Pyrrolizidine Alkaloids: Chemistry, Pharmacology, Toxicology and Food Safety
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International Journal of Molecular Sciences Review Pyrrolizidine Alkaloids: Chemistry, Pharmacology, Toxicology and Food Safety Rute Moreira, David M. Pereira * ID , Patrícia Valentão ID and Paula B. Andrade * ID REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, R. Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal; [email protected] (R.M.); [email protected] (P.V.) * Correspondence: [email protected] (D.M.P.); [email protected] (P.B.A.); Tel.: +351-220-428-655 (D.M.P.); +351-220-428-654 (P.B.A.) Received: 19 April 2018; Accepted: 23 May 2018; Published: 5 June 2018 Abstract: Pyrrolizidine alkaloids (PA) are widely distributed in plants throughout the world, frequently in species relevant for human consumption. Apart from the toxicity that these molecules can cause in humans and livestock, PA are also known for their wide range of pharmacological properties, which can be exploited in drug discovery programs. In this work we review the current body of knowledge regarding the chemistry, toxicology, pharmacology and food safety of PA. Keywords: pyrrolizidine alkaloids; chemistry; toxicity; pharmacological properties; food safety 1. Introduction Alkaloids are a diverse group of amino acid-derived and nitrogen-bearing molecules that display a wide range of roles in nature, where they occur in plants, microorganisms or animals [1]. In plants, alkaloids can be found in the form of salts of organic acids, mainly malate, acetate and citrate, or combined with other molecules, such as tannins [1]. Most alkaloids display basic properties and present a lipophilic character, being soluble in apolar organic solvents and alcohol [1]. Several alkaloids are known for their remarkable biological properties, which can be either marked toxicity or potent pharmacological capacity [2]. The class of alkaloids has a long history of use, both lawful and illicit, as pharmaceuticals, stimulants and narcotics [3]. Within the many known families of alkaloids, pyrrolizidine alkaloids (PA) have been receiving increasing attention due to their occurrence in several species relevant for human and animal nutrition, as well as for their toxicological and pharmacological properties. The increasing awareness of PA contamination in all sorts of foodstuff worldwide justifies the interest and concern around this topic. Although in most cases their levels are insufficient to cause acute poisoning, they are frequently consumed in quantities that exceed the maximum daily intake suggested by authorities, which can be a contributory factor to chronic diseases. This work reviews the available information on PA, mainly regarding their chemistry, toxic and pharmacological properties, and food safety. 2. The Chemistry of PA PA are a group of alkaloids derived from ornithine that are distributed in plants of certain taxa, being also found in insects that uptake them for defense against predators [1,4]. They rarely occur in the free form as a pyrrolizidine base, being instead found as esters (mono-, di- or macrocyclic diesters) formed by a necine base (amino alcohols) and one or more necic acids (mono- or dicarboxylic aliphatic acids), which are responsible for their structural diversity [1,5]. They are usually found in the form of tertiary bases or pyrrolizidine alkaloids N-oxides (PANO) (Figure1)[1,5,6]. Int. J. Mol. Sci. 2018, 19, 1668; doi:10.3390/ijms19061668 www.mdpi.com/journal/ijms Int.Int. J.J. Mol.Mol. Sci. 2018,, 19,, 1668x FOR PEER REVIEW 22 of 2222 Int. J. Mol. Sci. 2018, 19, x FOR PEER REVIEW 2 of 22 Figure 1. Structure of a PA and its different forms. R and R correspond to different necic acids. FigureFigure 1. Structure 1. Structure of ofa PA a PA and and its its different different forms. R R1 1and and R 2R correspond22 correspond to differentto different necic necic acids. acids. AminoAminoAmino alcohols,alcohols, alcohols, oror necines,ornecines, necines, areare are derivedderived derived fromfrom pyrrolizidine.pypyrrolizidine.rrolizidine. The TheThe pyrrolizidine pyrrolizidinepyrrolizidine core, core,core, comprising comprisingcomprising twotwo saturatedsaturatedtwo saturated five-memberedfive-membered five-membered ringsrings rings withwith with aa a nitrogennitrogen nitrogen atom atom between betweenbetween them, them,them, sometimes sometimessometimes displays displaysdisplays a double aa double bond in the 1,2 position, which frequently results in enhanced toxicity [7]. They can also have a single bondbond inin thethe 1,2 position, whichwhich frequentlyfrequently resultsresults inin enhancedenhanced toxicitytoxicity [[7].7]. TheyThey cancan alsoalso havehave aa singlesingle alcohol at C-1, a second alcohol in position C-7 (di-hydroxylated) and less often a third in C-2 or C-6 alcohol at C-1, a second alcohol in position C-7 (di-hydroxylated) and less often a third in C-2 or C-6 alcohol(tri-hydroxylated) at C-1, a second [8–10]. alcohol Esterification in position can C-7 take (d placei-hydroxylated) at C-7 and/or andC-9 positions less often [9]. a third in C-2 or C-6 (tri-hydroxylated)(tri-hydroxylated)According [ [8–10].8to– 10the]. structure EsterificationEsterification of the cannecinecan taketake base, placeplace PA atmayat C-7C-7 be and/or and/orsorted intoC-9 fourpositions groups: [9]. [9 retronecine-,]. Accordingheliotridine-,According to tootonecine- the the structure structure and of platynecine-types the of necine the necine base, (FigurePA base, may PA2) be [11]. sorted may Retronecine-, beinto sorted four groups:otonecine- into four retronecine-, and groups: retronecine-,heliotridine-,heliotridine-types heliotridine-,otonecine- are unsaturatedand otonecine- platynecine-types andbases, platynecine-types while pl(Figureatynecine-type 2) (Figure [11]. is2 )[ Retronecine-,saturated11]. Retronecine-, [12,13]. otonecine- From otonecine- a and andheliotridine-types heliotridine-typesstructural point ofare view, areunsaturated otonecine unsaturated isbases, the bases, most while distinct while pl among platynecine-typeatynecine-type all types, sinceis issaturated it saturated is oxidized [12,13]. [12 at, 13C-8]. andFrom From aa structuralstructuraldisplays point a monocyclic of of view, view, otonecine otonecinering, thus is isdiverging the the most most from distinct distinct the amongother among groups, all all types, types,which since sincedisplay it is it oxidized a is bicyclic oxidized at ring C-8 at C-8and anddisplays displays[8,10,14]. a monocyclic Retronecine a monocyclic ring, andring, heliotridinethus thusdiverging diverging are diastereom from from theers, other the with other groups, distinct groups, whichorientation which display at display position a bicyclic a C-7 bicyclic ring ring[8,10,14]. [[15].8,10 ,Retronecine14]. Retronecine and andheliotridine heliotridine are diastereom are diastereomers,ers, with with distinct distinct orientation orientation at position at position C-7 C-7[15]. [ 15]. Figure 2. Groups of PA, according to the necine base. Necic acids are aliphaticFigure 2. carboxylic acids that can be simple (angelic and tiglic acids), Figure 2. Groups of PA, accordingaccording toto thethe necinenecine base.base. monocarboxylic acids with hydroxyisopropylbutanoic structures at C-7 (trachelantic and viridifloric acids) or dicarboxylic acids at C-8 or at C-10 (senecic and isatinecic acids) (Figure 3) [1]. Necic acids are aliphatic carboxylic acids that can be simple (angelic and tiglic acids), NecicThe acids combination are aliphatic of the above-mentioned carboxylic acids structures that can results be insimple mono- (angelicor di-esters. and Within tiglic the acids), monocarboxylicmonocarboxylicmonocarboxylic acidsacids acids, withwith characteristic hydroxyisopropylbutanoichydroxyisopropylbutanoic of the Boraginaceae structuresstructures family, some atat C-7C-7have (trachelantic(trachelantic a hydroxyl group andand viridifloricviridifloricat C-9 acids)acids)esterified oror dicarboxylicdicarboxylic by a hydroxyisopropylbutanoic acidsacids atat C-8C-8 oror atat C-10C-10 acid, (senecic(senecic such and andas intermedine isatinecicisatinecic acids) acids)(Figure (Figure(Figure 4) [1].3 In)[3) 1cases[1].]. where ThethereThe combinationis a second necic of of acid,the the above-mentionedit above-mentioned usually occurs in the structures structures hydroxyl resultsgroup results of in C-7, in mono- mono-in the or form ordi-esters. di-esters.of angelic Within acid Within the themonocarboxylic monocarboxylicor tiglic acid, acids, as in acids, echimidinecharacteristic characteristic (Figure of the 5) of Boraginaceae[1]. the Macrocyclic Boraginaceae family, diesters, family, some characteristic somehave a have hydroxyl from a hydroxyl Asteraceae group groupat C-9 atesterified C-9family, esterified by have a hydroxyisopropylbutanoic also by abeen hydroxyisopropylbutanoic described, which correspond acid, such acid, to asC-7 such intermedine and as C-9 intermedine esterified (Figure by (Figure a4) dicarboxylic [1].4 In)[ cases1]. acid In where cases wherethere(Figure is there a second is6) a[1]. second necicUnusually, acid, necic itnecines acid, usually it may usually occurs be esterified occurs in the in hydroxylwith the aromatic hydroxyl group or group arylalkyl of C-7, of in C-7,acids the in [1].form the form of angelic of angelic acid According to the most widely accepted pathway, the biosynthesis of the pyrrolizidine core acidor tiglic or tiglic acid, acid, as in as echimidine in echimidine (Figure (Figure 5)5 )[[1].1 ].Macrocyclic Macrocyclic