Methoxylated Flavones Citrus Lipophilic Flavonoids

Phytochem Rev (2016) 15:363–390 DOI 10.1007/s11101-015-9426-0 Methoxylated flavones: occurrence, importance, biosynthesis Anna Berim . David R. Gang Received: 13 March 2015 / Accepted: 20 July 2015 / Published online: 28 July 2015 Ó Springer Science+Business Media Dordrecht 2015 Abstract Lipophilic flavones with several methoxyl Keywords Flavonoids Á Lipophilic Á O-methylation Á residues occur in various clades of land plants, from Bioactivity Á Biosynthetic network liverworts to core eudicots. Their chemodiversity is mediated by the manifold combinations of oxygena- Abbreviations tion and methoxylation patterns. In the Lamiaceae, CHS Chalcone synthase Asteraceae, and Rutaceae, (poly)methoxylated fla- FNS Flavone synthase vones are thought to be produced by secretory tissues FOMT Flavonoid O-methyltransferase and stored externally or in oil cavities. They exhibit an F(digit)OMT Flavonoid (digit)-O- array of bioactivities in vitro and in vivo, and may methyltransferase constitute part of the plants’ chemical defense mech- 2-ODD 2-Oxoglutarate-dependent anisms and represent promising natural lead mole- dioxygenase cules for the development of potent antiproliferative, PMF Polymethoxylated flavones antidiabetic, or anti-inflammatory drugs. The biosyn- PTC52 Protochlorophyllide a oxygenase thesis of (poly)methoxylated flavones in sweet basil RO Rieske-type oxygenase (Ocimum basilicum L.) has been largely elucidated in the past few years. The knowledge obtained in those studies can be used for enzymatic semi-synthesis of these flavones as well as for further cell biological and physiological studies of basil trichome metabolism. In addition, these findings create an excellent starting Introduction point for investigations into (poly)methoxylated flavone metabolism in more and less distantly related Flavonoids are a large and diverse group of specialized taxa, which would shed light on the evolution of this metabolites comprising, according to recent accounts, biosynthetic capacity. over 9000 distinct chemical units (Ferrer et al. 2008). The basic skeleton of a flavonoid is a C6–C3–C6 structure formed by the stepwise condensation of a & & A. Berim ( ) Á D. R. Gang ( ) phenylpropenoyl-CoA starter molecule, mostly p- Institute of Biological Chemistry, Washington State University, 100 Dairy Road, Pullman, WA 99164, USA coumaroyl-CoA, with three malonyl-CoA units, each e-mail: [email protected] of which undergoes decarboxylation, and by the D. R. Gang subsequent cyclization of the polyketide chain to form e-mail: [email protected] a phloroglucinol ring (Fig. 1). Compounds with this 123 364 Phytochem Rev (2016) 15:363–390 OH O S-CoA 3 4 OH Enz OH 2 OH 3´ O HO 4´ 2´ OH 5 HO O O O CHS O S β CHS 6 1´ α + 3x HO S-CoA 5´ 6´ OH O OH O -3xCO2 O O OH p-coumaroyl-CoA malonyl-CoA tetraketide chalcone aurone intermediate 3´ 4´ OH OH OH OH 8 B HO 7 O 2 5´ HO OH HO O HO O A C 6 3 4 OH OH 5 OH O OH O OH O OH O flavonol dihydroflavonol flavanone dihydrochalcone FNS I or FNS II OH OH HO O HO O HO O+ OH OH O OH O OH OH flavone isoflavone anthocyanin Fig. 1 Biosynthetic origin and types of flavonoids. Depicted is dependent dioxygenases, or FNS II, cytochrome P450-depen- the first committed step of flavonoid biosynthesis, catalyzed by dent monooxygenases) are responsible for the formation of chalcone synthase (CHS), and types of flavonoid backbones flavones. The backbone numbering is indicated on chalcone and formed by downstream cyclizations and further core structure flavanone structures modifications. Flavone synthases (FNS I, 2-oxoglutarate- parental bicyclic C6–C3–C6 structure are called chal- compounds reported as of 2005 (Martens and Mithofer cones, and the type III polyketide synthase catalyzing 2005), with their numbers steadily increasing. About this first committed step of flavonoid biosynthesis is 60 new flavones were reported between 2007 and 2009 designated chalcone synthase (Abe and Morita 2010; (Veitch and Grayer 2011). Like in all natural product Winkel 2006). To give rise to the tricyclic phenylchro- groups, their chemical diversity is achieved by man- mane backbone typical for the majority of flavonoids, ifold modifications of the flavone backbone sub- chalcones are further transformed by chalcone iso- stituents. These modifications lead to differing merase (Ferrer et al. 2008). Based on modifications to chemical properties of the individual flavone entities. the structure of this phenylchromane skeleton, flavo- Conjugations with saccharides, i.e., glycosylations noids are subdivided into several groups, such as make the molecule more hydrophilic. Among glyco- flavanones, flavonols, dihydroflavonols, flavones, iso- sylated flavones, both C- and O-glycosylations are flavones, anthocyanins, etc. (Fig. 1). The accumula- found. Other modifications, such as