Natural 6-hydroxy-chromanols and -chromenols: structural diversity, biosynthetic pathways and health implications

We present the first comprehensive and systematic review on the structurally diverse toco-chromanols and -chromenols found in photosynthetic organisms, including marine organisms, and as metabolic intermediates in animals. The focus of this work is on the structural diversity of chromanols and chromenols that result from various side chain modifications. We describe more than 230 structures that derive from a 6-hydroxy-chromanol- and 6-hydroxy-chromenol core, respectively, and comprise di-, sesqui-, mono- and hemiterpenes. We assort the compounds into a structure–activity relationship with special emphasis on anti-inflammatory and anti-carcinogenic activities of the congeners. This review covers the literature published from 1970 to 2017.


Introduction
In 1922, Bishop and Evans discovered a-tocopherol as an essential lipid-soluble factor that promotes the gestation of rat fetuses. 1 Since then, numerous structurally related 6-hydroxychromanols and -chromenols have been discovered. Tocochromanols of the vitamin E class represent the most widely distributed and predominant chromanols in nature. However, only photosynthetic organisms, such as plants, algae, and cyanobacteria as well as fungi, corals, sponges and tunicates, are able to perform the biosynthetic steps leading to a chromanol ring system. However, mammals, including humans, rely on these resources (esp. plant oils), since vitamin E is essential for a wide range of higher organisms. 2 The term vitamin E is traditionally used for the eight structurally related vitamers a-, b-, g-, d-tocopherol, and a-, b-, g-, dtocotrienol, with a-tocopherol being the compound with the highest vitamin activity. 3 Tocochromanols belong to the family of prenylquinones that also include plastochromanol-8, phylloquinones (vitamin K), and ubiquinones (coenzyme Q 10 ). Due to its unique 6-hydroxychromanol structure, the vitamin E forms may act as antioxidants that prevent lipid peroxidation in cellular membranes and quench harmful reactive oxygen species (ROS) in plants and animals (including humans). The proton of the 6-hydroxy group can quench a reactive radical, in turn leading to a tocopheryl radical that, depending on the substitution pattern of the ring system, remains stable, with a half-life of several seconds, and can be subsequently recycled by vitamin C. The review does not aim to discuss the complex antioxidant and redox chemistry of tocopherols forming corresponding radicals, quinones, dimers or polymers. These issues have already been discussed in several excellent reviews. 4,5 Further, biosynthesis, bioactivity and chemical properties of tocopherols and tocotrienols are summarized in several outstanding reviews, 6 and will be discussed here only briey. This work focuses on the structural diversity of chromanols due to side chain modications and attempts to merge structural aspects with biological activity.
Besides the methylation pattern (R 1 -R 3 ) of the chromanol ring system, side chain modications (at R 4 ) show the highest structural variability. In particular tocotrienols are prone to (partial) reduction of the double bonds or oxidation of the methyl groups by cytochrome P 450 -dependent hydroxylases and oxidases, which ultimately results in the formation of oxidation products, such as alcohols, ketones, aldehydes, carboxylic acids, and truncations of the side chain. Furthermore, intramolecular cyclisation and/or rearrangements of the isoprene units can build up mono-, bi-, and tri-cyclic ring systems. These modications are well known for compounds in marine organisms, especially in brown algae and sponges (see below), but have been found also in higher plant species. Along with side chain modications, increased bioactivity is observed for many of these structures in vitro and in vivo.
The following chapters describe these compounds, sorted by the length of the carbon skeleton, following the order (mero)diterpenes, -sesquiterpenes, -monoterpenes and -hemiterpenes.

Methods
Chromanols and chromenols presented here were selected by a chemical substructure search of 1 and 2, respectively, within several databases. We received 307 matches from the Dictionary of Natural Products and 128 matches from the Dictionary of Marine Natural Products (both at Chemnet BASE). We included a PubChem substructure search and PubMed keyword searches for "tocochromanol*", "tocochromenol*" and "mero(di) terpenoid*". Patents were searched by chemical names at the website of the European Patent Office. 7 Finally, we performed a reference-related snowball sampling and deleted all doublets. All identied meroterpenoids were sorted by the length of their carbon-skeleton and number of prenyl units, respectively. Numbering of the carbon skeleton of metabolites was conducted in analogy to IUPAC rules, however for better clearness, side chain numbers were primed (e.g. 13 0 , see Fig. 3). Metabolites were further classied by their occurrence in the abovementioned species (including animal metabolism) and not by structural matching. Within each species, metabolites were sorted by functionalization of the side chain (e.g. saturated, unsaturated and oxidized). Physio-chemical properties were predicted by Molinspiration WebME editor version 1.16 (http:// www.molinspiration.com).
With respect of the extent of the review, we excluded corresponding oxidized 1,4-benzoquinones or dimeric (and polymeric) structures that derive from natural or chemical oxidation processes that may occur during work-up procedures.
Many natural products with phenolic hydroxy groups, e.g. avonoids, cumarins, caffeic acids, anthraquinones, or xanthones, bear a prenyl or to a minor extent geranyl or farnesyl residues in ortho position to the phenol. In some cases, this phenol forms a six-membered chromene ring by addition to the double bond of the prenyl (geranyl, farnesyl) residue. These mainly plant-derived compounds are not related to tocopherol biosynthesis and usually do not have the substructure of the 6-OH-chromanol. These chromanols are also not covered by this review.

