{Furofuran lignans of artemisia genus: Isolation, biosynthesis and biological activity} J. Serb. Chem. Soc. 85 (5) 575–600 (2020) JSCS–5323 Review 575 REVIEW Furofuran lignans of Artemisia genus: Isolation, biosynthesis and biological activity JOVANA D. ICKOVSKI, JOVANA LJ. PAVLOVIĆ, MILAN N. MITIĆ, IVAN R. PALIĆ, DANIJELA A. KOSTIĆ, GORAN M. PETROVIĆ and GORDANA S. STOJANOVIĆ*# Department of Chemistry, Faculty of Science and Mathematics, Višegradska 33, 18000 Niš, Serbia (Received 10 December 2019, revised 20 January, accepted 31 January 2020) Abstract: Since ancient times, medicinal plants and pharmacologically active products obtained from different natural sources play an important role in human health. Plants belonging to the genus Artemisia possess a great bio- logical potential and it is a well-studied genus in the fields such as systematics (including molecular phylogenetics) and genome organization. Many species of the genus (e.g., A. absinthium, A. annua, A. vulgaris, A. abrotanum, A. arbo- rescens) are widely exploited, because of their high economic value as medi- cines, food and ornamentals. Withal, in such a large genus, some hiatus must inevitably exist, concerning attainments and potentials that individual species possess. Most of the studies are focused on bioactivity and pharmacology of sesquiterpene lactones. Lignans are unjustly neglected, even though they as well exhibit a wide range of bioactivities. Motivated by that fact, we tried to consolidate findings on bioactive lignans accumulated through the years, with the logical perspectives on further work on isolation and identification of new bioactive lignans and the exploitation of lignans as substances of potential pharmacological interest. Keywords: artemisia; lignan; sesamin; sesartemin; diayangambin; epiyan- gambin. CONTENTS 1. INTRODUCTION 1.1. Genus Artemisia L.: an overview 1.2. Lignans 1.3. Lignans of Artemisia genus 2. LIGNANS BIOSYNTHESIS 3. ISOLATION OF LIGNANS * Corresponding author. E-mail: gocast@pmf.ni.ac.rs https://doi.org/10.2298/JSC191210009I ________________________________________________________________________________________________________________________ (CC) 2020 SCS. Available on line at www.shd.org.rs/JSCS/ 576 ICKOVSKI et al. 4. BIOLOGICAL ACTIVITY OF FUROFURAN LIGNANS 5. CONCLUSION 1. INTRODUCTION 1.1. Genus Artemisia L.: An overview The genus Artemisia L. is the largest of subtribe Artemisiinae Less. and tribe Anthemideae Cass., and one of the largest and most widely distributed genera of the family Asteraceae, which has been divided into four subgenera (Artemisia, Absinthium, Dracunculus and Seriphidium),1–4 whose number is increased with the proposal of another subgenus endemic to North America (Tridentatae).5 It is a heterogenous genus that comprises around 600 species at specific and sub- specific levels, present in all continents but Antarctica, mostly distributed in the Northern Hemisphere (temperate zones of Europe, Asia and North America), with no more than 25 species in the Southern Hemisphere.1 In addition to the widespread distribution and a large representation of species within the genus Artemisia, the occurrence of the endemic species in certain areas is quite high. Some examples are the whole subgenus Tridentatae (Rydb.) McArthur in the western United States of America, where some of its species dominate land- scapes, A. afra Jacq. in South Africa, A. argentea L’Hér. in Madeira, A. canariensis Less. (A. thuscula Cav.) in the Canary Islands, A. gorgonum Webb. in Hook in Cape Verde, A. granatensis Boiss. in the Spanish Sierra Nevada, A. magellanica Sch. Bip. in Argentina, A. mauiensis Skottsb. in Hawaii (USA), A. melanolepis in the Iranian mount Damavand, A. molinieri Quézel, Barbero & R. Loisel in only two locations in south-east France and A. negrei Ouyahya in Mor- occo.1 Withal the genus has been the object of numerous systematic, including molecular phylogenetics4–11 and taxonomic studies.12,13 The genus has also been thoroughly studied from the phytochemical,14–18 pharmacological19–22 and bio- technological point of view.23–29 Many of Artemisia species have been fre- quently utilized for many various purposes such as medicines (A. cina, A. san- tonica L., A. maritime, A. herba-alba, A. pallens Wallich ex Besser, A. afra, A. ludoviciana Nutt. for their antihelminic activity and A. annua, A. apiacea. Hance, A. lancea Vaniot, A. afra, A. abrotanum for their antimalarial activities),30–36 food (edible plants, condiments and ingredients of beverages: A. absinthium, A. dracunculus, A. genipi and related species and A. vulgaris)1,37,38 and ornaments (A. arborescens and A. vulgaris).39–41 An intensive investigation of the phytochemicals of the genus Artemisia rev- eals that the Artemisia species comprise mainly terpenoids, flavonoids, coum- arins, caffeoylquinic acids, sterols and acetylenes.42–50 The literature review rev- ealed that most of the attention was paid to bioactive constituents of the essential oils, with a major focus on sesquiterpene lactones with potential pharmacological and medicinal activity.51–55 Despite the vast number of phytochemical compo- ________________________________________________________________________________________________________________________ (CC) 2020 SCS. Available on line at www.shd.org.rs/JSCS/ FUROFURAN LIGNANS OF Artemisia GENUS 577 sition related studies of species belonging to genus Artemisia, majority of them are still based on the investigation of sesquiterpene lactones, as a consequence of their pharmacological activity.14,56–60 Artemisinin, a cadinane-type sesquiter- pene lactone with a 4,6-endoperoxide function, is an antimalarial drug derived from A. annua L.61 Santonin, a sesquiterpene lactone, isolated from various Asian species of Artemisia genus, especially A. china and A. maritima, is respon- sible for antihelmintic activity.62 Arglabin, a guaianolide type of sesquiterpene lactone, isolated from A. glabella Kar. et Kir. and A. myriantha, shows promising antitumor activity against different tumor cell lines.63 On the other side, lignans are still insufficiently explored. These compounds are found in diverse species of the plant kingdom, including members of pterido- phytes, gymnosperms and angiosperms.64 Although lignans exhibit a wide vari- ety of bioactivities on plants, insects and mammals,65–69 they are of especial int- erest due to the unique antitumor-associated activities70–74 and reduction of life- style-related diseases (anti-inflammatory, immunosuppression, cardiovascular and antioxidant).75–79 The plant lignans most commonly distributed in foods are lariciresinol, mat- airesinol, pinoresinol and secoisolariciresinol. Several other lignans are present in some foods, including medioresinol (in sesame seeds, rye and lemons), syring- aresinol (in grains), sesamin and the lignan precursor sesamolin (in sesame seeds).80–82 The amount of lignans in food is generally low, with the exceptions of flaxseed and sesame seeds, which have a lignan content a hundred times higher than other dietary sources.82,83 The specific distribution and the low amount of production in plants, some of which are endangered species, restrain the efficient and stable production of beneficial lignans.84 Therewithal, plant sources of lignans are frequently limited because of the high cost of plant col- lection, poor cultivation systems and long growth phase.85–89 An exhaustive literature survey on phytochemical reports of the genus Artemisia reveals that the Artemisia species comprises mainly furofuran lignans (2,6-diarylfurofurans).90–98 1.2. Lignans Lignans represent a large group of naturally occurring phenolic compounds, widely distributed within the plant kingdom. The term lignan originated from Haworth,99 to describe a group of secondary plant metabolites, which molecular backbone consists of two phenylpropanoid (C6-C3) units. Lignans are phenyl- propane dimers linked via β-β′ (8-8′) carbon atoms, with a different degree of oxidation in the side-chain and a different substitution pattern in the aromatic moieties.100 The lignans are bioactive, non-nutrient, non-caloric phenolic plant compounds, and they should not be confused with lignins.82 Lignans are stereo- specific dimers of monolignols, coniferyl or cinnamyl alcohol, while lignins are racemic polymers built from the hydroxycinnamic alcohols, coniferyl alcohol and ________________________________________________________________________________________________________________________ (CC) 2020 SCS. Available on line at www.shd.org.rs/JSCS/ 578 ICKOVSKI et al. sinapyl alcohol, with minor amounts of p-coumaryl alcohol.82,101–103 Based on the type of carbon skeleton, cyclization pattern and the way in which oxygen is incorporated in the molecule, lignans are classified into six subgroups: dibenzyl- butanes, dibenzylbutyrolactones, arylnaphthalenes, dibenzocyclooctadienes, sub- stituted tetrahydrofurans and 2,6-diarylfurofurans.100 In addition, these lignans can be further classified into three categories depending on the oxidation state of the C9(C9′) positions, which are located at the terminal of the propyl side chain: lignans with 9(9′)-oxygen, lignans without 9(9′)-oxygen and dicarboxylic acid lignans (Fig. 1). Fig. 1. Lignans classification based on the type of carbon skeleton, cyclization pattern and oxidation state of the C9(C9′) positions. Apart from the fact that lignans are structurally diverse, they show substan- tial diversity in the terms of enantiomeric composition.104 Naturally occurring lignans have been found to exist exclusively as one enantiomer, or as enantio- meric mixtures with various enantiomeric compositions. The enantiomeric com- position of the plant lignans in trees and medicinal herbs and shrubs is commonly known, and usually only one of the enantiomers occurs in a certain species.105–107 1.3. Lignans of Artemisia genus Lignans are a large and diverse class of natural products composing of phenyl- propanoid dimers in which C6-C3 units are linked by the central carbon of their propyl side chains. The furofuran lignans represent one of the major subclasses of the lignan family. Due to their structural diversity and broad bioactivities, nat- ural furofuran lignans have attracted increasing research attention. As previously mentioned, a literature survey on the type of lignans in members of the genus Arte- misia revealed that furofuran lignans are characteristic for Artemisia species (lig- nan’s profile mainly consists of furofuran lignans). Furofuran