Cyberlipid

 

 

HYDROCARBONS

 

 

These compounds form the simplest form of lipids, they contain only carbon and hydrogen. They may be divided into aliphatic hydrocarbons with a carbon chain which may be linear (normal), branched, saturated (alkanes) or unsaturated (alcenes), cyclic hydrocarbons and carotenoids. Several hydrocarbons may be substituted with oxygen-containing groups.
These organic compounds include :

 

ALKANES, ALKENES

CYCLIC HYDROCARBONS

CAROTENOIDS

 

 

ALKANES – ALKENES

 

These molecules are found mainly in petroleum but living organisms, eukaryotic or prokaryotic, contain frequently hydrocarbons which are directly derived from fatty acids. They are known to be present in living matter since 1892 when Shall C (Chem Ber 1892, 25, 1489) identified undecane in ants, and Etard A (C R Acad Sci Paris 1892, 114, 364) identified eicosane in Bryonia dioica.

Hydrocarbons derived from fatty acids (i.e. alkanes and alkenes) are ubiquitous in plants and insects where they often represent a major part of cuticular waxes and play an essential role in preventing water loss from the organisms to the dry terrestrial environment. In several insects, specific cuticular alkenes also act as sex pheromones. Occurrence of alkanes or alkenes has also been reported in various microorganisms (Ladygina L et al., Process Biochem 2006, 41, 1001). For example, synthesis of hydrocarbons is widespread in cyanobacteria (Coates RC et al., PLoS One 2014, 9:e85140), and it is thought that cyanobacterial alka(e)nes contribute significantly to the hydrocarbon cycle of the upper ocean. It has been demonstrted that several microalgae have the ability to convert C16and C18 fatty acids into alkanes and alkenes by a new, light-dependent pathway (Sorigué D et al., Plant Physiol 2016, 171, 2393). The decarboxylation of fatty acids is initiated through electron abstraction from the fatty acid by the photoexcited FAD with a quantum yield >80%, the enzyme complex was named fatty acid photodecarboxylase, thus it may be useful in light-driven, bio-based production of hydrocarbons (Sorigué D et al., Science 2017, 357(6354):903). Alkanes and alkenes of various chain lengths are important targets for biotechnology as they are major components of gasoline (mainly C5-C9 hydrocarbons), jet fuels (C5-C16), and diesel fuels (C12-C20).

These lipids are distinct from the terpenoid hydrocarbons. They have usually a straight chain of up to about 36 carbon atoms but may also be branched, with one or more methyl groups attached at almost any point of the chain. Usually, the methyl group is near the end of the chain (iso or anteiso). They are either saturated or unsaturated (mono or diunsaturated). In contrast with the diversity of methyl-branched alkanes found in insect species, n-alkanes predominate in plants. Among the least polar components of plant surface lipids hydrocarbons with the odd number carbon chains (C15 up to C33) are predominant.

Allenic hydrocarbons, such as 9,10-tricosadiene, 9,10-pentacosadiene, and 9,10-heptacosadiene were isolated from Australian insects (melolonthine scarab beetles) (Dembitsky VM et al., Prog Lipid Res 2007, 46, 328).
Many microalgae contain the highly unsaturated alkene n-C21:6 formed by decarboxylation of the 22:6n-3 fatty acid (Lee RF et al., Phytochemistry 1971, 10, 593). A few species also contain the n-C21:5 alkene (Volkman et al., Org Geochem 1994, 21, 407). Several microalgae were shown to contain long-chain unsaturated alkenes from 19 to 38 carbon atoms and one to four double bonds (review in Volkman JK et al., Org Geochem 1998, 29, 1163).

Hydrocarbons are found at the outer surface in higher plant leaves. As an example, C27, C29, and C31 n-alkanes are the most abundant (from 11 to 19%) in needle wax of the Pinaceae Picea omorika (Nikolic B et al., Chem Nat Compounds 2009, 45, 697). In general, long chain n-alkane abundances (i.e. n-C25 and above) are typically higher in angiosperm trees and shrubs than in many gymnosperms, and more specifically, conifers (except Araucariaceae, Podocarpaceae, Taxaceae, and the Cupressoideae  and Callitroideae groups within Cupressaceae which have n-alkane concentrations similar to those of angiosperms). The factors that influence the concentration of plant biomarkers and their carbon isotope composition and their use to understand climate, ecosystem, and carbon cycling in the geologic past have been reviewed (Diefendorf AF et al., Org Geochem 2017, 103, 1).

Environmental parameters such as temperature and humidity can affect the composition of higher plant leaf hydrocarbon wax. The abundance and distribution of long-chain n-alkanes in sediments have been proposed as chemical indicators reflecting climate change. Thus, it has been shown that aridity specifically affected the concentration and distribution of n-alkanes in Acacia and Eucalyptus sampled in the North of Australia. Their n-alkane concentration increased by a factor of ten from the sea to the dry center of Australia, but Acacia-alkanes decreased in average chain length towards the arid center of Australia, whereas Eucalyptus average chain length increased under arid conditions. (Hoffmann B et al., Org Geochem 2013, 62, 62).
Field bioassays enabled the discovery of alkanes as bee sex pheromones and orchid attractants. Thus, C21 to C27 alkanes elicited bee pollinator approaches, landings and attempted copulation (Bohman B et al., Curr Opin Plant Biol 2016, 32, 37).

They are also abundant at the outer surface of insects and several marine organism. They are thought to serve as a barrier to water influx in the organism, to act as sex attractants (or anti-aphrodisiacs), to affect the absorption of chemicals and microorganisms. Wild populations of Drosophila melanogaster use several cuticular hydrocarbons (mainly 7,11-heptacosene) as sexual pheromone (Cobb M et al., Anim Behav 1990, 39, 1058). The roles of hydrocarbons in the recognition systems of insects has been reviewed (Singer TL, Amer Zool 1998, 38, 394). The blend of linear and branched hydrocarbons from 22 to 34 carbon atoms found on the cuticle of  various species of the Coleoptera genus Chrysochus has been shown to mediate mate choice and sexual isolation (Petereson MA et al., Chemoecology 2007, 17, 87). The 7-methyltricosane is a male-predominant cuticular hydrocarbon used as a contact pheromone in the western flower thrips Frankliniella occidentalis (Thysanoptera) (Olaniran OA et al., J Chem Ecol 2013, 39, 559).
Several hydrocarbons are produced as alarm pheromones by the Dufour’s gland in the ants (Regnier F E et al., J Insect Physiol 1968, 14, 955). Five hydrocarbons have been described, undecane, tridecane, pentadecane, 2-tridecanone, 2-pentadecanone. During the act of stinging, formic acid and hydrocarbons are discharged simultaneously from these glands in fine droplets. These hydrocarbons act also as spreading agents for formic acid. 9-Tricosene (23 C)  is found in the web of some male spiders (Pholcidae) (Schulz S, J Chem Ecol 2013, 39, 1).