Plants
In the last decades, hundreds of publications referring to tocopherols and tocotrienols have been published, covering chemical, physical and biological properties of vitamin E as well as analytical procedures to detect the vitamers from biological origin.
The main sources of the fat-soluble vitamin E are plant oils. To understand the structural variability of tocochromanols in plants and other photosynthetic organisms, a brief introduction into their biosynthesis is presented. The biosynthesis of tocochromanols was primarily investigated in the leaves of green plants, however all photosynthetic organisms as well as apicomplexa parasites such as Plasmodium falciparum 8 are capable of the necessary biosynthetic steps. The biosynthetic pathways of tocotrienols, tocomonoenols, tocopherols and plastochromanol-8 are depicted in Fig. 2 and consist of ve main steps. First, the transformation of p-hydroxyphenylpyruvate (HPP) to homogentisic acid (HGA), which is catalyzed by hydroxyphenylpyruvate dioxygenase (HPPD). Second, the synthesis of the isoprenoid side chain that originates from the 1-deoxy-D-xylulose-5-phosphate (DOXP) pathway in plastids. Here, geranylgeraniol reductase (GG-reductase) determines the degree of side chain saturation that leads to dihydrogeranylgeraniol diphosphate (DHGG-DP), tetrahydrogeranylgeraniol diphosphate (THGG-DP) and phytyl diphosphate, respectively. The reduction of the double bonds between C-3 0 -C-4 0 and C-7 0 -C-8 0 results in two R-congurated stereogenic centers at C-4 0 and C-8 0 of the later tocopherols (Fig. 3).
The methylation pattern of tocochromanols depends on the next steps (step 4 and 5) of the biosynthesis. dand b-tocochromanols are formed by immediate cyclization, followed by Sadenosyl methionine-dependent methylation of the chromanol ring, whereas g-tocochromanols are build by methylation followed by cyclization. Finally, a-tocochromanols results from methylation of g-tocochromanols. The cyclization of the prenylated quinones to chromanols by tocopherol cyclase occurs within plastoglobules. The latter biosynthetic step yields R-conguration at C-2 atom and thus seems to be unique for plant species. For in-depth details of the biosynthetic pathways, the reader is referred to previously published excellent reviews. 10, 11 According to the methylation pattern of the 6-hydroxychromanol ring system, tocopherols are divided into the most prominent vitamers a(5,7,8-trimethyl)-tocopherol (3), b(5,8dimethyl)-tocopherol (4), g(7,8-dimethyl)-tocopherol (5) and d(8-methyl)-tocopherol (6), respectively (Fig. 3). The tocopherols are ubiquitously found in most plant oils, whereas tocotrienols occur only in non-photosynthetic organs of higher plants, mainly eudicots and monocots. 11,12 Alternative methylations of the chromanol ring lead to 3tocopherol (5-methyltocol) (7), h-tocopherol (7-methyltocol) (8) and z-tocopherol (5,7-dimethyltocol) (9), which are found in trace amounts in rice bran. 13 The latter congeners have not been described in recent literature and therefore their existence seems to be questionable and may have been the result of analytical artifacts.
a-Tocodienol (26) has recently been discovered as a trace compound (0.2% of the total vitamin E content) in palm oil. 30 Interestingly to note is a recent publication by Hammann et al., who have tentatively identied 170 unsaturated tocochromanol compounds in palm oil by GC-MS, which were most likely produced (in trace amounts) by the thermal oil rening process and are thus unlikely genuine natural products. 31 Beside tocopherols and tocotrienols, some plant species produce plastochromanol-8 (27), a g-tocochromanol with eight isoprenoid units in the side chain. The biosynthesis of the polyterpene follows that of tocotrienols except of the use of solanesyl-diphosphate synthase to form the elongated side chain of plastochromanol-8 (Fig. 4). 32 Plastochromanol-8 was rst discovered in leaves of the rubber tree (Hevea brasiliensis) and since then in many higher plants, where it acts as a fatsoluble antioxidant. [32][33][34] Nutritional sources, such as rapeseed and linseed oil, accumulate between 5.57 and 18.47 mg/100 g, respectively. 34 Nutritional or physiological effects of plastochromanol-8 in animals or humans have not been described so far. As a result of the non-enzymatic oxidation of plastochromanol-8 by singlet oxygen, hydroxy-plastochromanol (28) was identied in Arabidopsis leaves. 35 Solanachromene (29) (plastochromenol-8) contains a double bond in the chromanol ring and was found in relatively high amounts (0.05% of dry weight) in aged ue-cured tobacco leaves. 33,36 d-Garcinoic acid (30) (E-13 0 -carboxy-d-tocotrienol, d-garcinoic acid), an oxidation product of d-tocotrienol, is probably the most investigated plant tocotrienol with side chain modication, so far (Fig. 5). 37 d-Garcinoic acid was rst isolated from Clusia grandiora by Delle Monache et al. and later by Terashima et al. from the African bitter nut Garcinia kola and was further characterized for its chemical and physiological properties. [37][38][39][40][41][42] It has been detected in different amounts within the Clusiaceae family including Tovomitopsis psychotriifolia, Clusia obdeltifolia, Clusia burlemarxii, Clusia pernambucensis, Garcinia kola and together with g-garcinoic acid (31) in the bark of Garcinia amplexicaulis. 43,44 Recently, g-garcinoic acid was isolated in small amounts from the Algerian conifer Cedrus atlantica (Pinaceae). 45 A mixture of 2(Z)-d-garcinoic acid and 2(E)-d-garcinoic acid was isolated from the stem of Clusia obdeltifolia. 46 d-Garcinoic acid exerts potent anti-inammatory, antiproliferatory and antibacterial properties (see corresponding sections). As a possible target for its anti-inammatory action, microsomal prostaglandin E 2 synthase has been identied recently. 44 The two natural (d-and g-garcinoic acid) isoforms as well as semi-synthesized band a-garcinoic acid inhibited the enzyme with IC 50 values of 6.7, 2.0, 2.8 and 7.8 mM, respectively. d-Garcinoic acid reduced the growth of C6 cells and RAW264.7 mouse macrophages with an EC 50 of 10 mM and 5 mM, respectively. 37,38 As demonstrated by Maloney and Hecht, dgarcinoic acid inhibits DNA polymerase b with an IC 50 of about 4 mM. 47 Whether this inhibition is a useful approach to prevent growth of cancer cells needs to be elucidated.
As a by-product of the isolation of garcinoic acid, garcinal (34) (d-(E)-garcinal), with a terminal aldehyde group, was found in the G. kola nut. 41 So far, the bioactive properties of garcinal are unknown.
Another interesting group of side chain-modied compounds with large structural variability has been isolated from the bark of Garcinia amplexicaulis, an endemic shrub from New Caledonia. dand g-amplexichromanol (35) and (36) are terminal-hydroxylated dand g-tocotrienols, respectively, carrying two hydroxy-groups at carbon-13 0 and -14 0 (Fig. 5). 43 Both compounds inhibited capillary formation of VEGFinduced human primary endothelial cells at 25 nM concentration. Interestingly, only d-amplexichromanol decreased the adhesion of VEGF-induced human primary endothelial cells whereas g-amplexichromanol had no signicant effect, suggesting different modes of action. d-Dihydroxyamplexichromanol (37) results from dihydroxylation of the double bond between C-7 0 and C-8 0 . Besides g-(Z)and g-(E)deoxy-amplexichromanol (38) as well as d-(Z)and d-(E)-deoxyamplexichromanol, two aldehydes, namely g-(E)-deoxyamplexichromanal (39) (which is identical to g-(E)-garcinal) and d-(E)-amplexichromanal (40) were isolated from Garcinia amplexicaulis. 43 46 In addition, dimeric oxidation and condensation products of amplexichromanols have been characterized. 43 From the methanolic extract of leaves of Litchi chinensis (Sapindaceae), several d-tocotrienol derivatives with side chain and chromanol modications were isolated and investigated for their anti-cancerogenic potential. 49 Litchtocotrienols A-G (41)(42)(43)(44)(45)(46)(47) are hydroxylated at C-11 0 with R-conguration and E-F (45, 46) contain a ketone group at C-11 0 (Fig. 6). An additional methoxy-group is introduced at position C-5 of the chromane ring for litchocotrienols B, D, F and G, respectively. Position C-12 0 is hydroxylated for A, B, G or methoxylated for C and D. Macrolitchtocotrienol A (48) derives from an intramolecular condensation between C-12 0 and C-6 to form an ansa-chromane. The structural motive is similar to the smenochromene sesquiterpenes. Finally, cyclolitchtocotrienol A (49) with a cyclohexene ring within the side chain was isolated. The latter compound is a structural isomer of walsurol (50) with related biosynthesis (Fig. 7). Litchtocotrienols presumably derive from the precursor 11 0 -12 0 -epoxide that undergoes nucleophilic ring opening and further modications. Litchtocotrienols A-G and macrolitchtocotrienol A showed moderate cytotoxicity in HepG2 liver cells and gastric epithelial cells (AGS), with IC 50 values ranging from 10-50 mM ( Table 2).
All isolated compounds from Garcinia amplexicaulis and Litchi chinensis show high structural similarity to tocochromanols from Saragassum species (see section on Algae). In conclusion, Garcinia amplexicaulis and Litchi chinensis present the highest degree of structural variability among angiosperms.
Side chain-modied tocochromanols have been found in the fruits of the Amazonian Myristicaceae Iryanthera juruensis and Iryanthera grandis, [50][51][52] and in vegetal parts of the Mexican Asteraceae Roldana barba-johannis. 53 Iryanthera leaves were used by the indigenous population to treat infected wounds and cuts, and the latex of the bark was used against infections. 52 d-Sargachromenol (51) was found in all the above-mentioned plants and was obtained in 0.4% and 0.8% yield (dry mass) from Roldana and Iryanthera species, respectively. d-Sargachromenol is a d-dehydrotocotrienol derivative with a carboxyl group located at C-15 0 of the side chain and is thus a structurally related form of d-garcinoic acid (30) (Fig. 5). Sargachromenol was named aer the brown algae Sargassum serratifolium, from which it was rst isolated by Kusumi et al. 54 For a detailed description of the biological properties, please see the section on Algae.
Besides d-sargachromenol, 7-methyl-sargachromenol (52) (gsargachromenol) was isolated from the fruits of Iryanthera juruensis by Silva et al. 50 To the best of our knowledge, besides cyclolitchtocotrienol A (49), walsurol (50) obtained from the bark of the Yunnan tree Walsura yunnanensis (Meliaceae) is the only meroditerpene in higher plants that forms a 6-membered ring structure within the side chain. 55 Interestingly, walsurol was obtained as the main lipid constituent from powdered bark (0.08% yield). Here, the authors discussed a possible mechanism that leads to cyclization reactions in the side chain. Epoxidation of the   terminal double bonds in isoprenoid structures are well described for squalene and also for tocotrienols. 56,57 Nucleophilic ring-opening results in a 11 0 ,12 0 -diol structure that has also been described for algae. 58-60 Etse et al. proposed an acidcatalyzed rearrangement that leads to a variety of cyclic structures formed from the diol. Elimination of water and ring closure between carbon 7 0 and 12 0 forms endo-(e.g. (49).) and exo-double bonds (e.g. (50)), respectively (Fig. 7). 61 The metabolic pathway described here also applies to the formation of chromarols (see section on sponges).