lignans have been ________________________________________________________________________________________________________________________ (CC) 2020 SCS. Available on line at www.shd.org.rs/JSCS/ FUROFURAN LIGNANS OF Artemisia GENUS 579 found throughout the plants from roots, stems, leaves, bulbs, barks to seeds. Res- earch progress on the naturally occurring furofuran lignans within the plant species of Artemisia genus reported in the literature (chemical structures, names, corresponding sources and references) is summarized in Fig. 2. and Table I. Fig. 2. Structures of lignans isolated form Artemisia species. ________________________________________________________________________________________________________________________ (CC) 2020 SCS. Available on line at www.shd.org.rs/JSCS/ 580 ICKOVSKI et al. TABLE I. The lignans isolated from Artemisia species Plant Plant part Lignans Ref. A. absinthium L. Aerial parts 9, 1, 28, 27, 18 94 A. absinthium L. Fresh roots 1, 2, 3, 4, 26, 27, 28, 9, 11, 12, 22, 14 92 A. absinthium L. Aerial parts 28, 1, 27, 23, 18, 20, 26 108 A. absinthium L. Fresh roots 6, 9, 1 91 A. arborescens L. Aerial parts 6, 26, 27, 8, 11, 1, 15, 31, 25 92,95 A. canariensis Less. Fresh roots 6, 8, 1, 26, 27, 11 91 A. caruifolia Buch.-Ham. ex Roxb. Aerial parts 16, 17, 18, 19 97 A. gorgonum Webb. Aerial parts 21, 13, 14, 8, 5, 6 93 A. gorgonum Webb. Fresh roots 6, 8, 1, 26, 14, 11 92 A. jacutica Drob. Fresh roots 6, 8, 1, 26 92 A. macrocephala Jacq. ex Bess. Fresh roots 1, 26 92 A. minor Jacq. ex Bess. Aerial parts 23, 24 98 A. sieversiana Willd. Fresh roots 1, 26, 27, 28, 9, 8, 12, 11, 22, 14, 6 92 A. sieversiana Willd. Aerial parts 27, 28, 7, 29, 30, 10 96,90 A. austro-yunnanensis Whole plant 25, 23 109 2. LIGNANS BIOSYNTHESIS Phenylpropanoid metabolism is a convoluted network of biosynthetic path- ways, which lead to the synthesis of a vast number of secondary metabolites. The plant shikimate pathway is the entry to the biosynthesis of phenylpropanoids, where just a few intermediates represent the core unit for the further biosynthesis of secondary metabolites, including flavonoids, isoflavonoids, lignins and lig- nans. The shikimate pathway results in the biosynthesis of chorismate, which is the branch point for the synthesis of aromatic amino acids tryptophan on the one hand and phenylalanine and tyrosine on the other hand.110,111 Chorismic acid is transformed into prephenic acid via a Claisen rearrangement, which transfers the phosphoenolpyruvate derived side-chain so that it becomes directly bonded to the carbocycle and thus builds up the basic carbon skeleton of phenylalanine. Decarboxylative aromatization of prephenic acid yields phenylpyruvic acid and pyridoxal phosphate-dependent transamination leads to L-phenylalanine.112,113 The conversation of phenylalanine to the hydroxycinnamic acids (p-coumaric, ferulic and sinapic acids) and the monolignols (p-coumaryl, coniferyl and sinapyl alcohols) is the start point of phenylpropanoid pathway. Phenylalanine ammonia- lyase and tyrosine ammonia-lyase catalyze the non-oxidative deamination of phenylalanine to trans-cinnamate and direct the carbon flow from the shikimate pathway to the various branches of the general phenylpropanoid metabolism.112 Subsequent steps, i.e., hydroxylation of cinnamic acid by cinnamate 4-hydroxy- lase which leads to the biosynthesis of p-coumaric acid and activation of coum- aric acid by 4-coumaroyl CoA-ligase which leads to the biosynthesis of p-coum- aroyl-CoA, are mandatory and provide the basis for all subsequent branches and resulting metabolites.113,114 p-Coumaroyl-CoA is a precursor for the biosyn- ________________________________________________________________________________________________________________________ (CC) 2020 SCS. Available on line at www.shd.org.rs/JSCS/ FUROFURAN LIGNANS OF Artemisia GENUS 581 thesis of p-coumaryl alcohol and coniferyl alcohol. As part of monolignol bio- synthesis (building blocks of lignans and lignins), p-coumaroyl-CoA can undergo two types of modifications: reduction of the carboxyl group on the propane side chain to alcohol and substitution of the phenyl ring. The two predominant mono- lignols are coniferyl alcohol and sinapyl alcohol.114 Although lignans and neolignans are abundant class of phytochemicals, little is known about the specific biosynthetic steps leading to the biosynthesis of com- plex lignans. During the years, the majority of the studies were devoted to understanding the biosynthesis of podophyllotoxin, thanks to which the biosyn- thesis of lignans with 9(9′)-oxygen is very well studied. These type of lignans are formed by enantioselective dimerization of two coniferyl alcohol units with the aid of a dirigent protein to give rise to pinoresinol (25, furofuran). Pinoresinol (25) is then reduced to secoisolariciresinol (dibenzylbutane) by pinoresinol/lari- ciresinol reductase, via lariciresinol (furan), which is in turn oxidized to afford matairesinol (dibenzylbutyrolactone) by secoisolariciresinol dehydrogenase. The conversion from coniferyl alcohol to secoisolariciresinol has been demonstrated in various plant species (Forsythia, Linum and Podophyllum), which strongly suggests that this is the general biosynthetic pathway of