Cuticular hydrocarbons have proved to be useful for identifying insect species and differentiating populations. In combination with cuticular hydrocarbons, isoprenoid soldier defensive secretions have been used in some termite species for chemotaxonomic analyses. Thus, analyses have shown that the hydrocarbon profiles of French populations of subterranean termites, Reticulitermes flavipes, were closer to termite populations from Louisiana than to those from Florida (Perdereau E et al., J Chem Ecol 2010, 36, 1189). In ants (Formica exsecta), the chemical profile has been extensively studied across Europe, demonstrating a hydrocarbon profile, composed mainly of homologous series dominated by three n-alkanes (C23, C25, and C27) and three (Z)-9-alkenes (C23:1, C25:1, and C27:1) (Martin SJ et al., J Chem Ecol 2013, 39, 1415). Only the (Z)-9-alkenes have been shown to act as nest-mate recognition cues, with changes in n-alkanes corresponding with task differences. Similar results have been described in other ants and in honeybees. It has been shown that n-alkanes and (Z)-9-alkenes respond to environmental factors, but often in different ways, indicating that their production is controlled by different genetic pathways. Studies of phenotypic variations in various ant population support the primary role of (Z)-9-alkenes as recognition cues and that of n-alkanes, and other cuticular lipids, as anti-desiccants.
Field bioassays enabled the discovery of alkenes as bee sex pheromones and orchid attractants. Thus, (Z)-9, (Z)-11 and (Z)-12 alkenes (C25, C27, C29) elicited bee pollinator approaches, landings and attempted copulation (Bohman B et al., Curr Opin Plant Biol 2016, 32, 37). Additive bioassays indicated the importance of the alkene double bond position for controlling pollinator preference.

Several hydrocarbons (octane, nonane, dodecane, hexadecane…) belong to aroma compounds which are found in environmental or food systems (see the website Flavornet).

Various hydrocarbons are present in the photosynthetic prokaryotes but in low concentrations. Most species have from 15 to 20 carbon atoms, heptadecane being by far the most predominant in all species. In some species, mono- or di-unsaturated chains (alkenes) were found, in others (Cyanobacteria) methyl-branched alkanes are present.
Several alkenes with 8 or 11 carbon atoms and 3 or 4 double bonds play a role in algae gamete attraction (pheromones) : cystophorene in Cystophora sp, finavarrene in Ascophyllum sp and Sphaerotrichia sp, fucoserratene in the brown seaweed Fucus serratus and in the freshwater diatom Asterionella formosa (Bacillariophyceae).

 

alcenes

During the investigation of marine aroma components in the brown algae Sargassum thunbergii, characteristic volatile hydrocarbons have been detected. Thus, (6Z,9Z,12Z,15Z,18Z)-1,6,9,12,15,18-henicosahexaene and (6Z,9Z,12Z,15Z-1,6,9,12,15-henicosapentaene have been analyzed (Lu SJ et al., J Oleo Sci 2018, 67, 1463). 

Hydrocarbons are also formed as products of fatty acid cleavage during peroxidation processes. Alkanes as well as alkenes appear during hydroperoxide decomposition. 

Long-chain (>C25) n-alkyl hydrocarbons are among the most important biomarkers for reconstructing past environmental and climatic conditions. For example, long-chain n-alkanes are considered biomarkers for terrestrial inputs to remote sediments in the South Pacific of the Southern Ocean through long-range aeolian dust transport and in ArabianSea. Nevertheless, it has been demonstrated that  long-chain n-alkyl lipids can originate from aquatic microbial sources as they are present in Antarctic lakes, where no vascular plants are present (Chen X et al., Org Geochem 2019, 138:103909).

Chlorinated hydrocarbons with more than 15 carbons have been reported in the leaf waxes of halophytic Chenopodiaceae (Grossi V et al., Phytochemistry 2003, 63, 693). Occurrence of long chain chloroalkenes and chloroalkanes with 30 to 36 carbons have been reported in lake sediments from the Galapagos Islands (Zhang Z et al., Org Geochem 2013, 57, 1). The precursor of these long chain lipids remains yet an enigma.

Among hydrocarbons, a variety of forms are described (saturated or unsaturated):

The normal paraffins : their general formula is CH3(CH2)nCH3 (n= 6 – 40 or greater).

Paraffins may have branched chains :

one methyl group (monobranched), iso-branched hydrocarbons (methyl group on the second carbon) or anteiso-branched hydrocarbons (methyl group on the third carbon)
(as below)

 

paraffins

 

Among the almost 1,000 cuticular hydrocarbons present in ant species, about 200 monomethylakanes and 600 dimethylakanes are used for chemical communication (Martin S et al., J Chem Ecol 2009, 35,1151). Odd chain lengths and positions of methyl at odd carbon numbers are far more numerous than even chain-length compounds. That chemical recognition, fundamental in insect societies, is known for over 100 years in ants and was shown to be based on antennal detection of non-volatile compounds found on cuticle (Fielde AM, PNAS 1901, 53, 521). Since 1987, the nest-mate discrimination systems in several ant species are known to be based on hydrocarbons (Bonavita-Cougourdan et al., J Entomol Sci 1987, 22, 1).
In longhorned beetle, Mallodon dasystomus (Coleoptera, Cerambycidae), cuticular hydrocarbon profiles of females contained 13 compounds that were not present in profiles of males. Among the female-specific compounds, two co-dominant methylbranched alkanes, 2-methylhexacosane and 2- methyloctacosane, are contact pheromes and accounted for 17% of the total hydrocarbons (Spikes AE et al., J Chem Ecol 2010, 36, 943).

several methyl groups (multibranched), one for each unit deriving from the isoprene formula : CH2=C(CH3)-CH=CH2. Hydrocarbons formed of isoprene units belong to the large group of terpenes.