Fungi
Although mushrooms and fungi produce a large number and variety of meroterpenoids, 62,63 our database search found only scarce information on long-chain or cyclic 6-hydroxychromanols or -chromenes. The occurrence of a-, b-, g-, and d-tocopherols has been summarized in a review by Ferreira et al. 64 Interestingly, no tocotrienols have been found in fungi so far. Several meroterpenoid structures were described with a 5hydroxy-chromene ring, which originated from orsellinic acid as the aromatic precursor. 62

Marine organisms
Since 1960, more than 20 000 distinct chemical compounds were discovered from marine organisms. 65 Of these, algae and sponges form two third of all natural marine products found from 1965 to 2007. 66 Marine natural products (MNP) with isoprenoid structures account for almost 60% of all natural products found in marine organisms. 67 Several excellent reviews have summarized meroterpene structures from marine fungi, 68 invertebrates, 69 and algae. 67,70,71 Tocopherols are well known to be produced by algae as well as marine invertebrates and microorganisms. 69,72 Most interestingly, d-tocotrienol (17) is widely distributed (especially in algae and sponges) and appears as the lead structure of most of the diverse compounds described in this review. Among them, sargachromanols, sargachromenols, cystoseira metabolites, chromarols, epitaondiols, smenochromenes and strongylophorines constitute the largest and best studied groups. Anti-bacterial, anti-viral, anti-inammatory and cytotoxic properties were attributed to these compounds, making them potential lead structures for drug development. 73 3.3.1 Brown algae (Phaeophyceae). Brown algae (Phaeophyceae) consist of around 2000 species of which the family of Sargassaceae, Dictypophycidae and Fucaceae produce most of the meroditerpenes described here. 74 There is increasing interest in and knowledge about the isolation, and structural elucidation of meroditerpenes and their quinone precursors from brown algae. Recently, Culioli and colleagues described the analytical procedure for the extraction, chromatographic isolation and structural determination by sophisticated one-and two-dimensional nuclear magnetic resonance spectroscopic methods. 74 As mentioned above, sargachromanols and sargachromenols show the highest structural diversity among all meroditerpenes. They derive from the common precursor geranylgeranyltoluquinol and subsequently from d-tocotrienol and d-dehydro-tocotrienol, respectively. d-Tocotrienol-11 0 -12 0epoxide (53) was one of the rst sargachromanols discovered in brown algae by Kato et al. in 1975. 57 The activation of the terminal double bond leads to hydroxyl-, oxo-, and cyclic derivatives, respectively. However, the sequence of the chemical reactions leading to cyclic derivatives remains elusive (see also Fig. 7). Observational studies showed that an extract of Sargassum tortile induced the settling of swimming larvae of the hydrozoa Coryne uchidai, thus obviously acting as an intercellular signaling molecule. 75 The epoxide was found by bioactivity-guided fractionation of the lipid extract.
It was suggested that the following cyclic diterpenes origin from a common biosynthetic precursor, namely bifurcarenone (81) (Fig. 11). Among them, mediterraneols C (82), D (83), and E (84) have been isolated as their trimethoxyderivatives from Cystoseira mediterranea in high yield (0.11, 0.14 and 2.0% from dry weight algae, respectively). 106,107 Mediterraneols C and D are stereoisomers at C-4 0 and compromise a bridged cyclooctane structure with two dienol moieties. Mediterraneol E (84) is a tricyclic oxygen-bridged diterpene with antineoplastic activity. 107 So far, the biosynthesis of mediterraneols is largely unknown. 106,108 Mediterraneols have been found to inhibit the mobility of sea urchin sperm and the mitotic cell division (ED 50 values of 2 mg ml À1 ) of fertilized urchin eggs. 106 Recently, cystophloroketal E (85), a meroditerpene with a 2,7dioxabicylo[3.2.1]octane core was isolated from Cystoseira tamariscifolia. 108 The authors assumed that ketal formation was preceded by a Michael addition of phloroglucinol onto the unsaturated carbonyl of 4-methoxy-bifurcarenone. The compound showed anti-bacterial, anti-microalgal and antiinvertebrate activity (Table 3).
Finally, bifurcarenone chromane (94), the cyclization product of 81, was found in Cystoseira baccata, 104,115 and Sargassum muticum, 116 from which it was isolated as epimeric mixture at C-2 (Fig. 11). The mixture showed anti-leishmanial activity at IC 50 values of 44.9 mM and decreased the intracellular infection index (IC 50 value of 25.0 mM). 117 Sargaol (95) or dehydro-d-tocotrienol is the potential biosynthetic precursor for most of the chromenols found in brown algae. It was originally isolated from Sargassum tortile collected at the Japanese Tanabe Bay. A lipid extract of the algae exhibited high cytotoxic activity and was used as a skinlightening agent. 118,119 Fractionation of the extract resulted in the isolation of sargaol (95), sargadiols-I (96) and -II (97), and sargatriol (98) (Fig. 12). 120,121 All compounds were moderately cytotoxic towards murine P-388 leukemia cells with ED 50 values of 52, 34, 41 and 42 mM, respectively (Table 2). 118,120 Sargadiols (96) and (97) bear a hydroxyl group at C-6 0 and C-8 0 , respectively, and sargatriol has two hydroxyl groups at C-5 0 and C-6 0 . All compounds were suggested to be artefacts of the isolation since epimers at C-2 were found in all cases. In addition, heating of the corresponding 1,4-hydroquinones in organic solvents led to the epimeric chromenes described in this paragraph.
Two chromenols were isolated as minor compounds from Desmarestia menziesii collected from the Antarctic King George Island, one bearing a hydroxy group at C-13 0 (99) and the other a carboxy group at C-13 0 (100). The latter is a structural isomer of d-sargachromenol (51) (see below) and shares structural similarity with garcinoic acid (30). 122,123 Again, no optical activity was found for the two chromenes suggesting an epimeric center at C-2. However, the authors suggested a non-enzymatic ring closure within the living algae since no corresponding 1,4benzoquinone was found as a potential precursor.
A C-15 0 -aldehyde-bearing chromenol (101) with antileishmanial activity was found as minor compound in the  Southern Australian brown alga Sargassum paradoxum and the Japanese algae Sargassum yamadae. 124 d-Sargachromenol is one the most investigated meroditerpenoid obtained from marine organisms. As mentioned above, its unique structure resembles a d-chromenol ring system with an unsaturated side chain containing a carboxy group at C-15 0 . d-Sargachromenol is widely distributed in Sargassum species such as Sargassum sagamianum, 73,125,126 Sargassum serratifolium, 54,127,128 Sargassum micracanthum, 129 Sargassum horneri, 130 Sargassum macrocarpum, 131,132 and Sargassum fallax. 133 The latter species contains d-sargachromenol as high as 0.13% of the dry weight. It has also been isolated from Myagropsis myagroides (Sargassaceae), 134 from the tunicate Botryllus tuberatus 135 and other algae. 134 Kusumi et al. claimed 51 to be an artefact that is produced from sargaquinoic acid during the clean-up procedure. Although there is an asymmetric carbon center at C-2, the authors found no optical rotation. Literature data on the stereochemistry of sargachromenol are inconsistent. d-Sargachromenol isolated from plant species showed optical  135 It is yet not clear whether sargachromenol should be considered as an artefact of the work-up procedure or as a natural product. 136 Sargachromenol received attention in drug research since it has inhibitory activity against enzymes related to Alzheimer's disease, strong anti-inammatory activity and antihyperproliferative properties in skin cells (Tables 1-3). Several patents are pending on the use of sargachromenol as drug candidate. 137 Choi et al. Molecular docking experiments revealed that sargachromenol interacts with the allosteric side of BACE1. 127 In line with these results, sargachromenol promotes neurite outgrowth and survival of rat PC12D pheochromocytoma cells via activating phosphatidylinositol-3 kinase. 131 Based on its lipid-solubility and low molecular weight (<500 Dalton), sargachromenol should be able to cross the blood brain barrier, making d-sargachromenol an interesting drug candidate for treating Alzheimer's disease and other neurodegenerative diseases.
Similar to d-garcinoic acid, sargachromenol is a potent anti-inammatory compound that prevented TPA-induced ear edema in mice with an IC 50 value of 0.36 mg per ear. 53 In addition, d-sargachromenol inhibits lipoxygenase (LOX) (76% at 100 ppm) and cyclooxygenase (COX)-1 and -2 (98% and 84% at 100 ppm; Table 1). 52 Sargachromenol inhibited LPS-induced inammation markers in murine RAW 264.7 macrophages. Production of PGE 2 and nitric oxide was inhibited (IC 50 values of 30.2 and 82 mM, respectively) accompanied by a reduced protein expression of iNOS and COX-2. 129 Kim et al. reported the inhibition of nitric oxide formation in LPS-stimulated murine microglial BV-2 cells with an EC 50 value of 1.14 mg ml À1 (2.7 mM). These effects are accompanied by a suppression of the  release of TNF-a, IL-1b, and IL-6. 134 Several markers of vascular inammation were also decreased in primary endothelial cells by d-sargachromenol, namely TNF-a induced ICAM-1 and VCAM-1 expression, adhesion of monocytes to HUVEC and decreased production of monocyte chemoattractant protein-1 and matrix metalloproteinase-9 (MMP-9). 128 Both epimers of sargachromenol bind to human farnesoid X receptor and inhibit its transactivation (IC 50 values of 9.0 mM (R-epimer) and 17.0 mM (S-epimer), respectively). It is known that farnesoid X receptor agonists decrease plasma triacylglycerides and increase HDL cholesterol by regulating the expression of apolipoprotein C-I and C-IV. 135 Summarizing the evidence (also from plant species), d-sargachromenol (51) clearly is a candidate for an anti-atherogenic drug. Sargachromenol has also been suggested as a drug for skin health, since it induced apoptosis in hyperproliferative human keratinocyte HaCaT cells and suppressed MMP-1, -2 and -9. 126,130 Finally, insecticidal activity was found against the larvae of Spodoptera frugiperda with a LD 50 value of 2.94 mg ml À1 . 136 Iwashima et al. synthesized a dihydroxylation product of sargachromenol from the corresponding plastoquinone precursor that had been isolated from Sargassum micracanthum. 58 To the best of our knowledge, 11 0 -,12 0 -dihydroxysargachromenol (102) (Fig. 13) has never been isolated as a natural product from algae before. However, the compound has been investigated for its anti-viral activity against human cytomegalovirus, 58,60 its anti-ulcer activity in ethanol-induced gastric lesions in rats, 138 and inhibitory activity in osteoclastogenesis (bone resorption), thus suggesting that this compound is an interesting pharmacological lead structure. 59 Multiple biosynthetic oxidation steps lead to a highly oxidized chromane (103), which was found in Halidrys siliquosa (Sargassaceae) from the French Atlantic coast. 139 Two keto groups at positions C-2 0 and C-10 0 and a hydroxyl group at C-9 0 with R-conguration could be assigned by two-dimensional NMR spectroscopy.
Natural derivatives of d-sargachromenol 52 have been isolated from different algae species. Besides d-sargachromenol, sargothunbergol A (104), a sargachromenol with two additional hydroxyl groups at C-11 0 and C-12 0 , was isolated as a minor compound from Sargassum thunbergii, collected from the shore of the Korean Youngdo Island. 66,140 Fallachromenoic acid (105) from the Australian alga Sargassum fallax is an interesting variation as it bears a chlorine atom at C-11 0 and a terminal double bond (Fig. 13). 133,141 Fallachromenoic acid was isolated in 0.06% yield (dry mass) and exhibited moderate anti-tumor activity in the murine leukemia P388 cell assay (IC 50 value of 29 mM).
Along with the sargachromanols described by Jang et al., 76 mojabanchromanol (106) has been isolated from Sargassum siliquastrum, 142 showing a rearranged carbon skeleton at C-3 0 of the side chain.
Only two chromenols with cyclic side chain modications were found in the literature. A 3,4-unsaturated analogue of bifurcarenone chromane (107) was identied in Cystoseira amentacea collected from the French Riviera and an unsaturated analogue of compound 107 from Cystoseira baccata. 143 3.3.2 Phytoplankton (green algae, cyanobacteria, phytoagellates). Green algae, cyanobacteria, phytophlagellates and other microalgae are members of the phytoplankton that produces a-tocopherol, which is essential for higher marine organisms. In addition, spirulina (Arthrospira platensis) is nowadays used in human nutrition as a food supplement. A screening of microalgae for a-tocopherol content reported various amounts starting from 58.2 mg g À1 (dry weight) for Isochrysis galbana up to 669 mg g À1 (dry weight) for Chlorella stigmatophora. 144 The amount of a-tocopherol in spirulina varied between 5 and 14 mg g À1 dried spirulina. 145 As a subject of culture conditions, the phytoagellate Euglena gracilis Z produces high amounts of a-tocopherol and -tocotrienol (7 mg g À1 and 2.6 mg g À1 dry weight, respectively). 146 As reported by Yamamoto et al., cold water sh contains a substantial amount of marine-derived tocopherol (25) (MDT), Review an a-tocomonoenol with a terminal double bond between C-12 0 and C-13 0 (Fig. 14). 147 Since tocochromanols are only synthesized by photoactive organisms, the authors suggested a dietary source for MDT in sh. In fact, phytoplankton contains up to 21% (of total tocopherol) MDT. Also Antarctic krill (Euphasia superba) contains up to 8% (of total tocopherols) MDT. 148 The biosynthesis of 25 is largely unknown; however, the authors suggested that the terminal double bond is introduced by side chain desaturation of a-tocopherol, similar to that of fatty acids.