lignans.84,105,115 Lig- nans and neolignans are normally found in optically active forms. They are com- posed of only one enantiomer or both, but with one of them being in excess. This implies that lignan biosynthesis is under strict enantioselective control.86 For example, (+)-pinoresinol (25) is found in F. suspense116,117 and (–)-sec- oisolariciresinol and (–)-matairesinol occur in F. intermedia.118 Lignans are gen- erally believed to be formed by a phenolic oxidative coupling process119 more precisely, by a large number of distinct radical coupling modes of phenoxyl radi- cal. Those coupling modes can be either stereoselective and/or regiospecific in coupling origin.120 The first demonstration of phenoxyl radical coupling control was reported during the investigation of (+)-pinoresinol (25) formation from coniferyl alcohol in Forsythia species.121,122 It was suggested that the dirigent protein bind and orient coniferyl alcohol-derived radicals in such a way as to enable 8,8′ coupling at the si-si face with subsequent intramolecular cyclization to afford (+)-pinoresinol (25).122 Since the initial discovery of this protein from F. intermedia, homology searches in sequence databases have revealed the exist- ence of additional genes encoding putative dirigent proteins, from a variety of species. One of the proposed biosynthetic routes123 starts with coniferyl alcohol and subsequent formation of (+)-pinoresinol (25). The enzyme pinoresinol/lariciresi- nol reductase converts this compound to (+)-lariciresinol and then to (–)-secoiso- lariciresinol. The enzyme secoisolariciresinol dehydrogenase converts into (–)- -matairesinol. The conversion from (–)-matairesinol to podophyllotoxin is likely to be similar to the route shown in Scheme 1. Matairesinol is metabolized to arc- ________________________________________________________________________________________________________________________ (CC) 2020 SCS. Available on line at www.shd.org.rs/JSCS/ 582 ICKOVSKI et al. Scheme 1. (Adapted from literature86,101,114) Part of the shikimate and phenylpropanoid biosynthetic pathways and possible biosynthetic pathways for various types of lignans. The ________________________________________________________________________________________________________________________ (CC) 2020 SCS. Available on line at www.shd.org.rs/JSCS/ FUROFURAN LIGNANS OF Artemisia GENUS 583 enzymes involved in the shikimate pathway are: DAHP synthase (EC 2.5.1.54), 3-dehydro- quinate synthase (EC 4.2.3.4), 3-dehydroquinate dehydratase (EC 4.2.1.10), shikimate de- hydrogenase (EC 1.1.1.25), shikimate kinase (EC 2.7.1.71), 5-enolpyruvylshikimate 3-phos- phate synthase (EC 2.5.1.19), chorismate synthase (EC 4.2.3.5), chorismate mutase (EC 5.4.99.5), prephenate aminotransferase (EC 2.6.1.78) and arogenate dehydratase (EC 4.2.1.91). The enzymes involved in phenylpropanoid pathway are: phenylalanine ammonia lyase (EC 4.3.1.24), cinnamic acid 4-hydroxylase (EC 1.14.13.11), 4-coumaric acid:CoA ligase (EC 6.2.1.12), cinnamoyl-CoA:NADP oxidoreductase (EC. 1.2.1.44), hydroxycin- namoyl-CoA shikimate/quinatehydroxy-cinnamoyl transferase (HTC), p-coumaroyl-CoA 3′-hydroxylase (EC 1.14.14.1), caffeoyl-CoA O-methyltransferase (EC 2.1.1.104), cinnamyl alcohol dehydrogenase (EC 1.1.1.195), aldehyde/coniferyl alcohol 5-hydroxylase (EC 1.14.13), 5-hydroxyconiferaldehyde/5-hydroxyconiferyl alcohol O-methyltransferase (EC 2.1.1.68). tigenin by matairesinol O-methyltransferase via methylation of a phenolic hyd- roxyl group in various plants including F. koreana, Carthamus tinctorius and Anthriscus sylvestris.124,125 In Linum, Anthriscus and Podophyllum plants, mata- iresinol is also converted into hinokinin, yatein, or PTOX via multiple biosyn- thetic pathways, although all of the relevant enzymes have not yet been iden- tified.86,107 In Sesamum plants pinoresinol (25) is metabolized into piperitol, followed by further conversion into (+)-sesamin (6) by a cytochrome P450 family enzymes.86,107,126 3. ISOLATION OF LIGNANS Lignans are natural products with highly diverse structures, which affects their separation. Lignan aglycones are the most prevalent natural form of this compounds, so the high hydrophobicity of this compounds, as well as the separ- ation itself can be influenced by skeletal substitution, the position of the substi- tuent, partition coefficient, isomerism and size of the molecule. For example, in aryltetraline lignans podophyllotoxine and α-peltatine the position of OH group is decisive factor: if it is in 7α position the substance is less hydrophobic, than in the case of substitution in position 6 on the aromatic ring. In the case of hydroxyl group glycosylation, hydrophilicity rises significantly.127 The introduction of an additional hydroxyl group on position 7′ (matairesinol transformation to hydro- xymatairesinol) leads to a significant increase of polarity. A similar effect occurs during glucosylation (mono and diglucoside of secoisolariciresinol). Size of the molecule has a significant influence on the separation of the lignan molecules. The higher molecular mass of an aglycone the lower mobility, though in this case the chromatographic behavior can hardly be predicted. Solvent extraction is a traditional method for extracting