This chain type is frequently found in several lipid forms, either isolated or combined with other chemical structures. A series of long-chain methylated alkanes (more than 23 carbon atoms), saturated or with one double bond, were identified in settling particles and surface sediments from Japanese lakes and were shown to be produced by planktonic bacteria being thus useful molecular markers (Fukushima K et al., Org Geochem 2005, 36, 311). Laboratory experiments have demonstrated that n-alkanes up to C35 may be formed in the laboratory under hydrothermal conditions (Fischer-Tropsch-type reactions) from formic acid or oxalic acid (Mccollum TM et al., Orig Life Evol Biosph 1999, 29, 153). These results support the theory of the origin of life in hydrothermal systems.
Methoxyalkanes have been identified on bodies or silk of spiders : 1-methoxy-16,20,24,28-tetramethylhentriacontane and 1-methyl-2,24-dimethyloctacosane (Schulz S, J Chem Ecol 2013, 39, 1).
It must be noticed that highly branched and unsaturated (2-5 double bonds) isoprenoids are widespread components in marine sediments (review by Rowland SJ et al., Marine Envir Res 1990, 30, 191; Belt ST et al., Geochim Cosmochim Acta 2000, 64, 3839). The identification of C25 and even of C30 highly branched isoprenoid alkenes in diatoms (Johns L et al., Org Geochem 1999, 30, 1471) have clearly established that they are the source of these compounds found in sediments.
Among the saturated isoprenoids found in geological sediments and oils, the most frequent are pristane (2,6,10,14-tetramethylpentadecane) and phytane (2,6,10,14-tetramethylhexadecane). Both compounds can be generated diagenetically from the phytol side chain of chlorophyll. Pristane may also derive from the side chain of tocopherols while phytane is also generated by Archaea.

 

pristane, crocetane, phytane, biphytane

 

The widespread use of pristane as a biological marker is related to its structural similarity to phytol and its apparent stability, in connection with inability of microorganisms to carry out its anaerobic destruction. pristane is present in photosynthetic organisms, it has been detected in bacteria, algae, and higher plants. Marine sources of pristane include zooplankton, lobster, fish, sharks, sperm whale. Fossil fuels such as coal and petroleum contain this compound. The stable structure persists even in Precambrian rocks and perhaps in extraterrestrial meteorites. The coexistence of microfossils with pristane and phytane in Precambrian rocks is significant to the paleobotanist. Despite this inertness, pristane can be utilized as the sole source of carbon and energy for growth of a coryneform soil isolate ( McKenna EJ et al., PNAS 1971, 68, 1552).
Crocetane is formed by four isoprene units arranged symmetrically around a tail-to-tail linkage (2,6,11,15-tetramethylhexadecane). It was initially synthesized and named by Karrer et al. (Helv Chim Acta 1930, 13, 707). Crocetane is mainly present in oils and in methane-rich sediments, as it was shown to be produced by microorganisms utilizing methane as their carbon source. 2,6,10,15,19-Pentamethylicosane differs from crocetane by the addition of a single isoprene unit, joined head to tail, at one end of the molecule. This compound is present in methane-rich sediment and is likely produced by anaerobic methanotrophs.
Phytane and biphytane, present in sediments and petroleum, are thought to derive from ether-lipids (archaeol, caldarchaeol) of Archaea, the only organisms known to possess such structures.

The separation of straight chain and branched chain alkanes is efficient on a micro scale using the urea complex formation as described for fatty acids (Xu S et al., Org Geochem 2005, 36, 1334). That efficient method is based on the urea inclusion directly on the TLC plates and successive elutions with two solvents to separate straight and branched alkanes.

One important member of isoprenoid polyenes is squalene (C30H50) which is a metabolic precursor of sterols and steroids and classified into the triterpenoids. It is also a component of sebaceous lipids (12-15% of sebum weight) found on human skin. It consists of 6 isoprene units and contains 6 trans double bonds. It was discovered in 1906 in shark oil (Tsujimoto M, J Soc Chem Ind Jpn, 1906, 9, 953). It was suggested that squalene and its peroxidized derivatives (6 are possible) occurring by UV irradiation have an important role in the occurrence of sunburn, and/or protection from sunburn skin damage (Ohsawa K et al., J Toxicol Sci 1984, 9, 151). Furthermore, it has been suggested that squalene peroxides may play an important part in the pathology of acne, pityriasis versicolor, and skin aging. There is some evidence that squalene reduces colon cancer (Rao et al., Carcinogenesis 1998, 19, 287) and skin cancer (Owen R et al., Food Chem Toxicol 2000, 38, 647). This activity is likely related to its antioxidant effect (Amarowicz R, Eur J Lipid Sci Technol 2009, 111, 411).

 

SQUALENE

 

It must be mentioned that if squalene is found in large quantities (from 0.2 to 0.9 g per Kg) in some fish liver oils (shark), it is also found in olive oil (its content may vary from 1 to 40 mg per Kg) where it is used to detect any adulteration. Other vegetable oils contain only traces of this compound (from 0.02 up to 0.3 mg per Kg). Squalene was also found in the epicuticular wax of fruit (grapefruit) and in the hydrocarbon fraction of wheat. 
Squalene, and its saturated derivative (squalane) present in skin sebum, are largely used in cosmetics. Squalane is obtained by hydrogenation of the squalene pool isolated mainly from olive oil.

A range of C25 highly branched isoprenoid alkenes were discovered in filtered phytoplankton samples from Arctic waters and from sub-Antarctic waters. These alkenes contained 3–5 double bonds and had structures identified previously from analysis of laboratory diatom cultures.They were also identified in diatoms of the genus Rhizosolenia isolated from seawater collected in the South Atlantic (Belt ST et al., Org Geochem 2017, 110, 65).

It has been shown that presqualene diphosphate, intermediate between farnesyl diphosphate and squalene, carries biological activity in human neutrophiles and serves as a negative intracellular signal preventing superoxide anion generation (Levy BD et al., Nature 1997, 389, 985). An inhibition of phosphatidylinositol 3-kinase in the same cells was also demonstrated (Bonnans C et al., J Exp Med 2006, 17, 203, 857). During that signaling step, squalene diphosphate is transformed into the inactive monophosphate species (Fukunaga K et al., J Biol Chem 2006, 281, 9490).