Invertebrates (sponges, Ascidiacea, so corals).
Sponges or Porifera comprise a group of more than 9000 species. In the last decades, sponges have attracted scientists to investigate the diversity of natural products and their properties. 150 From a chemotaxonomic point of view, it is worth to note that some of the structures found in sponges that contain a chromene core lacking the typical methylation pattern. These sarcochromenols and the group of strongylophorines possess the highest structural variability in the organisms presented in this review.  A hypothetic biosynthetic precursor of the chromene structure was found in the Western Australian sponge Fasciospongia species (order of Dictyoceratida, family of Thorectidae). 151 Fascioquinol F (109) is a demethylated 3-4-dehydro-tocotrienol that might undergo cyclization to form complex ring systems in analogy to taondiols (see the section on Brown algae). The structure is similar to sargaol (95), but lacks the methyl group at C-8 (Fig. 14). Fascioquinol F revealed moderate antibacterial activity against Staphylococcus aureus and Bacillus subtilis (IC 50 values of 13 and 30 mM, respectively).
Sarcochromenols A (110), B (111) and C (112) are a group of long-chain tocochromenols with ve, six and seven isoprene units, respectively (Fig. 14). They were isolated from the Pacic Ocean sponge Sarcotragus spinulosus (Schmidt) (family of Thorectidae) and showed Na + /K + -ATPase inhibitory activity similar to that of the sargachromanols D, F, H and L (IC 50 value for sarcochromenol A of 1.6 mM). 78,152 The compounds have also been isolated from the Indian sponge Ircinia fasciculate (Spongillidae). 153 In addition, an un-sulfated form of sarcachromenol B was isolated in 0.1% yield.
A screening for selective human 15-LOX inhibitors from an extract of the Papua New Guinean sponge Psammocinia (order of Dictyoceratida, family of Irciniidae) revealed chromarols A to D (113 to 116; Fig. 15). 154 The IC 50 values for chromarols A to D were 0.6, 4.0, 0.7 and 1.1 mM, respectively. The authors found high selectivity since the IC 50 values for 12-LOX were above 100 mM. The biosynthesis of the cyclohexene ring system in the side chain of chromarols presumably derives from an acidcatalyzed cyclization.
On their search for inhibitors of protein tyrosine phosphatase 1B, an enzyme that plays a crucial role in the regulation of insulin and leptin signalling, Lee et al.  (127) were isolated from the Okinawan sponge Petrosia corticata and displayed moderate cytotoxic activity against uman cervical carcinoma epithelial (HeLa) cells (Table 2). 163 All strongylophorines exhibited ichthyotoxic, insecticidal, anti-bacterial, fungicidal, and cytotoxic properties. Strongylophorine 22 and fascioquinol D are epimers at C-2 and were isolated from Fasciospongia sp. 151 The latter compounds displayed anti-microbial activity against Staphylococcus aureus and Bacillus subtilis with IC 50 values of 25 and 2.3 mM (for strongylophorine 22) and 7.8 and 2.8 mM (for fascioquinol D), respectively. Recently, Yu et al. presented the rst semi-synthesis of strongylophorine 2 starting from isocupressic acid. 164 3.3.4 Ascidiacea/tunicates. Ascidians, tunicates or sea squirts belong to a group of more than 3000 species, most of them not investigated in terms of bioactive metabolites. In a recent review, Palanisamy et al. described almost 600 chemical structures found in tunicates. 165 Here, we describe meroditerpenes, such as an epimeric mixture of R-and S-sargachromenol and two epimeric chromenes called tuberatolide B and 2 0 -epi-tuberatolide B (131), obtained from the tunicate Botryllus tuberatus. 135 Tuberatolide B contains a g-lactone moiety within the side chain that presumably derives from a C-15 0 -carboxy, C-6 0 -hydroxy-precursor (Fig. 17). Both tuberatolides were strong farnesoid X receptor agonists with IC 50 values of 1.5 and 2.5 mM, respectively. 135 3.3.5 So corals. So corals (Alcyonacea) belong to the class of Anthozoa and compromise approximately 800 species living mostly in warm seawater. In recent years, the number of new metabolites discovered from so corals was estimated to represent 22% of the total new marine natural products. 166 Many metabolites showed anti-tumor, anti-viral, anti-fouling and anti-inammatory activities (reviewed in (ref. 167)).
Bowden et al. isolated tocotrichromenol (132), an isomer of sargaol (95), and its dihydro derivative (133) from an unknown Australian Nephthea species. 168 The precursor quinone was also isolated, but did not convert into the chromenol under the work-up conditions; however, no optical activity was found at C-2.

