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Current Knowledge and Perspectives of Pyrrolizidine Alkaloids in Pharmacological Applications: a Mini-Review

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Current Knowledge and Perspectives of Pyrrolizidine Alkaloids in Pharmacological Applications: a Mini-Review molecules Review Current Knowledge and Perspectives of Pyrrolizidine Alkaloids in Pharmacological Applications: A Mini-Review Xianqin Wei 1,*, Weibin Ruan 1 and Klaas Vrieling 2 1 Institute of Entomology, College of Life Sciences, Nankai University, Tianjin 300071, China; [email protected] 2 Plant Science and Natural Products, Institute of Biology, Leiden University, Sylviusweg 72, P.O. Box 9505, 2300 RA Leiden, The Netherlands; [email protected] * Correspondence: [email protected] or [email protected] Abstract: Pyrrolizidine alkaloids (PAs) are a widespread group of secondary metabolites in plants. PAs are notorious for their acute hepatotoxicity, genotoxicity and neurological damage to humans and animals. In recent decades, the application of PAs for beneficial biological activities to cure disease has drawn greater attention. Here, we review the current knowledge regarding the pharmacological properties of PAs and discuss PAs as promising prototypes for the development of new drugs. Keywords: plant secondary metabolites; pharmacy; alkaloids; herb medicine; defense; regulations 1. Introduction Pyrrolizidine alkaloids (PAs) are an important group of secondary metabolites in Citation: Wei, X.; Ruan, W.; Vrieling, plants [1,2]. More than 500 different PAs were identified in more than 6000 plant species K. Current Knowledge and to date [1,3]. PAs have been identified in Apocynaceae (Alafia, Aristeguietia, Brachyglottis, Perspectives of Pyrrolizidine Cacalia, Eupatorium, Ligularia, Pittocaulon, Senecio and Tephroseris), Boraginaceae (Anchusa, Alkaloids in Pharmacological Borago, Cynoglossum, Echium, Heliotropium, Lithospermum, Onosma, Rindera and Solenanthus), Applications: A Mini-Review. Convolvulaceae (Argyreia), Fabaceae (Castanospermum and Crotalaria), Hyacinthaceae (Mus- Molecules 2021, 26, 1970. https:// cari and Scilla), Orchidaceae (Cremastra and Liparis), and Santalaceae (Amphorogyne and doi.org/10.3390/molecules26071970 Osyris)[4–6]. PAs are ester alkaloids composed of a necine base (two fused five-membered rings Academic Editor: Maria José Ferreira joined by a single nitrogen atom) and a necic acid (one or two carboxylic ester arms) (Figure1) [7]. The combination of a set of necine bases and necic acids results in a consid- Received: 28 February 2021 erable amount of structural diversity in PAs. This is further amplified by modifications, Accepted: 27 March 2021 including N-oxidation of the tertiary nitrogen of the necine base, hydroxylation of the Published: 31 March 2021 necine base and/or the necic acid, dehydrogenation, halogenation and acetylation of hy- droxy groups of the acid moiety. It is not surprising that several hundreds of different PAs Publisher’s Note: MDPI stays neutral have already been identified, and each year new PAs are detected. Based on the structure with regard to jurisdictional claims in of the necine base, the majority of the PAs can be sorted into four groups: retronecine- published maps and institutional affil- type, heliotridine-type, otonecine-type and platynecine-type (Figure2)[ 8,9]. Except for iations. otonecine, the other three bases can form N-oxides [9]. The platynecine type of PAs con- tain a saturated necine base unit and are less toxic, while the other three bases contain a 1,2-unsaturated necine base unit and are highly toxic. PAs are notorious for their serious hepatotoxicity, genotoxicity and neurological Copyright: © 2021 by the authors. damage, affecting livestock, wildlife and humans [7,10,11]. PAs were detected in honey, Licensee MDPI, Basel, Switzerland. milk and other food supplements [12–16]. However, for plants PAs play an important This article is an open access article role in defense against herbivores and pathogens [17–19]. Several PA-containing plants distributed under the terms and are used in herb medicines in many countries [20–25]. For example, in India Heliotropium conditions of the Creative Commons subulatum Attribution (CC BY) license (https:// plants were used for boils, insect stings, cores, throat infections, ulcers and snake creativecommons.org/licenses/by/ bite [26]. Anti-microbial, anti-inflammatory, anti-cancer and anti-viral effects are known 4.0/). Molecules 2021, 26, 1970. https://doi.org/10.3390/molecules26071970 https://www.mdpi.com/journal/molecules MoleculesMolecules 2021 2021, 26, 26, x, xFOR FOR PEER PEER REVIEW REVIEW 2 2of of 13 13 Molecules 2021, 26, 1970 2 of 13 bitebite [26]. [26]. Anti-microbial, Anti-microbial, anti-inflammatory, anti-inflammatory, anti-cancer anti-cancer and and anti-viral anti-viral effects effects are are known known from several PAs isolated from plants. In this review, we will focus on the pharmacologi- fromfrom several several PAs PAs isolated isolated from from plants. plants. In In this this review, review, we will focusfocus onon thethe pharmacologicalpharmacologi- cal properties of PAs by summarizing the related papers published in the past 50 years. calproperties properties of of PAs PAs by by summarizing summarizing the the related related papers papers published published in thein the past past 50 50 years. years. Figure 1. Schematic structure of pyrrolizidine alkaloid. FigureFigure 1. 