prenylations or tion of flavonoids of some type or other is ubiquitous methylations, render the molecule more lipophilic. It in land plants (Winkel-Shirley 2001). is relevant to mention at this point that C-methylation Flavones, the subject of this review, differ from the of flavonoids in Pinus strobus has been shown to flavonols by the lack of a hydroxyl residue at position originate during the scaffold formation step catalyzed 3 of the C ring. However, they are not intermediates en by a specialized chalcone synthase that utilizes an route to flavonols and are formed via a separate branch unusual substrate (methylmalonyl-CoA), resulting in a of the greater flavonoid biosynthetic network (Fig. 1). C-methyl moiety at positon 6 (Schroder et al. 1998), Flavones are one of the most frequently occurring sub- rather than being introduced by C-methyltransferases classes of flavonoids, with more than 500 distinct as happens, e.g., in the biosynthesis of sterols 123 Phytochem Rev (2016) 15:363–390 365 (Nes 2003). However, there are currently no data other algae concerning the analogous reaction in non-gym- “viridiplantae” green algae nosperms. Prenylated lipophilic flavonoids have been land plants liverworts Marchantiales reported from a number of species and exhibit strong mosses hornworts cytotoxic potential, as recently reviewed by Smejkal vascular plants lycophytes (2014). In the present review, we will focus on lipophilic ferns Polypodiales seed plants gymnosperms O-methylated (or methoxylated) flavones. The desig- angiosperms basal angiosperms Laurales nation ‘‘polymethoxylated flavonoids’’ has traditionally magnoliids Piperales been reserved for compounds with four and more monocots Poales Sapindales methoxyl residues. The occurrence of polymethoxy- Gentianales lated flavones (PMFs) sensu stricto is rather restricted. eudicots Lamiales Asterales In addition, even plant species accumulating PMFs Fabales Fagales fitting this definition tend to additionally accumulate sets of flavones with fewer ‘‘decorations’’,which belong Fig. 2 Occurrence of (poly)methoxylated flavones in land to the same pathway or metabolic network and probably plants. Depicted are the major clades of the land plants. Orders represent biosynthesis intermediates or alternative end- for which the occurrence of (poly)methoxylated flavone occurrence has been documented are shown next to branches. points. We therefore describe the topic of this review as The list of orders is not comprehensive for the eudicots (poly)methoxylated flavones, and will try to present an overview of their occurrence in the plant kingdom, their importance for plants and humans, and the current status broad conclusions concerning the occurrence of of knowledge concerning the biochemistry and genetics (poly)methoxylated flavones must await comprehen- of their production. Special attention will be paid to sive and systematic studies. Nevertheless, it is already flavones with additional hydroxylations at positions 6 obvious that the ability to biosynthesize and 8 of the phenylchromane scaffold (Fig. 1), whose (poly)methoxylated flavones is widespread in land biosynthesis we have recently studied in detail. plants from liverworts and ferns to core eudicots (Fig. 2). This biosynthetic capability thus appears to have emerged early on after plants invaded terrestrial The distribution and diversity environments, if not sooner. Indeed, certain ferns, such of (poly)methoxylated flavones in the plant as selected Cheilanthes and Nothoelana species, kingdom Pteridaceae (Wollenweber and Schneider 2000) and liverworts, such as Monoclea, Monocleaceae (Kraut While a great and growing number of phytochemical et al. 1992), Marchesinia, Lejeuneaceae (Nagashima studies reporting already known and novel compounds et al. 1999) and Asterella, Aytoniaceae (Neves et al. are published every year, the majority of these reports 1998) accumulate compounds identical to those found refer to investigations in angiosperms, which receive in angiosperms. Remarkably, an overview of plant the largest share of scientific attention. The angios- families accumulating (poly)methoxylated flavonoids perm families in which the production of modified at positions 6 and 8 (including flavones and (poly)methoxylated flavones has been very well other types of flavonoids) reveals there are very few or documented include the Lamiaceae, Asteraceae and no reports on the occurrence of these compounds in Rutaceae. A large number of species from each of gymnosperms. Only a few occurrences have been those families have been studied by experts in this reported for monocots, such as the grass Gynerium field, such as Eckhard Wollenweber, Renee Grayer, sagittatum (Benavides et al. 2007). And from the Jeffrey Harborne, and Tom Mabry. The findings from magnoliid clade, a few

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