Plants
The biosynthesis of chroma(e)nols with sesqui-, mono-and hemi-terpene moieties within the plant kingdom is only poorly understood. These molecules most likely derive from homogentisate condensed with farnesyl-, geranyl-and isoprenyldiphosphates, respectively.
Oligandrol (136), a sesquiterpenechromane with an unsaturated side chain, was isolated together with methoxy-oligandrol (137) from the bark of the Australian tree Beilschmiedia oligandra (Lauraceae), 170 and from the leaves of the genus Pseuduvaria indochinensis Merr, an Annonaceae variety from the Yunnan province in China (Fig. 18). 171 Cytotoxic assessment revealed no activity against promyelocytic HL-60 leukemia cells and human SMMC-7721 hepatocarcinoma cells. 171 The methoxy-derivative of dehydrooligandrol (138) was obtained from the root of Beilschmiedia erythrophloia 172 and the free dehydrooligandrol (139) from the leaves of Seseli farreynii (Umbelliferae). However, the latter was suggested to be an artefact from the work-up procedure. 173 Zhao et al. isolated a dehydrooligandrol with a terminal (Z)-carboxy and a 13 0hydroxy group, respectively, which the authors named pseudindochin (140). 171 Polycerasoidol (141), an oligandrol derivative with a terminal (Z)-carboxy-group and its 6-methoxy-derivative polycerasoidin (142) were found in the stem bark of the Papua New Guinean Polyalthia cerasoides. 174 Later, the methyl ester of polycerasoidin (143) and the E-isomer of polycerasoidol, termed isopolycerasoidol (144), were identied in the same species. 175 Polycerasoidin was isolated at 0.13% yield (dry weight). Polyalthidin (145), a structural isomer of polycerasoidin with a double bond shi from C-7 0 -C-8 0 to C-6 0 -C-7 0 was isolated from P. cerasoides at a yield of 0.09% (Fig. 18). 176 Polycerasoidol, polycerasoidin and polyalthidin were found to be inhibitors of the mitochondrial electron transfer chain that block NADPH oxidase activity with IC 50 values of 37, 11 and 4.4 mM, respectively. 176 Riccardiphenol C (146), a sesquiterpene from the New Zealand liverwort Riccardia crassa, is an example of a chromanol that undergoes intramolecular cyclization to form a condensed ring system. Purication of the crude extract yielded riccardiphenol C in 4 mg g À1 of dry liverwort (Fig. 18). The compound showed cytotoxicity against African green monkey BSC-1 kidney cells and inhibited the growth of Bacillus subtilis. 177

Fungi
A sesquiterpene chromene (147) with a truncated tocochromene-like structure was isolated from Chroogomphus rutilus. 178 The mushroom is also known as brown simecap and lives ectomycorrhizally with Pinus species. The compound shows R-conguration at the chiral center C-2 (Fig. 19).
Dictyochromenol (153) and its cyclization product chromazonarol (154) were both isolated from the Japanese brown alga Dictyopteris undulata. [181][182][183] Dictyochromenol is comprised of a demethylated chromanol ring which is attached to an unsaturated sesquiterpene moiety. A chemical synthesis route of dictyochromenol was described by Aoki et al. 184,185 Kurata et al. suggested an acid-catalyzed cyclization of farnesyl hydroquinone towards zonarol (1,4-hydroquinone) followed by a second acid-catalyzed formation of the epimeric center at C-2 of chromazonarol (Fig. 20). 186 Chromazonarol showed algicidal activity towards Heterosigma and Chattonella species. 182  (155), and its 5-chloro-derivative (156) were isolated from the Caribbean sponge Smenospongia aurea. 187,188 It has been suggested that aureol results from a rearrangement of the drimane skeleton of chromazonarol. Aureol showed moderate cytotoxic activity against several cell lines, such as human adenocarcinomic A549 alveolar basal epithelial cells, human colon adenocarcinoma HT-29 cells, and murine EL4 lymphoma cells with IC 50 values of 13.6, 14.9 and 31.5 mM, respectively. 189 In 2002, Nakamura et al. presented a chemical synthesis of aureol. 190 Besides aureol, 2-epichromazonarol was isolated (2.2% dry weight) from Smenospongia aurea. 187 Recently, a structurally related meroterpenoid, puupehenol (157), with potent antimicrobial properties was isolated from the Hawaiian sponge  Dactylospongia sp. (Fig. 20). 191 The authors suggested that the well-known puupehenone may be a work-up artefact of the natural precursor puupehenol.
Two epimeric sesquiterpene chromenols, named cyclorenierin A and B (158), were found in Haliclona sp., an Indo-Pacic sponge from Vanuatu. 192 The biosynthesis of the cyclohexenone ring system seems to follow that of walsurol (Fig. 6).
Panicein B2 (159) bears a chromene ring and an aromatic ring system in the side chain (Fig. 21). It was rst isolated by Cimino et al. from Haliclona panacea and later from the Mediterranean sponge Reniera fulva. 193,194 Panicein B2 was also found in Reniera mucosa along with panicein A2 (160) and F2 (161). 195 It has been suggested that the aromatic group of the side chain is formed from cyclorenierin A/B by a 1,2-methyl migration and subsequent oxidation. 193 All paniceins show racemic carbon centers at C-2 suggesting that these compounds may be artefacts from the work-up procedure.
Faulkner et al. isolated a series of unusual ansa chromene macrocycles from Smenospongia sp., a sponge from the Seychelles. 196 Smenochromes A to D (162)(163)(164)(165) were isolated with 0.26% yield (dry weight) for A and 0.037% for B, C and D, respectively (Fig. 22). The compounds showed no optical activity and thus occurred as racemic mixtures. The structurally related likonides A (166) and B (167) were isolated from the Kenyan sponge Haytella sp. with 0.06 and 0.04% yield. 197 The biosynthesis of ansa chromenes presumably starts from a farnesylated hydroquinone followed by alkylation at C-5 of the activated hydroquinone ring or alternatively by O-alkylation of the terminal double bond. 197 4.3.3 Ascidiacea/tunicates. Longithorol E (168) was isolated as a minor metabolite from the Australian ascidian Aplidium longithorax (Fig. 22). 198 4.3.4 Molluscs. There is emerging interest in the metabolites of marine nudibranchs. Since these animals completely lost their protective shell, the production or accumulation of toxins from their prey is used as defense systems. 199 Two oligandrol-like structures (169) and (170) were isolated from Cratena peregrine, and a chromenol (171) with a C-6 0 ketone moiety was found in the frilled nudibranch Leminda millecra that is only found in South Africa 200 (Fig. 23).
4.3.5 So corals. Although sesquiterpenes are widely distributed in so corals, we only found sparce information on sesquiterpene chromanes and chromenes, respectively. 201 Capillobenzopyranol (172) was isolated from the Australian so coral Sinularia capillosa and showed moderate cytotoxicity against P-388 cells (ED 50 values of 12.7 mM). 202 Its quinone precursor has been isolated from Sinularia lochmodes. 203 The compound with a terminal furanyl moiety showed in vitro anti-inammatory activity against LPS-activation in murine RAW 264.7 macrophages. Protein expression of iNOS was inhibited by 36.7% at 10 mM concentration of 172 (Table 1), however expression of COX-2 was not affected.

