Sulphated Flavonoids: Biosynthesis, Structures, and Biological Activities
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molecules Review Sulphated Flavonoids: Biosynthesis, Structures, and Biological Activities Yanna C. F. Teles 1, Maria Sallett R. Souza 2 and Maria de Fátima Vanderlei de Souza 2,3,* 1 Department of Chemistry and Physics, Agrarian Sciences Center, Universidade Federal da Paraíba, Areia 58397-000, PB, Brazil; [email protected] 2 Post graduation Program in Bioactive Natural and Synthetic Products, Health Sciences Center, Universidade Federal da Paraíba, João Pessoa 58051-900, PB, Brazil; [email protected] 3 Post graduation in Development and Technological Innovation in Medicines, Health Sciences Center, Universidade Federal da Paraíba, João Pessoa 58051-900, PB, Brazil * Correspondence: [email protected]; Tel.: +55-83-3216-7351; Fax: +55-83-3216-7511 Received: 13 January 2018; Accepted: 12 February 2018; Published: 23 February 2018 Abstract: The great diversity of enzymatic reactions in plant secondary metabolism allows the continuous discovery of new natural compounds and derivatives. Flavonoids, for example, can be found as aglycone or as several sorts of glycosylated, acetylated, methylated, and sulphated derivatives. This review focuses on sulphated flavonoids, an uncommon group of flavonoid derivatives found in some plant families. This work presents a compilation of sulphated flavonoids and their natural sources reported in the literature. Biosynthetic aspects and biological activities have also been reviewed, showing that these particular kinds of natural compounds play an interesting role in plant metabolism, as well as being potential candidates for the development of new drugs. Keywords: sulphated flavonoids; sulphation; secondary metabolism; sulphotransferases 1. Introduction Secondary metabolites are specialized compounds produced by plants and microorganisms in response to environmental changes as a result of the organism adapting to, or as a defence mechanism against, pathogens or predators. They are not involved in the central (primary) metabolism and their biosynthesis is frequently taxonomically restricted. Some examples of secondary compounds are alkaloids, terpenoids, lignans, and phenolic compounds [1]. The great diversity of secondary metabolism in plants has given phytochemistry research a continuous process of discovery of new naturally occurring compounds and derivatives. The production of over 200,000 structures from plant metabolism is estimated, and a great part of this number may be due to enzymatic modifications of known compounds resulting in derivatives, such as prenylated, acetylated, methylated, sulphated, glucuronated, and glycosylated substances, among others [2,3]. Polyphenols are one of the most relevant groups of secondary metabolites. They are usually divided in classes, such as stilbenes, phenolic acids and simple derivatives, lignans, tannins, and flavonoids. Flavonoids comprise the most studied group of polyphenols [4]. They are characterized by the 2-phenyl-benzyl-γ-pyrone nucleus, with great structural diversity resulting in different flavonoid types, e.g., aurones, flavanonols, isoflavones, flavones, flavonols and anthocyanins. The structural variation is also a result of different attached substituents. For example, flavonoids can suffer enzymatic methylation by methyltransferases and glycosylation by specific glycosyltransferases [5]. Figure1 shows the flavonoid basic skeleton and known flavonoids from which sulphated derivatives have been identified. Molecules 2018, 23, 480; doi:10.3390/molecules23020480 www.mdpi.com/journal/molecules Molecules 2018, 23, 480 2 of 11 Molecules 2018, 23, x FOR PEER REVIEW 2 of 11 Molecules 2018, 23, x FOR PEER REVIEW 2 of 11 FigureFigure 1. 1.Flavonoid Flavonoid characteristic characteristicskeleton skeleton andand known flavonoids. flavonoids. Figure 1. Flavonoid characteristic skeleton and known flavonoids. The biological and pharmacological activities of flavonoids have been described. They are The biological and pharmacological activities of flavonoids have been described. They are known known to protect plants from biotic and abiotic stresses, they can absorb UV-light and possess to protectThe plants biological from and biotic pharmacological and abiotic stresses, activities they of canflavonoids absorb UV-lighthave been and described. possess antioxidantThey are knownantioxidant to protect potential plants [6]. from In human biotic health,and abiotic many stresses, flavonoids they have can absorbbeen related UV-light to preventionand possess of potential [6]. In human health, many flavonoids have been related to prevention of cardiovascular antioxidantcardiovascular potential disease, [6]. ischemia, In human and health, inflammation many flavonoids, among others. have Quercetin, been