 

presqualene diphosphatePresqualene diphosphate

 


Two homologous series of trimethylalkanes, the 3,7,11-trimethylalkanes (C34H7), C36H74 and C38H78) and the 4,8,12-trimethylalkanes (C35H72, C37H76 and C39H80) have been described as the major constituents of the cuticular alkanes of the ant, Atta colombica (Martin MM et al.,
Tetrahedron 1970, 26, 307
). Each of these structures combines a reduced polyketomethylene chain and a modified isoprenoid chain, and hence combine structural units from two major metabolic pathways. Hydrocarbons of this type have not been previously isolated from natural sources.

Pheromones with an epoxy ring are biosynthesized from unsaturated hydrocarbons by action of epoxidases specific for one specific double bond. In the case of monoepoxides derived from 3,6,9-trienes, all three kinds of epoxydienes (3,4-epoxy- 6,9-dienes, 6,7-epoxy-3,9-dienes, and 9,10-epoxy-3,6-dienes) have been found in female moths, 9,10-epoxy-1,3,6-triene has been identified as a natural pheromone component from two species in Arctiidae, the fall webworm (Hyphantria cunea) (Tóth M et al., Tetrahedron Lett 1989, 30, 3405) and the mulberry tiger moth (Lemyra imparilis) (Ando T et al., Topics Current Chem 2004, 239, 51). 9,10-Epoxy-(3Z,6Z)-1,3,6-henicosatriene has been identified from a pheromone gland of arctiid species, such as Hyphantria cunea (Yamakawa R et al., J Chem Ecol 2012, 38, 1042).

 

CYCLIC HYDROCARBONS

 

Hydrocarbons may be classified into monocyclic and polycyclic species.

Monocyclic hydrocarbons :

Several branched-alkylbenzenes have been described in Archaebacteria such as Thermoplasma and Sulfolobus. They have mostly two methyl groups branched on a saturated chain of 9 to 12 carbon atoms. One of them is shown below.

 

alkyl benzene

Long chain alkyl benzenes and alkyl toluenes are common con- stituents of crude oils and sedimentary organic matter. Among them, phytanyl benzene (and phytanyl toluene) occurs in mudstones from Permian-Triassic Boundary sections from Spitsberg and Greenland), as well as Western Australia. Despite their ambiguous origin, the differences in their distributions indicate that they can be characteristic of specific microbial communities such as Archaea (Grotheer H et al., Org Geochem 2017, 104, 42).

 

Phytanylbenzene

 

After the first hypothesis of a communication system (chemotaxis) by Thuret MG for the fertilization of brown algae, 117 years were needed to know the structure of the first algal pheromone (Müller DG et al., Science 1971, 171, 815). This compound, ectocarpene, is an unsaturated heptacyclic hydrocarbon found in the brown algae Ectocarpus, Adenocystis and Sphacelaria. It belongs to a large group of chemicals named dictyopterenes. That compound has a fruity scent and can be sensed by humans when the female organs start emitting the substance to attract the male gametes.

 

ectocarpene

 

Among the numerous dictyocarpenes, dictyopterene A (trans-1-(trans-1-hexenyl)-2-vinylcyclopropane) is naturally present in marine and freshwater environments and in lipids extracted from several species of brown algae such as Dictyopteris (Phaeophyceae) (Jiittner F et al., Limnol Oceanogr 1984,  29, 1322). Dictyopteris is an important group of marine seaweeds and is widely distributed in tropical, subtropical and temperate regions. This genus is known by its richness in chemicals which are in part the source of its characteristic “ocean smell” (Zatelli GA et al., Revista Brasileira de Farmacognosia 2018, 28, 243).

 

 Dictyopterene A

 

Several heptacyclic compounds similar to ectocarpene play a role of pheromone in marine brown algae, dityotene in Dictyota sp, desmarestene in Desmarestia sp and Cladostephus sp, lamoxirene in Laminaria sp, Alaria sp and many others.

 

alkylbenzene
Heptacyclic compounds from brown algae

 

The C11-hydrocarbon ectocarpene was also detected as component in the odor of ripening mango (Berger RG et al., J Agric Food Chem 1985, 33, 232) but was also shown to be a metabolite in leaves of the Asteraceae Senecio isatideus (Bohlmann F et al., Phytochemistry 1979, 18, 79). Several biosynthetic studies suggest unsaturated fatty acids as precursors of these pheromone hydrocarbons (Pohnert G et al., Nat Prod Rep 2002, 19, 108). A review of hydrocarbon as chemical signals in algal gamete attraction has been released (Boland W, PNAS 1995, 92, 37).
Several parent molecules (linear, tri-, penta- or hexacyclic) with different degrees of unsaturation and chain lengths have been described in various algal species (Pohnert G et al., Nat Prod Rep 2002, 19, 108).

Cuminaldehyde or cuminal (4-isopropylbenzaldehyde) is a natural compound with an isopropyl group substituted in the 4-position. It is a constituent of the essential oils of eucalyptus, myrrh, cassia, and mainly cumin (Cuminum cyminum). It has a pleasant smell and is used commercially in perfumes and other cosmetics.

 

Cuminaldehyde (cuminal)

 

A benzyl cyanide derivative has been described in the butterfly Pieris brassicae ( Andersson J et al., J Chem Ecol 2003, 29, 1489). It functions as an antiaphrodisiac transferred by the male to the female.

 

Benzyl cyanide
Benzyl cyanide

 

Bicyclic hydrocarbons

 

The stilbenes (or stilbenoids) form a group of numerous compounds based on a simple one, stilbene. That compound consists of  two phenyl groups linked by a trans ethene double bond. Its name was derived from the Greek word “stilbos”, which means shining. Stilbene is mainly used in manufacture of dyes and optical brightening agents.

 

stilbene
trans-stilbene

 

Stilbenes, sometimes classed into the polyphenol group, are present in several vegetal sources. Several forms have been described, differentiated by various substitutions and combinations of hydroxyl or alkoxyl groups. Some stilbenes are glycosylated. Thus, 2,3,5,4′-tetrahydroxystilbene 2-O-b-D-glucoside, the major bioactive compound from Polygonum multiforum, can efficiently inhibit the formation of advanced glycation end products (Lv L et al., J Agric Food Chem 2010, 58, 2239).