lignans from plant sources. However, other less polar components present in most plant tissues may interfere with the subsequent separation of lignans if a polar solvent is used. There- fore, the sequential solvent extraction is recommended for efficient separation of lignan compounds. Extraction in Soxhlet extractor is a widely used method. It ________________________________________________________________________________________________________________________ (CC) 2020 SCS. Available on line at www.shd.org.rs/JSCS/ 584 ICKOVSKI et al. can be used for sequential extraction, with solvents with increasing polarity, which is usually started with non-polar organic solvents such as petroleum ether, hexane or dichloromethane.127,128 During this ”pre-extraction”, the extraction of a part of lignans can occur as well. Preparation of lignan extracts with a low content of ballast substances by a common extraction is practically impossible; lipophilic solvents extract not only undesirable substances but also lignans which are without OH groups or possibly with maximum one hydroxyl group.129–131 After removing lipidic substances, polar solvents (ethanol, methanol and acetone) are used for the preparation of the total extract. In some cases, the addit- ion of polar solvents such as water to the sample may increase the recovery of more polar compounds such as lignan glycosides. Lignans of low or medium polarity can be efficiently extracted with a less polar solvent. Direct extraction with a hot polar solvent, appropriate for lignans of low polarity, has also been used for extraction of some plant lignans.119,130,132,133 A recently introduced method for extraction of plant lignans. the accelerated solvent extraction, is carried out at higher temperature and pressure and under inert nitrogen atmosphere. This method may enable fast and convenient ext- raction using relatively small amounts of solvents128,134,135. It has been success- fully used for extraction of lignans from the wood of certain trees (Picea abies, Pineceae).128,136–138 Lignans in some plant materials require special pretreat- ments before extraction. Polar lignans, present in the plant as ester-linked oligo- mers or polymers,139,140 seem to be readily soluble in aqueous methanol or ethanol. Nonetheless, the subsequent hydrolysis is required to release free agly- cone. Furthermore, additional hydrolysis steps, enzymatic or non-enzymatic, can be used for the release of free aglycone.137,138 Percolation at room temperature is also used for lignan extraction (e.g., lignans from the twigs of Magnolia thai- landica were defatted with hexane and continuously extracted with mixture of dichloromethane and methanol).141 Purification of total extracts with lignan content is quite time-consuming and laborious. Methanol extracts are usually concentrated, diluted with water, this suspension fractioned with n-hexane and consequently with chloroform,142 dichloromethane143,144 or ethyl acetate,145 to obtain a lignan fraction. For example, syringaresinol (23) from the crude extract of M. thailandica was obtained as follows: crude extract was subjected to silica gel column chroma- tography with ethyl acetate–hexane and methanol–ethyl acetate mixtures to give seven fractions. Fraction which contained syringaresinol (23) was fractionated on a silica gel column with ethyl acetate-hexane mixture to yield six subfractions. Syringaresinol (23) was gathered from one of the subfractions via crystallization by ethanol.141 The details of the previously employed extraction and chromato- graphical methods for isolation of Artemisia genus plant lignans are summarized in Table II. ________________________________________________________________________________________________________________________ (CC) 2020 SCS. Available on line at www.shd.org.rs/JSCS/ FUROFURAN LIGNANS OF Artemisia GENUS 585 TABLE II. Details of previously employed analytical techniques for isolation of lignans from different plant sources Plant Part Isolated lignans Extraction Isolation technique Ref. A. absin- thium Aerial parts 28, 1, 27, 23, 18, 20, 26 Ethanol, 95 % Successive extraction with ether, CHCl3, ethyl acetate. Chromato- graphy: silica gel column (petroleum ether:ethyl acetate) gives 6 fractions. Fractionation (fraction 4): silica gel column chromatography (petroleum ether:ethyl acetate, 10:1 → 1:2) gives 14 sub-fractions. Separation (sub-fractions 8, 10, 13): open column chromatography (CH3OH:H2O, 40:60 → 90:10), semi-preparative HPLC (acetonit- rile:H2O, 50:50), sephadex LH-20 column chromatography (methanol). 108 A. arbor- escens Aerial parts 6, 26, 27, 8, 1, 15, 25 Maceration (methanol) Chromatography; silica gel column chromatography (hexane:ether, 2:1, ether, ether:CH3OH, 6:1) gives 3 fractions. Medium pressure column chroma- tography: hexane:ether, 1:2. 