related for example,to prevention has been of disease, ischemia, and inflammation, among others. Quercetin, for example, has been shown to inhibit cardiovascularshown to inhibit disease, ATP hydrolysis ischemia, and and inflammation synthesis by the, among ATP others.synthase Quercetin, [7,8]. for example, has been ATP hydrolysis and synthesis by the ATP synthase [7,8]. shownFlavonoid to inhibit ATPbiosynthesis hydrolysis is andpart sy nthesisof the byphenylpropanoid the ATP synthase pathway, [7,8]. and starts with the Flavonoid biosynthesis is part of the phenylpropanoid pathway, and starts with the condensation condensationFlavonoid of biosynthesis one p-coumaroyl-CoA is part ofmolecule the phenylpropanoid with three malonyl-CoA pathway, molecules and starts (biosynthesis with the by of onecondensationmixedp-coumaroyl-CoA pathway) of one resulting p-coumaroyl-CoA molecule in a chalcone with three molecule (4,2 malonyl-CoA′,4′,6 with′-tetrahydroxychalcone). three molecules malonyl-CoA (biosynthesis moleculesThis chalcone by (biosynthesis mixed is isomerized pathway) by 0 0 0 resultingmixedby chalcone pathway) in a chalconeisomerase resulting (4,2 to inform,4 a,6 chalcone a-tetrahydroxychalcone). flavanone (4,2′ ,4[5]′,6 (Figure′-tetrahydroxychalcone). 2). This chalcone This is isomerizedchalcone is isomerized by chalcone isomeraseby chalcone to form isomerase a flavanone to form [ 5a] flavanone (Figure2). [5] (Figure 2). 3 OH OH 2 3 4 OH OH 2 5' 1 4 HO OH 5 HO O 5' 6' 1 HO 4' OH β 6 5 HO O 4' 6'1' β 6 3' α chalcone isomerase 1' 3' 2' α chalcone isomerase 2' OH O OH O OH O chalcone OH flavanoneO chalcone Figure 2. Chalcone isomerization to formflavanone a flavanone. Figure 2. Chalcone isomerization to form a flavanone. Figure 2. Chalcone isomerization to form a flavanone. Molecules 2018, 23, 480 3 of 11 Flavanone suffers additional enzymatic reactions to yield several different flavonoid sub-classes or types,Molecules e.g., 2018 flavones,, 23, x FOR flavonols,PEER REVIEW flavanonols (dihydroflavonols), isoflavones, and anthocyanins3 of 11 [5]. Under natural conditions, flavonoids can be found as aglycones or as several sorts of glycosides, prenylated,Flavanone acetylated, suffers methylated, additional andenzymatic sulphated reactions derivatives. to yield several Each differentdifferent flavonoid substituent sub-classes or pattern of substitutionor types, creates e.g., flavones, new derivatives flavonols, flavanonols with particular (dihydroflavonols), characteristics isoflavones, and properties and anthocyanins [9]. [5]. ThisUnder review natural will focus conditions, on sulphated flavonoids flavonoids, can be found an as uncommonaglycones or groupas several of sorts flavonoid of glycosides, derivatives foundprenylated, in some plant acetylated, families, methylated, that has and developed sulphated pharmaceutical derivatives. Each interest different especially substituent because or pattern of their of substitution creates new derivatives with particular characteristics and properties [9]. potential use as candidates in the development of new drugs. This review will focus on sulphated flavonoids, an uncommon group of flavonoid derivatives 2. Methodologyfound in some plant families, that has developed pharmaceutical interest especially because of their potential use as candidates in the development of new drugs. The present study was carried out based on a literature review using the keyword ‘sulphated flavonoids’.2. Methodology The scientific publications were selected focusing on sulphated flavonoids with a sulphate group attachedThe present to the study aglycone, was carried considering out based their on a chemical literature structures,review using biosynthesis, the keyword ‘sulphated and biological activities.flavonoids’. The SciFinder The scientific database publications (Chemical were Abstracts selectedService, focusing Columbus, on sulphated OH, flavonoids USA) has with been a used. The literaturesulphate group source attached and the toselected the aglycone, studies consider referreding their to in chemical this review structures, have been biosynthesis, published and in the Englishbiological language. activities. The SciFinder database (Chemical Abstracts Service, Columbus, OH, USA) has been used. The literature source and the selected studies referred to in this review have been 3. Sulphatedpublished Flavonoids: in the English General language. Information and Chemotaxonomic Aspects Sulphated3. Sulphated flavonoids Flavonoids: may General be the Info lessrmation common and flavonoidChemotaxonomic derivative Aspects compounds found in some specific plant families [10]. They can be single sulphate or multi-sulphate esters of known flavonoid Sulphated flavonoids may be the less common flavonoid derivative compounds found in some skeletons,specific usually plant families flavones