Monoterpenes
Monoterpenes from plant origin have been used since ancient times to treat certain diseases, such as inammation or cancer. De Sousa and colleagues summarized the anti-cancer and anti-inammatory activities of monoterpenes in an outstanding recent review. 204

Plants
The monoterpene cordiachromene A (173) was isolated from the heartwood of the tropical American tree Cordia alliodora (Boraginaceae) by Manners et al. 205 The authors proposed geranyl benzoquinol as the biogenic precursor of the compound. Interestingly, the woods of Cordia alliodora are recognized for their durability in marine uses. Cordiachromene A was also  isolated from the extract of different tunicates and was further tested for its bioactivity (see section on Tunicates (5.2)).
As part of the investigation of Garcinia amplexicaulis (see section on Diterpenes), a short-chain chromane (175) with a truncated C-9 carbon skeleton was found (Fig. 24). 48 5.2 Marine organisms 5.2.1 Brown algae. Next to the large number of di-and sesqui-terpenes, only a few monoterpenes have been described in the literature. Numata et al. isolated side chain truncated aldehydes and named them sargasal-I (176) and sargasal-II (177), respectively (Fig. 24). 71,120 5.2.2 Green algae. Cymopochromenol (178) was the rst halogenated metabolite found in green algae. The 7-bromochromene was isolated from the Bermudan Cymopolia barbata as an optically inactive oil with 0.17% yield and also from Canary Island species with a yield of 0.02% dry weight. 181,206 Later, Dorta et al. isolated two further chromenes, namely 3 0 -(179) and 4 0hydroxycymopochromenol (180), from the same source. 207 Interestingly, both compounds showed optical activity with R-conguration at C-2. Two cyclic chromenes with two bromo atoms were isolated from Cymopolia barbata found in Puerto Rico. 208 Cymobarbatol (181) and its epimer isocymobarbatol (182) showed anti-mutagenic activity. Debromo-isocymobarbatol (183) was isolated from Cymopolia babata (yield 0.2%, dry weight) collected at the Florida Keys and exhibited anti-feedant activity. 209 5.2.3 Ascidiacea/tunicates. Targatt et al. rst reported the occurrence of cordiachromene A (173) in the marine ascidian Aplidium constellatum found around the Georgian coast. 210 Later, cordiachromene A was isolated from Aplidium antillense from Guadeloupe, Aplidium aff. densum from Masirah Island (Oman), Japanese Aplidium multiplicatum and Aplidium conicum, respectively. [211][212][213][214][215] Cordiachromene A showed anti-inammatory activity in vitro and in vivo. 211,214,216 The compound reduced carrageenan-induced rat paw edema with an IC 50 of 18.9 mM and inhibited PGI 2 synthesis in arachidonic acid-stimulated peritoneal rat macrophages (IC 50    and observed strong inhibitory activity against 15-LOX with IC 50 values of 0.82 mM and 1.9 mM, respectively. 214 Cordiachromene A showed anti-bacterial activity against methicillin resistant Staphylococcus aureus and Streptococcus faecalis, 212 but weak activity against Micrococcus luteus (the minimum inhibitory concentration was 0.51 mmol L À1 ). 213 Cytotoxic activity was found against a panel of cancer cell lines, such as murine leukemia P388 cells, human adenocarcinomic A549 alveolar basal epithelial cells, human colon adenocarcinoma HT-29 cells, and African green monkey CV-1 kidney broblasts, and drug-sensitive human leukemic lymphoblasts (IC 50 value of 30 mM). 213,217 So far, three cyclization products of cordiachromene A were found; conical (184), a mixture of C-3, C-4 epimers called epiconicol, and didehydroconicol (185) with a condensed aromatic ring system (Fig. 24). 213,215,217,218 All compounds showed cytotoxic and weak anti-bacterial activity.
Two optically active cordiachromenes were isolated from the Australian tunicae Aplidium solidum, one with an additional 2 0 -3 0 double bond (186), the other with a saturated side chain and a 2 0 -ketone group (187; Fig. 25). 219 5.2.4 Marine algal-derived endophytic fungi. Chaetopyranin (188) with a C-7 skeleton was isolated from the marine red algal-derived endophytic fungus Chaetomium globosum (Fig. 25). 220 Biosynthetically, it may be generated from a meromonoterpene and loss of two methyl groups ormore likelyfrom a derivative of avoglaucin, which is quite common in different fungi strains. The fungus was derived from the red alga Polysiphonia urceolata. Chaetopyranin was cytotoxic against human microvascular endothelial cells, hepatocellular carcinoma cells (SMMC-7721) and human lung epithelial cells (A549) with IC 50 values of 15.4, 28.5 and 39.1 mM, respectively.
All hemiterpenoid chromanols from fungi are derived from simple prenylated phenols and not related to the biosynthetic pathway of tocopherols.

Animal tocochromanol metabolism
For a complete overview of side chain-modied 6-hydroxychromanols, we present in the following animal and human vitamin E metabolites. In recent years, these metabolites have been intensively studied for anti-inammatory and cytotoxic activity (see also sections below) and were discovered as novel regulatory and signaling molecules. Studies on vitamin E metabolism were summarized in several outstanding reviews; 17,238,239 we therefore describe here only briey the formation and activities of these metabolites.