95 A. absin- thium Fresh roots 1, 2, 3, 4 Petrol (60–80 °C):ether, 2:1 Chromatography: resin was dissolved in ether, TLC on silica gel with ether:petrol, 4:1. Fractionation: silica gel column (pet- rol:ether, ether 100:0 → 0:100 and CH3OH:ether, 3:97 → 10:90 %). The lignan containing fractions (pet- rol:ether–CH3OH:ether, 50–10 %) were also subjected to preparative TLC. 92 A. carui- folia Aerial parts 6, 1, 16, 17, 18, 19 Refluxing (methanol). Methanol extract was partitioned with CHCl3 and H2O Chromatography (CHCl3 extract): silica gel column (hexane:ethyl acetate, 7:3→3:1 and ethylace- tate:ethanol:H2O, 6:2:1), gives 4 fractions. Open column chromatography (fraction 1) with 60–100 % methanol gives 3 sub-fractions. Preparative TLC (sub-fractions): SiO2, benzene:acetone, 9:1 gives sesamin (6) and sesartemin (1). Open column chromatography (fraction 2 and 3) with 40–60 % methanol. HPLC preparative chromatography of sub-fractions gives caruilignans. 97 ________________________________________________________________________________________________________________________ (CC) 2020 SCS. Available on line at www.shd.org.rs/JSCS/ 586 ICKOVSKI et al. TABLE II. Continued Plant Part Isolated lignans Extraction Isolation technique Ref. A. absin- thium Aerial parts 27, 1 Maceration (CH2Cl2, 2 days) Chromatography: silica gel, CH2Cl2:CH3OH, 98:2 → 40:60, gives 4 fractions. Semipreparative HPLC: isocratic, H2O:acetonitrile, 40:60. 46 9, 1, 28, 27, 18 Ethanol, 70 % Fractionation: petroleum ether, CH2Cl2, ethyl acetate and butanol, successively. Chromatography (CH2Cl2 fraction): silica gel column chromatography with petroleum ether:ethyl acetate, 10:0 → 5:1 and CH2Cl2:CH3OH, 100:0 → 5:1. Sephadex LH-20 column chromato- graphy with CHCl3:CH3OH, 1:1. 94 4. BIOLOGICAL ACTIVITY OF FUROFURAN LIGNANS Yamauchi et al.146 synthesized nine oxygenated furofuran lignans and found that the tertiary hydroxy group on the furofuran ring affected the degree of anti- oxidant activity. Pinoresinol (25), sesamin (6) and their glycosides are metabol- ized by intestinal microflora to yield enterodiol and enterolactone which are sup- posed to protect against estrogen-dependent cancers,147,148 and which are known as enterolignans or mammalian lignans.149–151 These metabolized lignans eli- cited their estrogen-like activity in mammals. For example, enterolignans bind to the mammalian estrogen receptors, which are key regulatory factors in the sexual maturation of genital organs.152,153 Enterolignans, combined with other intestinal flora-generating metabolites of isoflavones and coumestans, are also called phytoestrogens.84 In human intestinal Caco 2 cells, pinoresinol (25) decreased the production of inflammatory factors, such as interleukin-6 and prostaglandin E2, following the down-regulation of Cox-2, an inducible prostaglandin synthase that is res- ponsible for the synthesis of prostaglandin H.154 Sesamin (6) reduced signaling downstream of mitogen-activated protein kinase, and potently reduce breast tumor growth.155 Lee et al.156 demonstrate the role of magnolin (13) as a meta- static inhibitor in lung cancer cells. Epieudesmin (22) has been shown to have antineoplastic activity against the murine P388 lymphocytic leukemia cell line and several human cancer cell lines (BXPC-3, MCF-7, SF268, NCI-H460, KM20L2 and DU-145).157 Yangambin (26) prevents the cardiovascular collapse observed during ana- phylactic and endotoxic/septic shocks, as well as the vascular and cardiac hypo- ________________________________________________________________________________________________________________________ (CC) 2020 SCS. Available on line at www.shd.org.rs/JSCS/ FUROFURAN LIGNANS OF Artemisia GENUS 587 responsiveness to catecholamines in endotoxic shock.77 Diayangambin (28)158 and fargesin (11)159 have been reported to exert anti-inflammatory activity. The findings of Serra et al.160 indicate that yangambin (26) shows an anta- gonistic action on LTB4 receptors and suggest that it may be useful in the treat- ment of some allergic inflammatory responses. Phillyrin (29) has an anti-obesity effect in nutritive obesity mice.161 Cyclic adenosine monophosphate (AMP) is found to be the second mes- senger inside cells, so compounds that act to alter cyclic AMP metabolism have been the subject of many studies. Nikaido et al. presented in their paper that pinoresinol (25) and pinoresinol-β-D-glucoside showed cyclic AMP phosphor- diesterase inhibitory activity.162 Kobusin (5), fargesin (11) and epieudesmin (22) were assayed for inhibitory activity against nitric oxide production in LPS sti- mulated RAW 264.7 cell, but all lignans were inactive.163 Rimando et al.164 studied furofuran lignans epiyangambin (27), diayangambin (28), diasesartemin (4) and epiaschantin (9) for their phytotoxicity. Diayangambin (28) was the most phytotoxic to Lactuca sativa, showing strong inhibitory activity. Diayangambin (28) was more active than epiyangambin (27) and diasesartemin (4) in inhibiting the growth of Agrostis stolonifera. All of these compounds inhibited all phases of onion root cell division. Fargesin (11) and sesamin (6), which have very similar structures to epiyangambin (27), diayangambin (28), diasesartemin (4) and epi- aschantin (9), were shown to inhibit germination of peanut and cucumber.165 Sesamin (6) is used as an antioxidant.166 The antioxidative propensity of sesamin (6) is likely to be involved in protecting the liver from oxidation by alcohols, lipids and oxygen radicals.84,167–169 Sesamin (6) and its metabolites exhibited antihypertensive activities.76,170–172 Sesamin (6) is also an insecticide.173 Sesamin (6), pinoresinol (25) and kobusin (5) have various