Sesquiterpene Lactones: Promising Natural Compounds to Fight Inﬂammation

pharmaceutics Review Sesquiterpene Lactones: Promising Natural Compounds to Fight Inflammation Melanie S. Matos 1,2,† , José D. Anastácio 1,3,† and Cláudia Nunes dos Santos 1,3,* 1 Instituto de Biologia Experimental e Tecnológica (iBET), Apartado 12, 2781-901 Oeiras, Portugal; [email protected] (M.S.M.); [email protected] (J.D.A.) 2 Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República, 2780-157 Oeiras, Portugal 3 CEDOC, Chronic Diseases Research Centre, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056 Lisboa, Portugal * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: Inflammation is a crucial and complex process that reestablishes the physiological state after a noxious stimulus. In pathological conditions the inflammatory state may persist, leading to chronic inflammation and causing tissue damage. Sesquiterpene lactones (SLs) are composed of a large and diverse group of highly bioactive plant secondary metabolites, characterized by a 15-carbon backbone structure. In recent years, the interest in SLs has risen due to their vast array of biological activities beneficial for human health. The anti-inflammatory potential of these compounds results from their ability to target and inhibit various key pro-inflammatory molecules enrolled in diverse inflammatory pathways, and prevent or reduce the inflammatory damage on tissues. Research on the anti-inflammatory mechanisms of SLs has thrived over the last years, and numerous compounds from diverse plants have been studied, using in silico, in vitro, and in vivo assays. Besides their Citation: Matos, M.S.; Anastácio, anti-inflammatory potential, their cytotoxicity, structure–activity relationships, and pharmacokinetics J.D.; Nunes dos Santos, C. have been investigated. This review aims to gather the most relevant results and insights concerning Sesquiterpene Lactones: Promising the anti-inflammatory potential of SL-rich extracts and pure SLs, focusing on their effects in different Natural Compounds to Fight inflammatory pathways and on different molecular players. Inflammation. Pharmaceutics 2021, 13, 991. https://doi.org/10.3390/ Keywords: anti-inflammatory; bioactivity; sesquiterpene lactone-rich natural extracts; germacra- pharmaceutics13070991 nolides; guaianolides; eudesmanolides; heliangolides; pseudoguainolides; inflammatory pathway; NF-κB; pro-inflammatory mediators Academic Editor: Ariane Leite Rozza Received: 26 May 2021 Accepted: 22 June 2021 1. Sesquiterpene Lactones Published: 30 June 2021 Sesquiterpene lactones (SLs) are composed of a large and diverse group of phytochem- Publisher’s Note: MDPI stays neutral icals found in numerous plant families, with the greatest number of compounds belonging with regard to jurisdictional claims in to the Asteraceae family [1]. These molecules derive from two main precursors, isopentenyl published maps and institutional affil- diphosphate (IPP), and dimethylallyl diphosphate (DMAPP) [2,3]. These precursors can be iations. generated in plants via either the mevalonate pathway, which occurs within the cytosol, or the 2-C-methyl-D-erythritol pathway, occurring in the chloroplasts [2,3]. IPP and DMAPP are converted into farnesyl diphosphate (FPP) by the enzyme farnesyl diphosphate synthase [4,5]. FPP is considered a common precursor for SLs, but can be further converted to sterols, triterpenes, or used for prenylationed of proteins. Its cyclization by germacrene Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. A synthase into germacrene A is considered as the first step towards SL production [2]. This article is an open access article Germacrene A is subsequently oxidized by a cytochrome P450 enzyme, germacrene A oxi- distributed under the terms and dase, into germacrene A acid. This molecule can be further modified to produce different conditions of the Creative Commons subclasses of SLs, with the characteristic 15-carbon backbone structure [4–7]. Attribution (CC BY) license (https:// SLs are characterized by a 15-carbon backbone containing α,β-unsaturated carbonyl creativecommons.org/licenses/by/ structures, such as a conserved α-methylene-γ-lactone (Figure1). Numerous other modi- 4.0/). fications to the molecular structure are also known, including the presence of hydroxyls, Pharmaceutics 2021, 13, 991. https://doi.org/10.3390/pharmaceutics13070991 https://www.mdpi.com/journal/pharmaceutics PharmaceuticsPharmaceutics 2021 2021, ,13 13, ,x x FOR FOR PEER PEER REVIEW REVIEW 22 of of 40 40 synthasesynthase may may be be the the first first step step and and the the branching branching point point to to produce produce SL SL subclasses subclasses such such as as germacranolides,germacranolides, guaianolides, guaianolides, and and eudesmanolides eudesmanolides [5,7]. [5,7]. Pharmaceutics 2021, 13, 991 2 of 39 SLsSLs are are characterized characterized by by a a 15-carbon 15-carbon backbone backbone containing containing α α,β,β-unsaturated-unsaturated carbonyl carbonyl structures,structures, such such as as a a conserved conserved α α-methylene--methylene-γγ-lactone-lactone (Figure (Figure 1). 