Diethylstilbestrol, a stilbene derivative, (E)-11,12-diethyl-4,13-stilbenediol, is a nonsteroidal estrogen which was used for a variety of indications, including pregnancy support for women with a history of recurrent miscarriage, hormone therapy for menopausal symptoms and estrogen deficiency in women. Today, it is only used in the treatment of prostate cancer and less commonly breast cancer. It has been demonstrated it has the potential to cause a variety of significant adverse medical complications, including transgenerational effects, and thus it was largely discontinued.

 

Diethylstilbestrol

 


Resveratrol (3,4′,5-trihydroxystilbene) is the most studied because of its presence in grapes and wine and some berries (blueberries, Vaccinium) and its numerous pharmacological properties (anti-cancer, antiviral, neuroprotective, anti-aging, and anti-inflammatory).

 

resveratrol
Resveratrol

 

It has been determined that resveratrol is used by plants as a defensive element. Thus, grape vine attacked by mildew is able to product resveratrol which can be transformed into glycosylated or dimer compounds. The resistance of some cultivars seems to be related to the toxicity of the derivative (Pezet R et al., Physiol Mol Plant Pathol 2004, 65, 269). Similar observations were reported for conifers.

Piceatannol, an analogue and metabolite of resveratrol (4 OH groups instead of 3), is a natural stilbene commonly found in grape skins and wine. Compared to resveratrol, this molecule exhibits superior bioactivities as an inhibitor of COX-1 and 2. Piceatannol is thought to be a potent natural compound with many therapeutic effects, such as the prevention of hypercholesterolemia, arrhythmia, atherosclerosis, angiogenesis, and cardiovascular diseases. It also demonstrates vasorelaxation, antioxidant, and anticancer activities (Seyed M.A. et al., J Agric Food Chem 2016, 64, 725).

Pterostilbene is a methylated derivative (the two hydroxyl group on the left cycle) of resveratrol. Based on animal studies and cultured human cancer cells, it displays anti-cancer (Mak KK et al., Mol Nutr Food Res 2013, 57, 1123), anti-hypercholesterolemia, anti-hypertriglyceridemia properties, and may have also the ability to fight against cognitive decline. This derivative is prfesent in grape and in blueberries (Rimando AM et al., J Agric Food Chem 2013, 52, 4713).

Rhapontigenin, another methylated derivative of resveratrol, was identified in Rheum rhaponticum L. (rhapontic rhubarb), it has been primarily listed as one of the most important bioactive substances of various rhubarb species. It is mainly present as a glycol-conjugated compound (rhaponticin). Its structural characteristics and chemical properties are summarized in a paper (Sun Y et al., Mini Rev Org Chem 2017, 14, 24). Rhaponticin is also recognized as a potent anti-inflammatory component of rhubarb (Kolodziejczyk-Czepas J et al., Phytochem Rev 2019, 18, 1375). which may enhance its health-promoting actions or pharmacological potential.

 

Rhapontigenin


Pharmaceutic industries have developed stilbene derivatives which have estrogenic activity (non-steroidal estrogens) such as diethyl stilbestrol.

Diarylheptanoids belong to a compound group having phenyl rings at 1,7 positions of n-heptane, such as curcumin and several similar analogues found in the rhizomes of the ginger (Curcuma longa) family (Li J et al., J Nat Prod 2010, 73, 1667). Their common structure is shown below.

 

Diarylheptanoid
Diarylheptanoid 

 

Curcumin is the principal diarylheptanoid of the Indian spice turmeric, which is a member of the ginger family (Zingiberaceae).

 

Curcumin
Curcumin

 


That pigment, which gives the yellow color to turmeric (E100), was isolated two centuries ago, and its structure as diferuloylmethane was determined in 1910. Numerous therapeutic activities have been assigned to turmeric for a wide variety of diseases and conditions, they are likely partly related to its strong antioxidant properties (Aggarwal BB et al., Adv Exp Med Biol 2007, 595, 1). 
Plants of the Alnus genus (Betulaceae) have been found to be a valuable source of diarylheptanoids similar to curcumin but with various substituted chemical groups. Some of these compounds have valuable activities against LPS-induced inflammation and could be the source of new anti-inflammatory drugs (Lai YC et al., Phytochemistry 2012, 73, 84).

 

Polycyclic hydrocarbons :

These hydrocarbons, whose only few groups are present in plants, may contain fused rings containing only carbon or heterocycles including foreign atoms such as oxygen, nitrogen, or several others. 

Polycyclic hydrocarbons containing only carbon

Naphthalene is a constituent of Magnolia flowers (Azuma H et al., Phytochemistry 1996, 42, 999). It may function as protection of tissue against chewing insects and it may attract insects to pollinate by the UV absorption of accumulated naphthalene in the floral parts and floral scent.

 

Napthalene
Naphthalene

 

Naphthoquinones are present in the secretion of scent glands of Opiliones (Raspotnig G et al., J Chem Ecol 2010, 36, 158). The two main components which serve chemical defense in these animals are 1,4-naphthoquinone and its methylated derivative 6-methyl-1,4-naphthoquinone.

 


1,4-Naphthoquinone

 

Binaphthyl compounds have been isolated from the fungus (Ascomycetes) Daldinia concentrica (Hashimoto T et al., Chem Pharm Bull 1994, 42, 1528). One of them is shown below.

 

binaphthyl

 

Perylene is a typical polyaromatic hydrocarbon that occurs in many sediments. Possible precursors include binaphthyl compounds derived from fungi, as those cited above, in which case a high abundance of sedimentary perylene might indicate a moist and humid continental climate in the depositional environment (Suzuki N et al., Org Geochem 2010, 41, 234). Perylene has the chemical formula C20H12 and occurrs as a brown solid. It or its derivatives may be carcinogenic, and considered as a dangerous pollutant. Perylene is used as a fluorescent lipid probe for cell membrane cytochemistry. 

 

Perylene
Perylene

 

Several characteristic larger polycyclic aromatic hydrocarbons (PAHs) such as the eight-ring 1,2,3,4,5,6-hexahydrophenanthro[1,10,9,8-opqra]perylene (HHPP) have been isolated from fossil crinoids which contain phenanthroperylene quinone pigments. The diagenetic origin of these molecules has been studied in fossil crinoids (Wolkenstein K, Org Geochem 2019, 136:103892).