Anti-inflammatory activity of tocochromanols and -chromenols
Many diseases, including atherosclerosis, diabetes or even cancer, are related to inammatory processes. A decreased grade of inammation could lead to a reduced risk for these diseases. In the past, human clinical trials with a-tocopherol as an anti-inammatory agent revealed contradictory results. 17,239,250,251 We here like to broaden the view to structurally related chromanols and chromenols and compare their anti-inammatory in vitro activity.
The anti-inammatory activities of tocopherols and tocotrienols from the human diet are well known and are compiled in Table 1. 239,245,252 In general, the chromanols with saturated and unsaturated side chains showed good to moderate inhibitory activity depending on the anti-inammatory marker measured and the in vitro system used. 253,254 For example, Jiang et al. investigated the inhibition of COX-2 catalyzed PGE 2 synthesis in IL-1b stimulated human lung epithelial A549 cells of a series of tocopherols and tocotrienols, respectively. 245 The inhibitory activities reached from IC 50 > 50 mM for a-tocopherol to IC 50 ¼ 1-3 mM for d-tocopherol and g-tocotrienol.
The LCM of tocopherols and tocotrienols with a terminal C-13 0 -carboxy and -hydroxyl group, respectively, were found in nanomolar concentration in human plasma and intensively studied as anti-inammatory agents. The research on the LCM was promoted by the facile semi-syntheses from garcinoic acid that can be efficiently isolated from Garcinia kola. 38,39 a-13 0 -Carboxy-tocopherol (205) (a-13 0 -COOH) inhibited the expression of iNOS by 100% at 5 mM and the formation of nitric oxide by 100% at 2.7 mM, respectively. 255,256 A recent investigation on the anti-inammatory activity of a-13 0 -COOH showed strong inhibition of recombinant 5-LOX and only moderate inhibition of COX-1, leukotriene (LT) C 4 synthase, PGES-1 and epoxide hydrolase. 254 Human recombinant COX-2 was not inhibited by a-13 0 -COOH at low concentrations.
As described in the section on human metabolism, the metabolic truncation of the LCM leads to several medium-and short-chain metabolites, such as 9 0 -carboxy-tocopherols (9 0 -COOH), CMBHC and CEHC, respectively. In general, the anti-inammatory activities of the medium-and short-chain metabolites seem to decrease with the decreasing lengths of the side chains, resulting in higher IC 50 values (Table 1). 245 In summary, although the number of in vitro studies ist still limited and different markers of inammation cannot be compared directly, we roughly estimate the anti-inammatory activity of tocopherols, tocotrienols and their metabolites as follows: a-tocopherol < non-a-tocopherol $ tocotrienols ( 13 0 -OH $ 13 0 -COOH [ 9 0 -COOH > CMBHC $ CEHC. However, it must be kept in mind that the molecular modes of action of these molecules seem to be quite different. It is obvious that the impact of the metabolites depends on individual metabolism rates (pharmacokinetics) of the tocochromanols from the diet. Grebenstein et al. proposed that the affinity of vitamers towards the atocopherol transfer protein (a-TTP) may predict their degradation by cytochrome P 450 enzymes. 258 a-TTP has the strongest affinity for a-tocopherol with K d of 25 nM and much higher K d values for the other vitamin E forms, depending on their methylation pattern and side chain saturation. 239,259 Accordingly, the catabolism of non-a-tocopherol vitamers into the corresponding LCM may occur much faster than that of a-tocopherol, thus generating more anti-inammatory metabolites. As a result, a-tocopherol per se is less active than all other vitamers following the order: dtocopherol $ g-tocotrienol > g-tocopherol [ a-tocopherol. 239 d-Garcinoic acid (30) is the main constituent of several Garcinia species, which are known for their anti-inammatory properties in African ethnomedicine. 37 d-Garcinoic acid was reported to inhibit COX-2 (IC 50 ¼ 10 mM) and, even stronger, 5-LOX with IC 50 ranging from 0.04 to 1.0 mM. 257 d-Garcinoic acid downregulated the LPS-induced expression of pro-inammatory cytokines, such as TNF-a, IL-6, IL-1b, COX-2 and iNOS in macrophages and reduced production of nitric oxide (IC 50 value of 1 mM). 255,260 A direct comparison of several carboxytocotrienols (tocotrienol-13 0 -COOH metabolites) from plant origin as inhibitors of microsomal PGE 2 synthase-1 revealed the following order of activity: g-garcinoic acid (31) > b-garcinoic acid (232) > d-garcinoic acid (30) > a-garcinoic acid (209); however the methylation pattern had only moderate impact. 44 Structurally related forms of d-garcinoic acid, such as d-sargachromenol (51) with a 15 0 -COOH group and a chromene ring system, showed only moderate inhibitory activity on in LPSstimulated production nitric oxide and PGE 2 in murine RAW 264.7 macrophages (IC 50 values of 82 mM and 30.2 mM, respectively); 129 however, much higher activity was observed in BV-2 microglial cells (IC 50 value for inhibition of nitric oxide production of 1.3-2.7 mM). 134,261 As described above, 13 0 -OH metabolites have a similar anti-inammatory potential than the corresponding 13 0 -COOH. Thus, natural products such as sargachromanols D (57), E (58) and G (60), respectively, with hydroxyl-groups at C-9 0 and C-10 0 are interesting intermediates. They all showed moderate inhibitory activity on nitric oxide production in LPS-stimulated murine RAW 264.7 cells (IC 50 values of 15-40 mM). 79,83,84 Cyclic meroditerpenes such as epitaondiol (79) and the chromarols A to D (113 to 116) exhibited anti-inammatory activity in vitro and in vivo (Table 1). 99,154 The four chromarols A to D inhibited 15-LOX with IC 50 ¼ 0.6(113), 4.0(114), 0.7(115) and 1.1 mM (116), respectively, but not 12-LOX. Epitaondiol was effective in a TPA-induced mouse ear edema study (IC 50 ¼ 20.7 mg per ear) and inhibited eicosanoid synthesis with an IC 50 of 3.8 mM for thromboxane B 2 (TXB 2 ) and an IC 50 of 30.1 mM for LTB 4 .
The cyclic sesquiterpenes capillobenzopyranol (172) only moderately inhibited nitric oxide production in LPS-stimulated macrophages by 37% at 10 mM. 202 The monoterpene cordiachromene A (173) inhibited soybean 15-LOX with an IC 50 of 0.82 mM and lipid peroxidation with an IC 50 of 2 mM. 214 Only moderate anti-inammatory activity was observed for the hemiterpene quercinol (199), whereas it inhibited COX-2 expression with an IC 50 of 0.63 mM. 235 In Fig. 29 we postulate the structural motives that are essential for the anti-inammatory activity based on the structures and properties discussed above. The most effective compounds described are the diterpenes 13 0 -COOH, 13 0 -OH, garcinoic acid and d-sargachromenol, respectively, with strong potential as anti-inammatory drug candidates. A recent SAR study revealed that the effects of human LCM depend on the presence of the chromanol ring and modications in the side chain and less on the substitution pattern at the aromatic ring. 256 This study is in line with the observation of Silva et al. with d-sargachromenol (51) and its precursor 1,4-benzoquinone sargaquinoic acid; the latter had less inhibitory activity towards LOX-and COX-enzymes. 52 In addition to the natural compounds described above, the anti-inammatory and antidiabetic drug troglitazone exhibits a 6-hydroxy-chromane ring system. Troglitazone was used a PPAR-g-receptor agonist but was withdrawn from the market since it caused hepatotoxicity. 262 Obviously, anti-inammatory activity is enhanced by the occurrence of a 6-hydroxy-chromane and -chromene moiety, respectively.
In conclusion, meroditerpenoids with a functional group (COOH, OH) at the side chain have much higher anti-inammatory activity than the parent chromanols and chromenols, respectively.

Anti-proliferative and cytotoxic activity of chromanols and chromenols
Dietary tocopherols and tocotrienols have been extensively investigated for their cancer-preventive potential in several human intervention trials (reviewed in 263 and 6 ), but widely failed to prove benecial effects. 264 However, in vitro studies with tocopherols and tocotrienols in cell cultures and in vivo studies have shown pronounced anti-neoplastic and anticarcinogenic effects. 265,266 The susceptibility of the cell lines tested for anticarcinogenic activity varied tremendously and makes thus it difficult to compare the compounds discussed in this section. For example, HepG2 liver cells exhibit greater resistance to drugs and toxins compared to other cells lines, since they actively express phase I and II enzymes. As a result, higher IC 50 values are expected for drug resistant cell lines, such as HepG2.
Structure-activity relationship studies revealed that chemical modications at C-6 of the aromatic ring (ethers or esters) magnied the cytotoxic potential of vitamin E compounds. 266,267 In general, drug candidates that were 'redox-silent' at C-6, such as tocopherol-succinate, showed promising results in animal studies. 268 Although most of the redox-silent compounds were chemically synthesized, distinct structure-activity relationships have been derived from these experiments. 266 The studies revealed the importance of three major domains of the chromanols tested: rst, the functional domain (I) that needs to be 'redox silent' to exert the cytotoxic properties. Second, the signaling domain (II) modied by the methylation pattern of the chromanol ring system. Third, the hydrophobic domain (III) that is mostly covered by saturated and unsaturated side chains. 267 Reviewing the structural features of the molecules presented here, we further specify the domains that are relevant for cytotoxicity.
Tocotrienols showed anti-proliferative and pro-apoptotic effects in vitro and in vivo and are in general more potent in the prevention of cancer than tocopherols. 271 Several molecular targets were identied for gand d-tocotrienols (16) and (17) (gand d-tocotrienol), respectively (summarized by 272 ). Induction of mitochondrial apoptosis, demonstrated by activation of caspase-3 and -9, along with modulation of apoptogenic genes such as Bcl-2, Bcl-xl and Bax, respectively, has been observed for most of the tocotrienols tested.
Only recently, tocopherol-and tocotrienol-metabolites were investigated for their anti-carcinogenic activity. 13 0 -Carboxylic acids, including garcinoic acid, induced apoptosis in the lower micromolar range with slight differences depending on their methylation pattern and double bonds in the side chain, respectively. The tocopherol metabolites 13 0 -carboxy-atocopherol (205) and 13 0 -carboxy-d-tocopherol (229) induced caspase-3-dependent apoptosis in human HepG2 liver cells (IC 50 values of 13.5 mM and 6.5 mM, respectively). 39 Similar activities were observed in human THP-1 macrophages, glioma C6, colon carcinoma HCT-116 and colon adenocarcinoma HT-29 cells (Table 2). 38,257,277 The natural product and tocotrienol metabolite garcinoic acid (30) showed similar activities. d-Sargachromenol (51) and fallachromenoic acid (105) were both active in the lower micromolar range. 126,133 Thus, the shi of the carboxylic group at C-15 0 does not affect the pro-apoptotic activity.
Cyclizations of the tocotrienol side chain lead to epitaondiols, strongylophorines and bifurcarenone-derived chromanols. All compounds tested showed moderate to weak anticancerogenic activities (Table 2) Unfortunately, only few data exist for the anti-cancer activities of sesquiterpenes. Paniceins A2 (160) and F2 (161) both inhibited growth of P330, lung adenocarcinoma A549 cells, uveal melanoma MEL20 cells, and colon adenocarcinoma HT-29 cells with IC 50 values of around 15 mM (ref. 195) and riccardiphenol C (146) was not active. 177 Monoterpenes and hemiterpenes both demonstrated medium to low inhibitory activity towards cancer cells (Table 2).
In conclusion, meroditerpenoids exhibited the strongest inhibitory activity towards cancer cells among all meroterpenoids described, especially when a carboxy or more than one hydroxyl group is present at the terminal end of the side chain (Fig. 30).

