partic- O O ularly in the Asteraceae (Compositae) family [1]. In the folk medicine, SLs were frequently used as herbal remedies in a A B variety of conditions. The diversity of SLs is matched by a Fig. (1). General formulas of sesquiterpene lactones with α- variety of their biological activities. Such structures have methylene-γ-lactone motif (A) cis- and (B) trans-fused to the car- been shown to exert anti-inflammatory [2, 3], cytotoxic, an- bocyclic skeleton. ticancer [4-6], antibacterial [7], antifungal, insecticidal [8] and antiprotozoal [9, 10] activities. The exemptions are two SLs, artemisinin and thapsigargin (Fig. 2), which do not have an exo-cyclic double bond. SLs are 15-carbon terpenoids of lipophilic character, con- Artemisinin is used as a first-line antimalarial medication. taining, as their name indicates, a lactone ring. Biosynthesis of The source of its antimalarial effect is believed to be the per- SLs starts from three isoprene units and takes place in the en- oxide bond, whose cleavage in the body causes the release of doplasmic reticulum [11]. Most of the SLs possess an α- reactive oxygen species (ROS) detrimental for the Plasmodi- methylene-γ-lactone motif, characterized by an exo-cyclic um parasite [14]. Thapsigargin is a non-competitive inhibitor double bond, conjugated with a carbonyl function. The lactone of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) ring is either cis- or trans-fused to the carbocyclic skeleton [15, 16]. The best known and the most studied SL with α- *Address correspondence to this author at the Department of Biomolecular methylene-γ-lactone motif is parthenolide found in Tanace- Chemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, tum parthenium, which belongs to germacranolides (Fig. 2). Poland; Tel: +48 42 272 57 06; Fax: +48 42 272 56 94; Parthenolide showed promising anticancer properties but E-mail: [email protected] poor bioavailability [17] A semi-synthetic, water-soluble 1389-4501/18 $58.00+.00 ©2018 Bentham Science Publishers Pobrano z https://publicum.umed.lodz.pl / Downloaded from Repository of Medical University of Lodz 2021-09-24 2 Current Drug Targets, 2018, Vol. 19, No. 16 Drogosz and Janecka analog of parthenolide, dimethyl-aminoparthenolide is now Me Me in clinical trials as a new anti-leukemic agent [18]. SH H H 1 8 Me O O H 6 11 Me O Me O O O O HO Me O HO Me HS Helenalin Mexicanin H O Me O Fig. (3). Chemical structure of cis-fused helenalin with marked O Me alkylation centers and trans-fused mexicanin. O Parthenolide O Artemisinin The effects produced by helenalin and other SLs are mainly due to the capability of these compounds to inhibit, through alkylation, the activity of various enzymes and tran- O O scription factors in living cells. O Since helenalin reacts with thiol groups of cysteine resi- Me O dues, its molecular targets can be not only numerous proteins O in the body but also glutathione (GSH, Glu-Cys-Gly), an O important antioxidant. However, the reaction of helenalin with GSH remains controversial. Helenalin was observed by O O some authors to react with GSH in a reversible reaction, OH therefore allowing the alkylating groups of this SL to be re- O OH leased from the GSH adducts and to react with other protein Me targets [26]. Results presented by others indicated that at Thapsigargin O physiological pH, binding of helenalin to GSH was not sig- nificant [27]. Fig. (2). Chemical structure of parthenolide, artemisinin and thapsigargin. Modification of one of the two Michael acceptors in helenalin molecule, for example through reduction of the α- Yet another naturally occurring SL with diverse biologi- methylene-γ-lactone (yielding 11,13-dihydrohelenalin) or the cal activities is helenalin, classified as a pseudo-guaianolide. cyclopentenone (yielding 2,3-dihydrohelenalin), markedly Helenalin is found especially in Arnica montana and Arnica reduced activity in comparison to the native product [28, 29]. chamissonis [19-21]. Arnica preparations such as creams, The studies in the in vitro cell systems showed that between gels and alcoholic extracts are used to reduce muscle pain, the two electrophilic centers of helenalin, the α-methylene-γ- joint pain, minor sports injuries, bruises and swelling associ- lactone moiety was more reactive than the cyclopentenone ated with trauma, contusions, and sprains [22]. These appli- [30]. Reduction of both Michael acceptor centers destroyed cations result mainly from helenalin’s anti-inflammatory helenalin activity completely [23, 31]. properties. However, this compound has been found to possess multidirectional activity, that also includes antiprotozoal 3. BIOLOGICAL ACTIVITIES OF HELENALIN and anticancer characteristics. This review describes major activities and molecular mechanisms of helenalin's action. 3.1. Anti-inflammatory Activity Helenalin, among other SLs, can modulate many pro- 2. STRUCTURE AND MODE OF ACTION OF HELE- cesses that influence inflammatory reactions [32]. Helenalin NALIN inhibited human neutrophil migration and chemotaxis [33], Helenalin is a bifunctional SL, containing an α- as well as platelet aggregation in vitro, probably by reduction methylene-γ-lactone cis-fused to the carbocyclic skeleton of phospholipase A2 activity, leading to a decrease in the and an endocyclic α,β-unsaturated ketone (cyclopentenone) production of arachidonic acid [34]. The inhibitory effect of [23]. These two functional fragments are alkylating centers helenalin on the biosynthesis of leukotrienes, important me- that can react, through a Michael-type addition, with biologi- diators in inflammatory processes, was shown by Tornhamre cal nucleophiles, especially cysteine thiol (-SH) groups in et al. (2001). Helenalin inhibited the activity of leukotriene enzymes and other functional proteins, forming covalent C4 synthase in human blood cells, suggesting that the anti- adducts [3, 24] (Fig. 3). The hydroxy group in the central 7- inflammatory effect of this SL was, at least partially, exerted membered ring is also important for the activity. by the inhibition of leukotriene biosynthesis [35]. Mexicanin, an SL also classified as a pseudoguaianolide, The first extensive report on SL anti-inflammatory activi- has identical as helenalin structure, except that its carbocy- ty in several in vivo tests, such as rat paw and mouse ear clic skeleton is transfused to the lactone ring. Different ste- edema was published by Hall and co-workers in 1979. The reochemistry of the ring fusion between mexicanin and hele- authors showed that helenalin was more effective in sup- nalin must be responsible for much higher antiprotozoal ac- pressing inflammation than the non-steroidal drug indometh- tivity of the latter [25]. acin [36]. Pobrano z https://publicum.umed.lodz.pl / Downloaded from Repository of Medical University of Lodz 2021-09-24 Helenalin - A Sesquiterpene Lactone with Multidirectional Activity Current Drug Targets, 2018, Vol. 19, No. 16 3 Further studies demonstrated

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