biological activities, which include synergistic effects with pyr- ethrum insecticides174–177 and inhibitors of Δ5 desaturases in mammals.178 Ses- amin (6) has an anti-inflammatory effect by specifically inhibiting Δ5 desaturase in polyunsaturated fatty acid biosynthesis.179 Sesamin (6), pinoresinol (25) and kobusin (5) also have significant plant protective properties as antioxidants, as well as having important roles in health protection.180 This lignans, when provided in the diet, can reduce serum cholesterol level,181 as well as increase vitamin E activities182,183 and the availability of γ-tocopherol in vivo.184 The lignans epiyangambin (27) and sesartemin (1) red- uce spontaneous locomotor activity and isolation-induced aggression in mice.185 Epiyangambin (27) and epimagnolin (14) possessed strong selective inhibition of PAF-induced platelet aggregation.186 Epiyangambin (27) and yangambin (26) competitively inhibited platelet activating factor (PAF)-induced rabbit platelet aggregation in a dose-dependent manner, but they had no effect on the platelet aggregation induced by collagen, thrombin or ADP.187 These results indicated ________________________________________________________________________________________________________________________ (CC) 2020 SCS. Available on line at www.shd.org.rs/JSCS/ 588 ICKOVSKI et al. that both lignans were potent and selective antagonists of PAF.188,189 Sesamin (6) feeding is associated with reduced serum levels of triacylglycerol,190–192 cholesterol193,194 and phospholipid190 in rodents. Dietary sesamin (6) also reduces hepatic concentrations of triacylgly- cerol191,193 and cholesterol190,194 but increases phospholipid levels accomp- anying liver hypertrophy,190,191,195 although temporarily.194 Kiso196 found that sesamin (6) was absorbed by the route of the portal vein and metabolized to mono- or di- catechol metabolite by drug metabolizing enzymes in the liver cells. It is suggested that sesamin (6) ingestion regulated the transcription levels of hepatic metabolizing enzymes for lipids and alcohol. Ashakumary et al.197 demonstrated that dietary sesamin (6) greatly inc- reased the hepatic activity of fatty acid oxidation enzymes, including carnitine palmitoyltransferase, acyl-CoA dehydrogenase, acyl-CoA oxidase, 3-hydroxy- acyl-CoA dehydrogenase, enoyl-CoA hydratase and 3-ketoacyl-CoA thiolase. Sesamin (6) also increased the activity of 2,4-dienoyl-CoA reductase and Δ3,Δ2- -enoyl-CoA isomerase, enzymes involved in the auxiliary pathway for β-oxid- ation of unsaturated fatty acids. Furofuran lignans: sesamin (6), aschantin (8), sesartemin (1) and yangambin (26) showed weak activity against Staphylococcus aureus. Sesartemin (1) and yangambin (26) also showed weak activity against Escherichia coli, while sesamin (6) and aschantin (8) were inactive.198 Epi- aschantin (9) exhibited moderate antimicrobial activity against strains of Gram- -positive bacteria Staphylococcus aureus, Bacillus subtilis, Escherichia coli and the yeast Candida albicans.199 Kawamura et al.200 investigated the antifungal activity of epieudesmin (22) against Trametes versicolor and Fomitopsis palustris. Lignan showed antifungal activity. MacRae et al.201 tested a number of lignans and found that antiviral act- ivity is specific to a certain classes of lignans. Episesartemin B (3), sesartemin (1), epiyangambin (27) and yangambin (26) were all without antiviral effect, although these lignans are known to have a number of biological activities.202 Three diepoxy-pinoresinol glycosides, one diepoxy-syringaresinol glycoside, pinoresinol (25) and syringaresinol (23) were tested for inhibitory activity against tobacco mosaic virus. Pinoresinol-4′O-[4′′,6′′O-(E)-diferuloyl]-β-D-glucopyrano- side, pinoresinol-4′O-[3′′,6′′O-(E)-diferuloyl]-β-D-glucopyranoside and syringar- esinol-4′O-[4′′,6′′O-(E)-diferuloyl]-β-D-glucopyranoside exhibited moderate act- ivities in inhibiting the multiplication of the tobacco mosaic virus203. Ortet et al.57 evaluated in vitro cytotoxicity of eudesmin (21), magnolin (13), epimag- nolin (14), aschantin (8), kobusin (5) and sesamin (6) against various human and murine tumor and normal cells and antimalarial activity against chloroquine-res- istant Plasmodium falciparum. Tested compounds showed no cytotoxic activity against human tumor cells. With the exception of the sesamin (6), all other lig- nans showed weak cytotoxic activity against murine normal cells. Furthermore, ________________________________________________________________________________________________________________________ (CC) 2020 SCS. Available on line at www.shd.org.rs/JSCS/ FUROFURAN LIGNANS OF Artemisia GENUS 589 the cytotoxicity of sesamin (6) on mammalian normal cells was unnoticeable. Epimagnolin (14), aschantin (8), kobusin (5) and sesamin (6) showed mild anti- plasmodial activities. The cytotoxic activity of caruilignan A (16), caruilignan B (17), caruilignan C (18), caruilignan D (19), sesamin (6), and sesartemin (1) were tested using Meth-A (sarcoma) and LLC (Lowis lung carcinoma) cell lines. Caruilignan A (16), caruilignan B (17), caruilignan C (18), sesamin (6) and sesar- temin (1) were found to be cytotoxic only against the Meth-A cell line.97 Far- gesin (11), epieudesmin (22) and