 

HHPP

 

Several forms of phenanthrenes are present in in higher plants, mainly in Orchidaceae family but also in Dioscoreaceae, Combretaceae, Euphorbiaceae, Juncaceae and Hepaticae. The original phenanthrene molecule may be substituted in various positions by hydroxyl, methoxyl, methyl and/or prenyl groups. Most of them are monomeric but some dimeric and trimeric forms were described. As an example, the compound below (denthyrsinin) is reported in the orchid species Cymbidium pendulum, Dendrobium spp, Eulophia nuda, Nidema boothii, Scaphyglottis livida, Thunia alba. That compound, as others, displayed potent cytotoxic activities (review in Kovacs et al., Phytochemistry 2008, 69, 1084).

 

phenanthrenes
Denthyrsinin

 

New 9,10-dihydrophenanthrenes and phenanthrenes were isolated from Juncus setchuensis, a plant which has long been regarded as an antipyretic and detumescence agent in traditional Chinese medicine (Wang XY et al., J Nat Prod 2009, 72, 1209). Some of these compounds have shown strong antitumor and antialgal activities.
Many plants producing phenanthrenes are used in traditional medicine, likely in connection with the cytotoxicity, anti-microbial, spasmolytic, anti-allergic, anti-inflammatory activities of the natural phenanthrenes present in these plants.

The anthracene nucleus is present in several compounds detected in plants used in traditional medicine. Thus, anthraquinone is found in several plant species (Aloes), fungi and lichens but also in insects where they play a role of pheromone.

 


Anthraquinone

 

Hydroxyanthracene derivatives are a class of chemical substances naturally occurring in different botanical species and used in food to improve bowel function. EFSA has released advice concluding that hydroxyanthracene derivatives should be considered as genotoxic and carcinogenic unless there are specific data to the contrary. The hydroxyanthracene derivatives considered relevant for this risk assessment were those found in the root and rhizome of Rheum palmatum and/or Rheum officinale and/or their hybrids; leaves or fruits of Cassia senna and/or Cassia angustifolia; bark of Rhamnus frangula, bark of Rhamnus purshianus and in leaves of Aloe barbadensis and/or various Aloespecies, mainly Aloe ferox and its hybrids.

 

Hydroxy anthracene

 

Chrysophanol is a member of the anthraquinone family. Pharmaceutical studies have shown that it exerts a number of biological effects, including anticancer and antimicrobial. The mechanism underlying the anti-inflammatory effects of chrysophanol is likely through the inhibition of caspase-1(Kim SJ et al., Molecules 2010, 15, 6436).

 

Chrysophanol
Chrysophanol

 

Several anthraquinones are considered as bioactive constituents in Cassiae seeds (Chunjuan Y et al., J Ethnopharmacol. 2015, 169, 305). The species the most studied, Cassia obtusifolia belongs to Leguminosae and known as ‘Jue Ming-Zi’ in China, which has been used in adjuvant therapy for various diseases such as hyperlipidemia, diabetes, Alzheimer’s disease, acute liver injury, inflammation, photo-phobia, headache, dizziness and hypertension.

One of these anthraquinones, obtusin, was shown to be a strong inhibitor of human thrombin, thus being  a potential therapeutic strategy for the prevention and treatment of cardiovascular and thrombotic diseases.  

Obtusin from Cassiae seeds

 

Although not included in the living world but obviously derived by combustion of plants, many polycyclic aromatic hydrocarbons (PAHs), such as methylphenanthrene (3 cycles), triphenylene and chrysene (4 cycles), benzopyrene (5 cycles) and the coronene (6 cycles) have been identified in sediments dating from the early Triassic period to more recent times. Retene (1-methyl-7-isopropyl phenanthrene) derives here from the diagenesis of compounds which were abundantly produced by the early Palaeozoic bryophytes in the upper Silurian-lower Devonian period (Romero-Sarmiento MF et al., Org Geochem 2010, 41, 302).
 Some have a structure of terpenes, they are discussed in another chapter. Many others are outside the scope of this work because they obviously come from contamination by petroleum products or their derivatives.

 

Heterocyclic hydrocarbons :

 

Pyran compounds : A saturated ring pyre (a tetrahydropyran), 2,4-dimethyl-5-hexanolide, was shown to be an important and specific trail pheromone in an ant species (Camponotus modoc) (Renyard A et al., J Chem Ecol 2019, 45, 901).

 

2,4-Dimethyl-5-hexanolide

 

Coumarins : the simplest compound of this group is coumarin. Several others are coumarin derivatives by various additions.

 

coumarin
Coumarin

 

It is found in many plants, notably in the tonka bean from a tropical tree of the Fabaceae family (Dipteryx odorata). It is produced also by the Poaceae vanilla grass (Anthoxanthum odoratum) and buffalo grass (Hierochloe odorata), and by a Rubiaceae plant, woodruff (Galium odoratum). All these plants are strongly scented due to the presence of coumarin which has been used in perfumes since 1882 (imitation of vanilla products). Coumarin, used as rodenticide, and extracts from these plants are potential harmful as coumarin is the precursor for several anticoagulants, notably warfarin.

Some coumarin derivatives (phenylpropanoids or phenylpropanoids) are present in various plants. Among them, umbelliferone, aesculetin, herniarin, psoralen and neoflavones. Scopoletin (6-methoxy-7-hydroxycoumarin) is a phytoalexin produced by several Solanaceae, such as tobacco (Nicotania tabacum), which protects plants against virus, bacteria or fungi (Oirdi ME et al., Environ Microbiol 2010, 12, 239).
These compounds are found throughout the plant kingdom, where they give rise to numerous complex molecules. They may provide protection from ultraviolet light, against herbivores and pathogens, and mediation between plant and pollinators.
5-Methylcoumarins isolated and characterised from Clutia lanceolata, a medicinal plant native to sub-Saharan Africa and the Arabian Peninsula, strongly stimulated glucose-triggered release of insulin from β-cells (Ahmed S et al., Phytochemistry 2020, 170, 112213).