1. Schematic Schematic structure structure of of pyrrolizidine pyrrolizidine alkaloid. alkaloid. Figure 2. Most common necineFigureFigure bases 2. 2. Most Most in pyrrolizidine common common necine necine alkaloids bases bases (PAs).in in pyrrolizidine pyrrolizidine PAs are generally alkaloids alkaloids classified (PAs). (PAs). PAs intoPAs are four are generally generally types based classified classified on the representative necine basesintointo four (platynecine, four types types based based retronecine, on on the the representative representative heliotridine andnecine necine otonecine). bases bases (platynecine, (platynecine, retronecine, retronecine, heliotridine heliotridine and and otonecine).otonecine). 2. Pharmacological Effects 2.2.2.1. Pharmacological Pharmacological Anti-Microbial ActivityEffects Effects 2.1.2.1. Anti-Microbial Anti-MicrobialKilling or inhibiting Activity Activity the growth of microorganisms and especially pathogenic microor- ganismsKillingKilling is or defined or inhibiting inhibiting as anti-microbial the the growth growth of activity,of microorganisms microorganisms and it includes and and especially anti-bacterialespecially pathogenic pathogenic and anti-fungal micro- micro- organismsorganismsactivities [is27 is defined ].defined PAs with as as anti-microbial anti-microbial anti-microbial activity, activity, properties and and wereit it includes includes mainly anti-bacterial anti-bacterial isolated from and and the anti-fun- anti-fun- genus of galgalHeliotropium activities activities [27]., [27].Crotalaria PAs PAs with withand anti-microbial anti-microbialSenecio plants. pr propertiesoperties were were mainly mainly isolated isolated from from the the genus genus ofof Heliotropium HeliotropiumEuropine,, Crotalaria, heliotridine, Crotalaria and and lasiocarpine Senecio Senecio plants. plants. and lasiocarpine N-oxide were identified from the aerialEuropine,Europine, parts of heliotridine,Heliotropium heliotridine, ellipticumlasi lasiocarpineocarpine, and and and their lasiocarpine lasiocarpine anti-microbial N N-oxide-oxide activities were were were identified identified investigated from from thethe(Figure aerial aerial3 )[parts parts28]. of of Europine,Heliotropium Heliotropium lasiocarpine ellipticum ellipticum, andand, and lasiocarpinetheir their anti-microbial anti-microbialN-oxide activities activities showed were anti-bacterialwere investi- investi- gatedgatedactivity (Figure (Figure to Escherichia 3) 3) [28]. [28]. Europine, Europine, coli and lasiocarpineEnterobacter lasiocarpine cloacaeand and lasiocarpine lasiocarpine. Europine N hadN-oxide-oxide anti-fungal showed showed anti-bacte- activities anti-bacte- to rialrialAspergillus activity activity to flavusto Escherichia Escherichia, Drechslera coli coli and tetrameraand Enterobacter Enterobacterand Fusarium cloacae cloacae. Europine. moniliformeEuropine had had. Heliotridineanti-fungal anti-fungal activities hadactivities anti- D. tetramera N totofungal Aspergillus Aspergillus activities flavus flavus to, Drechslera, Drechslera tetramera tetramera, and lasiocarpine and and Fusarium Fusarium -oxidemoniliforme moniliforme had. anti-fungalHeliotridine. Heliotridine activities had had anti- anti- to Curvularia lunata and F. moniliforme. fungalfungal activities activities to to D. D. tetramera tetramera, and, and lasiocarpine lasiocarpine N N-oxide-oxide had had anti-fungal anti-fungal activities activities to to Cur- Cur- 9-Angeloylretronecine, supinine and lasiocarpine isolated from the aerial parts of vulariavularia lunata lunata and and F. F. moniliforme moniliforme. Heliotropium bursiferum had antimicrobial activity to Bacillus subtilis and phytopathogenic 9-Angeloylretronecine,9-Angeloylretronecine, supinine supinine and and lasiocar lasiocarpinepine isolated isolated from from the the aerial aerial parts parts of of He- He- fungi Candida tropicalis and Aspergillus niger at a dose of 50 mg/mL (Figure3)[29]. liotropiumliotropium bursiferum bursiferum had had antimicrobial antimicrobial activity activity to to Bacillus Bacillus subtilis subtilis and and phytopathogenic phytopathogenic fungifungi Candida Candida tropicalis tropicalis and and Aspergillus Aspergillus niger niger at at a adose dose of of 50 50 mg/mL mg/mL (Figure (Figure 3) 3) [29]. [29]. Molecules 2021, 26, 1970 3 of 13 Molecules 2021, 26, x FOR
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