1). Numerous Numerous other other modi- modi- ficationsfications to to the the molecular molecular structure structure are are also also known, known, including including the the presence presence of of hydroxyls, hydroxyls, esters,esters,esters, andand epoxidesepoxides epoxides [8[8,9]. [8,9].,9]. ThereThere There are are are over over over 5000 500 500 reported00 reported reported structures structures structures of SLs,of of SLs, SLs, divided divided divided into into sev-into severaleralseveral skeletal skeletalskeletal subtypes, subtypes,subtypes, the main thethe ones mainmain being onesonesgermacranolides, beingbeing germacranolides,germacranolides, guaianolides, guaianolides,guaianolides, eudesmanolides, eudes-eudesmanolides,heliangolides,manolides, heliangolides, heliangolides, and pseudoguaianolides and and pseudoguaianolides pseudoguaianolides (Figure2)[1 (Figure, 10(Figure]. 2) 2) [1,10]. [1,10]. β γγ β αα ββ FigureFigureFigure 1. 1. αα α-methylene--methylene--methylene-γγγ-lactone-lactone-lactone moiety moietymoiety core corecore structure structurestructure characteristic characteristic characteristic of of SLs. SLs. Figure 2. Structural backbone of the main SL subclasses. FigureFigure 2. 2. Structural Structural backbone backbone of of the the main main SL SL subclasses. subclasses. In recent years, the interest in SLs has risen considerably due to their vast array of In recent years, the interest in SLs has risen considerably due to their vast array of biologicalIn recent activities years, relevant the interest to human in SLs health.has risen This considerably curiosity hasdue ledto their to many vast studiesarray of biological activities relevant to human health. This curiosity has led to many studies re- regardingbiological theactivities isolation relevant of these to human compounds health. from This natural curiosity sources, has led the to developmentmany studies ofre- garding the isolation of these compounds from natural sources, the development of com- completegarding the or semi-synthesis isolation of these procedures, compounds and from the evaluation natural sources, of the pharmacological the development potential of com- plete or semi-synthesis procedures, and the evaluation of the pharmacological potential ofplete SLs or and semi-synthesis their derivatives. procedures, Some of and the the many evaluation known of activities the pharmacological reported for this potential class of SLs and their derivatives. Some of the many known activities reported for this class of ofof compoundsSLs and their include derivatives. anti-microbial, Some of the anti-fungal, many known anti-viral, activities anti-tumor, reported for anti-malarial, this class of compoundsanti-diabetic,compounds include include analgesic, anti-microbial, anti-microbial, and anti-inflammatory anti-fungal, anti-fungal, activities anti-viral, anti-viral, [1, 11anti-tumor, anti-tumor,]. There is anti-malarial, a anti-malarial, close relationship anti- anti- diabetic,betweendiabetic, analgesic, theanalgesic, pharmacological and and anti-inflammatory anti-inflammatory potential of SLsactivities activities and their [1,11]. [1,11]. respective There There is is ecologicala a close close relationship relationship purposes, since their main goals in nature consist of anti-microbial and anti-herbivore endeavors, as well as the growth inhibition of competing plants [12]. The electrophilic α,β-unsaturated carbonyl moieties present in SLs, which react by Michael-type addition with biological nucleophiles, can explain the wide range of observed biological activities. In particular, sulfhydryl groups present in biomolecules, such as Pharmaceutics 2021, 13, x FOR PEER REVIEW 3 of 40 between the pharmacological potential of SLs and their respective ecological purposes, since their main goals in nature consist of anti-microbial and anti-herbivore endeavors, as well as the growth inhibition of competing plants [12]. Pharmaceutics 2021, 13, 991 The electrophilic α,β-unsaturated carbonyl moieties present in SLs, which3 of react 39 by Michael-type addition with biological nucleophiles, can explain the wide range of observed biological activities. In particular, sulfhydryl groups present in biomolecules, such as glutathione (GSH) or proteins with free cysteine groups,

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