Hydrangenol is a dihydroisocoumarin which is present in Hydrangea macrophylla (Hydrangeaceae), in free form or as 8-O-glucoside. It has been used to treat allergic reactions. Several studies have reported that it has also anti-inflammatory, anti-diabetic, and anti-malarial activities. A study reported on the mode of action of hydrangenol as an inhibitor of bladder cancer (Shin SS et al., EXCLI Journal 2018;17:531). It was also suggested that hydrangenol can prevent cutaneous wrinkle formation by reducing matrix metalloproteinase and inflammatory cytokine levels and increasing the expression of moisturizing factors and antioxidant genes (Myung DB et al., Nutrients 2019, 11: 2354).

 

 

Several coumarins with short- or long-chain hydrophobic groups have been described in roots of Angelica dahurica, a well-known traditional Chinese medicine (Wei W et al., Phytochemistry 2016, 123, 58), some of them having potent anti-inflammatory properties.

– Umbelliprenin (7-farnesyloxycoumarin) has attracted the attention of several research groups due to its phytochemical, biological, and pharmacological properties.

 

Umbelliprenin

This oxyprenylated coumarin is commonly found in different plant species such as Ferula, Peucedanum, Seseli, Magydaris, and Ammi but also in some edible fruits and vegetables such as celery (Apium graveolens L.), wild celery (Angelica archangelica L.), and Citrus lemon. Umbelliprenin was shown to exert anti-inflammatory, immunomodulatory, and anticancer activities. A detailed investigation on its chemical stability and its catabolism has been released (Genovese S et al., J Nat Prod 2017, 80, 2424).

Osthole [7-methoxy-8-(3-methylpent-2-enyl)coumarin] is a coumarin derivative found in Cnidium monnieri, a plant used in traditional Chinese medicine to treat skin affections. Osthole was shown to exhibit several biological functions, including antiosteoporotic, antiallergic, anti-inflammatory, and antitumor functions. Recently, it was found that osthole might be a potent antidiabetic agent (Lee W.H. et al., J Agric Food Chem 2011, 59, 12874).

 

Osthole
Osthole

Myristicin is a phenylpropenoid compound present in small amounts in the essential oil of nutmeg and in several members of the carrot family. It is psychoactive, and acts as an anticholinergic agent. It is a precursor for the illicit synthesis of the psychedelic and empathogenic drug MMDA. Raw nutmeg contains 0.2-1.3% myristicin.

 

 

 

Umbelliferone (or 7-hydroxycoumarin) occurs in many familiar plants from the Umbelliferae family such as carrot or coriander but also from other families such the Asteraceae Pilosella officinarum. Umbelliferone absorbs ultraviolet light strongly but despite possible harmful mutagenic properties, is used in sunscreens. An umbelliferone methoxylated derivative, herniarin (7-methoxycoumarin) occurs in the leaves of tha Asteraceae water hemp (Eupatorium ayapana) and in several Herniaria (Caryophyllaceae).

Psoralen (or psoralene) is a furanocoumarin. It is a derivative from umbelliferone by addition of a furan ring. Psoralen has been described in the seeds of the Fabaceae Psoralea corylifolia, but is present in many plants such as several Rutaceae (Ruta, Citrus), Moraceae, Leguminoseae Psoralea, Coronilla) and Apiaceae. Psoralen-rich plants are used in Chinese and Indian medicines and psoralene, due to its UV absorption properties, is used in treatment of psoriasis, eczema, vitiligo and in some cutaneous lymphoma. Psoralen is used in tanning accelerators, but it should be kept in mind that it increases the skin’s sensitivity to light. 

 

psoralene

Psoralene

 

Bergapten is a methoxylated derivative of psoralen (on carbon 5). It is found in bergamot essential oil and in other citrus essential oils. As it has a high phototoxicity, bergapten-free bergamot oil is now used in perfumery. 

Many furanocoumarins are toxic and are produced by plants as a defense mechanism against various types of predators and in human, some of them (bergamottin) are responsible for the “grapefruit juice effect”, in which they affect drug metabolism. Bergamottin is present in the juice but is more concentrated in the essential oil of bergamot. It is a linear furanocoumarins functionalized with a side chain derived from geraniol on the carbon 5 of the central ring. Bergamottin and dihydroxylated derivatives have been found to inhibit the human intestinal cytochrome P450 3A4 isozyme (CYP3A4) involved in the metabolism of some prescribed medications (Edwards DJ et al., Drug Metab Dispos 1996, 24, 1287).
They are also bactericide, fungicide, antiviral and insecticide and in plant they have an important role as inhibitor of germination. 

The pyranonaphthoquinones are a large group of over one hundred natural products primarily isolated from bacteria and fungi, many of which have been found to exhibit antibacterial, antifungal and anticancer properties. The basic structure of the pyranonaphthoquinones is the naphtho[2,3-c]pyran-5,10-dione ring system (see below).

 

 

Pyranonaphthoquinone natural products vary in the substitution of the pyran and aromatic rings, and can possess additional fused ring systems. A review discussed the isolation, biological activity and synthesis of pyranonaphthoquinone natural products (Naysmith BJ et al., Nat Prod Rep 2017, 34, 25), Some derivatives, named ventiloquinones, have been isolated from Ventilago harmandiana (Rhamnacea), a plant used in traditional medicine in Thailand, and have shown potent anti-inflammatory activity (Panthong K et al., Phytochemistry 2020, 169, 112182).
 
Butenolides are modified hydrocarbons with a hetocyclic nucleus of the furan type. The simplest one is 2-furanone.

 

furanone
2-Furanone

 

That compound is characteristic of aroma of Apiacaea (genus Angelica). It can also inhibit the quorum sensing in bacteria. Several analogues or derivatives of 2-furanone are present in fruit aroma : 4-methoxy-2,5-dimethyl-3-furanone in pineapple and 4-hydroxy-2,5-dimethyl-3-furanone (furaneol) in strawberry and tomato. Furaneol is present in roasted peanut and tobacco smoke and 3,5,5’-trimethyl-2-furanone appears in roasted in hazel-nut. Some other derivatives are active as sexual pheromones in insects.