Discussion
This review describes more than 230 6-hydroxy-chromanols and -chromenols, respectively that were found in terrestrial and marine organisms. Fig. 31a highlights the distribution of meroterpenes within different phylae. Marine organisms, led by brown algae (Phaeophyceae), cover two thirds of the molecules presented in this review, followed by plants and fungi. Interestingly, sponges (porifera) produce 18% of the natural products presented here, mainly cyclic di-and sesqui-terpenes.
Meroditerpenes represent almost two thirds of all compounds discussed and are divided into 63% with linear and 37% with cyclic side chains, respectively (Fig. 31b). The occurrence of sesquiterpenes was dominant in sponges, whereas hemiterpenes were only found in plants and fungi.
During the course of this compilation, the question arose whether or not the stereo-controlled cyclization of toluquinols to a chromane or chromene ring with R-conguration at C-2 occurs exclusively in terrestrial species. The evidence for this process in plants is well documented and the isolation of several cyclases substantiates the biosynthetic step. Marinederived meroterpenes were oen isolated as mixtures of stereoisomers at C-2 and several authors debated the isolation of chrom(e)anols as artefacts of the work-up procedures or as non-enzymatic reaction products within the organism. In addition, the monocyclic 1,4-benzoquinone precursors were isolated in most cases with high yields, whereas toluquinols in plant species occur only in trace amounts and were rarely described. From the 49 diterpenes isolated from plants, 46 (94%) were described with R-conguration. A statistical analysis of chromanols and chromenols from marine species revealed that 73% of chromanols were isolated as R-enantiomers, whereas only 26% of all chromenols show optical activity with R-conguration. In conclusion, we postulate that marine organisms most likely produce chromanols via enzyme-catalyzed cyclization, whereas chromenols may mostly originate from non-enzymatically cyclization or as an artefact during sample work-up. The structural variability of the compounds described in this review is remarkable. Side chain modications by oxidation and/or cyclization occur widely, especially in marine organisms. Cytochrome P 450 enzymes are most likely responsible for the initial oxidation to epoxy-, hydroxy-and carboxy-derivatives, respectively, although the corresponding enzymes were studied only in animal vitamin E metabolism and are not fully understood yet. 248,249 Cyclization of the prenylated side-chain occurs via different pathways. The rst pathway begins with an acid-catalyzed cyclization cascade between C-2-C-7, C-6-C-11 and C-10-C-15 of the sesquiterpenes and diterpene backbone, respectively, that leads to di-or tricyclic 1,4-hydroquinones. This is followed by a second acid-catalyzed formation of the chromane ring as described by Kurata et al (Fig. 20). 186 Several examples for this cyclization, such as chromazoranol (154) or strongylophorines (117)(118)(119)(120)(121)(122)(123)(124)(125)(126)(127)(128)(129)(130), are described above.
With some exceptions, all higher plants produce side chainsaturated tocopherols with the typical methylation pattern a-, b-, g-, and d-, respectively. Next, several algae have the ability to produce tocopherols, although in low yields. 8-Methyl-or desmethyl-tocotrienol moieties were found in most of the structures described from marine organisms. Only three tocopherol-derivatives with a full methylation pattern (a-) were identied in marine organisms, namely marine-derived tocopherol (25) from phytoplankton, a-tocoxylenoxy (108) from the green alga Caulerpa racemosa and chrassumtocopherol from the so coral Lobophytum crissum.
The primary biological function of the side chain modications remains unclear. On the one hand, cytotoxicity, algicidal and anti-macroalgal activity was found for several metabolites. On the other hand, the settling of sea urchins and perna eggs was induced by several compounds. Thus, side chain-modied metabolites are presumably used as chemical protectants or as signalling molecules for intercellular communication or both.
Recent advances in the research on human vitamin E metabolites led us to a comprehensive search for chromanoland chromenol-structures with anti-inammatory and cytotoxic properties (see Tables 1 and 2). The number of structurally related compounds exceeded our expectations. We therefore merged the available information on over 30 compounds and identied structural motives that correspond to high anti-inammatory activities ( Table 1). Most of the compounds described here affected arachidonic acid metabolism and also the synthesis of pro-inammatory cytokines. Inhibition of COX-1 and COX-2 expression, respectively, reduced prostaglandin metabolite formation and inhibition of 5-and/or 12-LOX blocked leukotriene synthesis. Further studies will have to reveal if meroterpenoids have the potential to be developed into anti-inammatory drug candidates.
Cytotoxicity data of approximately 50 compounds were collected ( Table 2). Like the anti-inammatory activities of meroterpenoids, diterpenes showed the strongest activity, led by side chain-modied chromanols. Anti-proliferative and cytotoxic properties were modulated by the presence of hydroxyl and carboxy groups. Activation of caspases-3 and -9, respectively, suggested that most of these compounds induce a mitochondrial death pathway.
Rangasany et al. evaluated the drug-likeness of several natural products isolated from algae and found d-sargachromenol (51) and epitaondiol (79) as good ts to Lipinski's 'Rule of Five'. This rule estimates the potential of a drug candidate based on physio-chemical properties, such as molecular weight, number of hydrogen bond acceptors and donors, and distribution coefficient (log P). 73,141 We screened a series of compounds described in this review (ESI Table 1 †) and found many with good predicted oral bioavailability, based on these calculations which were conducted via Molinspiration WebME editor version 1.16 (http://www.molinspiration.com).
We and others tested several vitamin E metabolites for their biological activity in vitro and in vivo and found them to have anti-bacterial, anti-viral, anti-inammatory and cytotoxic properties (Tables 1 to 3). In general, any modication of the prenyl side chain increased their biological activity.
In this review, we thoroughly described the class of 6hydroxy-chromanols and -chromenols within living nature and summarize their biological properties, in particular their anti-inammatory and anti-carcinogenic potential. Based on the presented evidence, we conclude that the presence of a hydroxyl or carboxy group in the side chain enhances the anti-inammatory activity of natural chromanols and chromenols. With respect to anti-proliferative and anti-cancer activities, we conclude that, among all meroterpenoids described, meroditerpenoids have the strongest inhibitory activity towards cancer cells, in particular when, again, bearing a carboxy or more than one hydroxyl group at the terminal end of the side chain. We therefore propose that the presence of a terminal hydroxyl or carboxy group in the side chain of the long-chain vitamin E metabolites warrants further investigation and might help us to unravel the as yet unknown essential biological function(s) and modes of action of vitamin E in animals.

Conflicts of interest
There are no conicts to declare.