sesamin (6) were effective against trypomas- tigotes, but these compounds were highly toxic to mammalian cells and no para- site selectivity could be identified.204 5. CONCLUSION This review represents furofuran lignans, their isolation from the plants of the genus Artemisia, along with their biological activity. Extensive literature survey, revealed that lignans have been obtained just from ten species of the Artemisia genus: A. absinthium, A. arborescens, A. canariensis, A. caruifolia, A. gorgonum, A. jacutica, A. macrocephala, A. minor, A. sieversiana, A. austro- yunnanensis, although the genus includes a large number of species. Despite the isolation and characterization of numerous lignans from different plant species, there is a lot of an unfinished work left on this class of secondary metabolites, especially within the plant species of Artemisia genus, primarily because lignans represent a huge source of potentially bioactive compounds. Further work on the isolation of lignans and determination of differences in the lignan patterns among Artemisia species belonging to a different section of the genus could have chemotaxonomic significance. Lignans are characterized by the stereoselective oxidative coupling of two phenylpropane units; the presence of chiral centres is an interesting challenge that needs to be overcome for the synthesis of these compounds. Although during the last decade, the total syn- thesis of several biologically active lignans has been achieved, there is still much left to learn about the lignan biosynthetic pathways. ABBREVIATIONS ADP – adenosine diphosphate AMP – adenosine monophosphate BXPC-3 – human pancreatic cancer cell line CoA – coenzyme A Cox-2 – cyclooxygenase-2 DU-145 – human prostate cancer cell line EC 1.1.1.195 – cinnamyl alcohol dehydrogenase EC 1.1.1.25 – shikimate dehydrogenase EC 1.14.13 – aldehyde/coniferyl alcohol 5-hydroxylase EC 1.14.13.11 –cinnamic acid 4-hydroxylase EC 1.14.14.1 – p-coumaroyl-CoA 3′-hydroxylase ________________________________________________________________________________________________________________________ (CC) 2020 SCS. Available on line at www.shd.org.rs/JSCS/ 590 ICKOVSKI et al. EC. 1.2.1.44 – cinnamoyl-CoA:NADP oxidoreductase EC 2.1.1.104 – caffeoyl-CoA O-methyltransferase EC 2.1.1.68 – 5-hydroxyconiferaldehyde/5-hydroxyconiferyl alcohol O-methyltransferase EC 2.5.1.19 – 5-enolpyruvylshikimate 3-phosphate synthase EC 2.5.1.54 – DAHP synthase EC 2.6.1.78 – prephenate aminotransferase EC 2.7.1.71 – shikimate kinase EC 4.2.1.10 – 3-dehydroquinate dehydratase EC 4.2.1.91 – arogenate dehydratase EC 4.2.3.4 – 3-dehydroquinate synthase EC 4.2.3.5 – chorismate synthase EC 4.3.1.24 – phenylalanine ammonia lyase EC 5.4.99.5 – chorismate mutase EC 6.2.1.12 – 4-coumaric acid:CoA ligase HTC – hydroxycinnamoyl-CoA shikimate/quinatehydroxy-cinnamoyl transferase KM20L2 – human colon tumor cell line LLC – Lowis lung carcinoma cell line LPS – lipopolysaccharide LTB4 – leukotriene B4 receptors MCF-7 – human breast cancer cell line Meth-A – sarcoma cell line NCI-H460 – human lung cancer cell line P388 – murine lymphocytic leukemia cell line PAF – platelet activating factor PTOX – podophyllotoxin RAW 264.7 – murine macrophage cell line SF268 – human brain tumor cell line Acknowledgment. Support of the Ministry of Education, Science and Technological Development of Serbia (Project No. 172047) is gratefully acknowledged. И З В О Д ФУРАНОФУРАНСКИ ЛИГНАНИ РОДА Artemisia: ИЗОЛОВАЊЕ, БИОСИНТЕЗА И БИОЛОШКА АКТИВНОСТ ЈОВАНА Д. ИЦКОВСКИ, ЈОВАНА Љ. ПАВЛОВИЋ, МИЛАН Н. МИТИЋ, ИВАН Р. ПАЛИЋ, ДАНИЈЕЛА А. КОСТИЋ, ГОРАН М. ПЕТРОВИЋ и ГОРДАНА С. СТОЈАНОВИЋ Департман за хемију, Природно–математички факултет, Универзитет у Нишу, Вишеградска 33, 18000 Ниш Од давнина лековите биљке и фармаколошки активни производи добијени из разли- читих природних извора играју важну улогу у здрављу људи. Биљке које припадају роду Artemisia поседују велики биолошки потенцијал и прилично су добро проучаван род у областима као што су систематика (укључујући молекуларну филогенетику) и органи- зација генома. Многе врсте овог рода (A. absinthium, A. annua, A. vulgaris, A. abrotanum, A. arborescens) су широко искоришћаване, због своје велике економске вредности, као лекови, храна и украси. Ипак, у тако великом роду неизбежно постоје многобројне раз- лике, које се тичу употребљивости и потенцијала појединих врста. Већина студија усме- рена је на биоактивност и фармакологију сесквитерпенских лактона. Лигнани су непра- ведно занемарени, иако и они имају веома значајна својства. Мотивисани том чињени- ________________________________________________________________________________________________________________________ (CC) 2020 SCS. Available on line at www.shd.org.rs/JSCS/ FUROFURAN LIGNANS OF Artemisia GENUS 591 цом покушали смо да објединимо резултате о биоактивним лигнанима, који су објав- љивани током година, а са логичним циљем даљег рада на изоловању и идентификовању нових биолошки активних лигнана и њиховој, потенцијалној, фармаколошкој експлоата- цији. (Примљено 10. децембра 2019, ревидирано 20. јануара, прихваћено 31. јануара 2020) REFERENCES 1. J. Vallès, S. Garcia, O. Hidago, J. Martín, J. Pellicer, M. Sanz, T. 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