 

furaneol
Furaneol

 

Several derivatives of 2-furanone with a polyacetylenic side chain have been isolated from Asteraceae (Vernonia scorpioides) and displayed antiherpeetic activities (Pollo LAE et al., Phytochemistry 2013, 95, 375).
A review of the naturally occuring furanones may be consulted (Slaughter JC et al., Biol Rev 1999, 74, 259)

Karrikins are a butenolide family of plant growth regulators found in smoke derived from burning plant material (mainly cellulose) (Flematti GR et al., Science 2004, 305, 977). These compounds are derived from 2-furanone by condensation with a pyrane group. They act as a key germination trigger for many species from fire-prone plants. It was later shown that karrikins act by a mechanism requiring gibberellic acid synthesis and light (Plant Physiol 2009, 149, 863). The most active karrikin is 3-methyl-2H-furo[2,3-c]pyran-2-one (see below). Due to the fact that it has an effect at extremely low concentrations (as low as 1 nM), it has potential as an important agronomic and horticultural chemical. A parent compound (3,4,5-trimethylfuran-2-one) has been also isolated from plant-derived smoke, but it has inversely a germination inhibiting property (Light ME et al., J Nat Prod 2010, 73, 267). The interaction of these compounds may have important ecological implications.

 

karrikin
Karrikin

 

Brominated furanones are produced by Delisea pulchra, a marine alga endemic to the south-eastern coast of Australia. Some of which have strong inhibitory activity against fouling organisms and herbivores (de Nys R et al., Tetrahedron 1993, 49, 11213). Additionally, furanones have specific effects on colonization phenotypes of marine bacteria at concentrations found on the surface of the alga (Maximilien R et al., Aquat Microb Ecol 1998, 15, 233). Manefield M et al. have shown that these compounds inhibit acylated homoserine lactone-mediated gene expression in Escherichia coli (Manefield M et al, Microbiology 1999, 145, 283).

 

Quinolines, alkylquinolines and alkylquinolones

The core of quinolines is the 1-azanaphthalene nucleus. The simplest one is quinolin. That compound was first extracted in 1834 by a German chemist FF Runge, from coal tar. Quinoline is used to make dyes, to prepare hydroxyquinoline derivatives and niacin (nicotinic acid or vitamin B3).

 


Quinolin

 

That compound is rarely found in living material but is present, as its derivatives, in the plant Rutales and even in some insects. Quinolin is also present in some insects, as phasmids, where it plays a role against predators. Several of its derivatives are useful in diverse applications. As examples, quinine and 4-hydroxy-2-alkylquinoline are involved in antibiotic resistance.

The bacteria Pseudomonas aeruginosa was shown to produce, besides an alkyl homoserine lactone, new cell-to-cell signal molecules (quorum sensing system). This molecule was determined to have a 4-quinolone base structure with an alkyl chain (
2-heptyl-3-hydroxy-4-quinolone) and therefore has been designated as the Pseudomonas quinolone signal (Pesci E et al., Proc Natl Acad Sci 1999, 96, 11229). Similar compounds have been previously described for their antimicrobial activities (Hays EE et al., J Biol Chem 1945, 149, 725). It was found that this molecule controlled the expression of genes encoding for the major virulence factors. The maximal quinolone production occurs at the end of the exponential growth phase, supporting the hypothesis that it acts as a secondary regulatory signal for a subset of quorum sensing-controlled genes. 

 

2-Heptyl-3-hydroxy-4-quinolone
2-Heptyl-3-hydroxy-4-quinolone

 

Later, another analogue was isolated from the same bacteria, 3,4-dihydroxy-2-heptylquinoline, which could be the direct precursor of the previous quinolone and, likely, the message molecule involved in cell-to-cell communication (Deziel E et al., Proc Natl Acad Sci 2004, 101, 1339). A review of that type of quorum sensing may be read for further information (Dubern JF et al., Mol Biosyst 2008, 4, 882).
In contrast with Pseudomonas quinolone, Burkholderia spp produce several hydroxy-quinolines with a methyl group in position 3 and a hydroxyl group in position 4 and various alkyl chains (Vial L et al., J Bacteriol 2008, 190, 5339). It was later shown that these quorum-sensing signals control the bacterial synthesis of antibiotics (Duerkop BA et al., J Bacteriol 2009, 191, 3909).

A new quinoline-2-carboxylic acid, 4-hydroxy-6-methoxyquinoline-2-carboxylic acid (6-methoxy-kynurenic acid), has been isolated from Ephedra pachyclada. Kynurenic and 6-hydroxykynurenic acids, previously reported from plants, were also isolated from Ephedra (Starratt AN et al., Phytochemistry 1996, 42, 1477).

Compounds related to quinolines, the benzoxazinones, are present as inactive glucosides (phytoanticipines), mainly in Gramineae (rye, wheat, corn) (Niemeyer HM, Phytochemistry 1988, 27, 3349). They are sometimes described as cyclic hydroxamic acids. In rye, the principal compound is the glucoside of DIBOA (2,4-dihydroxy-1,4-benzoxazin-3-one), in wheat and corn, it is the glucoside of the methoxylated form, DIMBOA (2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one). 

 

benzoxazinones
Benzoxazinones 
(R = OCH3 : DIMBOA , R = H : DIBOA)

 

These glucosides are hydrolyzed during the plant infection by fungi or bacteria or after insect attacks. The benzoxazinones aglycones, and their breakdown products (phenoxazinones, acetamides, and malonamic acids), behave like antifungal, antibacterial and also insecticidal substances (allelopathy). These aspects of allelopathy have been reviewed for the sustainable weed control in rye fields (Schulz M et al., J Chem Ecol 2013, 39, 154).
Investigations in genetic engineering are performed to induce the production of these protective agents in other crop plants.

Berberine is a molecule belonging to the group of benzylisoquinoline alkaloids found in such plants as Berberis, Mahonia, Hydrastis, Xanthorhiza, Phellodendron, Coptis, and Eschscholzia. Due to berberine’s strong yellow color, Berberis species were used to dye wool, leather, and wood. Under ultraviolet light, berberine shows a strong yellow fluorescence, so it is useful in histology and biochemistry to detect lipids on chromatograms.

 

Berberin

 

Berberine was used in China as a folk medicine and is still a common over-the-counter medication for gastrointestinal infection in China. Studies have been conducted to determine if berberine may affect diabetes. Some research has shown that it may be used against some Staphylococcus aureus infection or diarrhea caused by enterotoxigenic E. coli. Recently, it has been reported that berberine helps in reducing cholesterol and lipid accumulations in both the plasma and in the liver (Doggrell SA, Expert Opin Investig Drugs 2005, 14, 683).

Unfortunately, there is insufficient evidence to conclude that berberine is safe or effective for any condition.

 

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