HYDROXY ACIDS

The hydroxyl group(s) may occur at various positions in the carbon chain which can be saturated or monoenoic. 
Some polyhydroxy fatty acids are also known, which are most frequently produced by lipoxygenase  activities, as for several mono-hydroxylated fatty acids. 
In some bacteria, complex hydroxy, branched-chain fatty acids (mycolic acids) are described. 

MONOHYDROXY FATTY ACIDS

a-Hydroxy acids or 2-hydroxy acids are found in plants (chain from 12 up to 24 carbon atoms) and in animal wool waxes, skin lipids and specialized tissues, mainly in brain. 
2-Hydroxylinolenic acid was reported at a level of 13% in the seed oil  of the Labiateae Thymus vulgaris (Smith CR et al., Lipids 1969, 4, 9). Along with the previous one, 2-hydroxylinoleic and 2-hydroxyoleic were detected in another Labiateae Salvia nilotica (Bohannon MB et al., Lipids, 1975, 10, 703).
 2-Hydroxytetracosanoic acid (cerebronic acid) and 2-hydroxy-15-tetracosenoic acid (hydroxynervonic acid) are constituents of the ceramide part of cerebrosides (glycosphingolipides found mainly in nervous tissue and in little amount in plants). 

The testis and spermatozoa of boar and rat contain sphingomyelin with 2-hydroxylated n-6 tetra- and pentaenoic acids with very long carbon chain (up to 34 carbon atoms) (Robinson BS et al., J Biol Chem 1992, 267, 1746). It has been postulated that these lipids play a role in reproduction.

The analysis of long-chain hydroxylated fatty acids in ancient ceramics or shells enables to identify the origin of these deposits. Thus, 13,14-dihydroxydocosanoic acid and 11,12-dihydroxyeicosanoic acid, derived from erucic acid (C22:1) and gondoic acid (C20:1) were shown to be  biomarkers for seed oil from Brassicaceae plants such as rapeseed (Brassica napus) or radish (Raphanus sativus) (Romanus K et al., Anal Bioanal Chem 2008, 390, 783).

A large variety of bacteria are able to synthesize polyesters (polyhydroxyalkanoates) forming linear chains of esterified 3-hydroxy acids (Kim YP et al., Adv Biochem Eng Biotechnol 2001, 71, 51). More than 90 different monomer units have been identifed as constituents of polyhydroxyalkanoates in various bacteria, but only a few members  include poly(3-hydroxybutyrate) or poly(3-hydroxybutyrate-co-3-hydroxyvalerate. They are sometimes, but erroneously, considered to be a carbohydrate, but their solubility characteristics are those of a lipid.

 Poly(3-hydroxybutyrate) is the most widespread and best characterized lipid polymer. These polyesters accumulate as intracellular inclusions and act as a carbon and energy reserve. They are produced by some bacteria when they have extra energy, then used as an energy source when needed. They have a great industrial interest because of their plastic and elastomer properties and as a source of biodegradable polymers for low-value commodity products. Their synthesis in crop plants would allow an efficient large-scale production which may lead to new substitutes for petroleum-derived plastics (Rezzonico E et al., Phytochemistry Rev 2002, 1, 87). Genetic engineering has been done to transfer the polymer-making capacity to Escherischia coli and to higher plants. It is theoretically possible to modify starch forming plants (such as potatoes) to grow these polymers.

b-Hydroxy acids or 3-hydroxy acids occur in some bacterial lipids. 

w-Hydroxy acids have their hydroxyl group at the methyl end of the carbon chain and can result in special glycerides with more than three acyl groups through acylation of one or more hydroxyl groups (ergot, Lesquerella and kamala oils). They participate also in the structure of suberin, a lipid polyester present in plant cell walls, and of cutin, a lipid polyester which is a component of the plant cuticle. After experimental depolymerization, monomers and oligomers containing glycerol are esterified by several hydroacids. The most frequent w-hydroxy acids were found to be C16, C:18, C18:1, C18:2 in cutin and C18 to C24 in suberin (Graca J et al., Chem Phys Lipids 2006, 144, 96; Pollard M et al., Tr Plant Sci 2008, 13, 236). In lipid polyesters extracted from Arabidopsis and Brassica seeds, w-hydroxy acids with 16 up to 26 carbon atoms were described (Molina I et al., Phytochemistry 2006, 67, 2597).
w-Hydroxy acids are the main building blocks of algaenan, the highly cross-linked constituent of the cell walls of green algae (Blokker P et al., Phytochemistry 1998, 49, 691). These ester-bound fatty acids are unsaturated, the monoene (n-9) having a C30, C32 or C34 carbon chain and the diene (n-18 and n-19) having a C30 and C32 carbon chain. 

10-hydroxy acids occur in the royal jelly of nurse bees (Apis mellifera). trans 10-Hydroxy-2-decenoic acid is considered as the genuine fatty compound of royal jelly (about 50 % of the total fatty acids) (Bloodworth BC, J AOAC Int 1995, 78, 1019), other hydroxylated fatty acids (10-hydroxydecanoic acid and 9-10-hydroxy-2-decenoic acid) were also detected. These components which are excreted in the salivary glands of bees are said to give specific therapeutic properties to royal jelly such as skin protection, bactericide, anti-inflammatory action, immuno-regulation and anti-cancer activities. Several parent molecules have been described in the royal jelly (Noda N et al., Lipids 2005, 40, 833). They include various hydroxy acids, a diacid, and mono- and diesters of 10-hydroxy-2-decenoic acid in which the hydroxyl group is esterified by another fatty acid unit (estolide-like molecules). In addition, a phosphorylated derivative was also detected (2E-decenoic acid 10-phosphate) . 

Different methods have been described for determination of 10-HDA in royal jelly, including HPLC and gas chromatography. The report of a study using HPLC and UV detection after ultrasound-assisted extraction may be consulted for literature review and technical aspects (Zhou J et al., Chromatographia 2007, 66, 185).

Among the 12-hydroxy acids, the most abundant is ricinoleic acid (12-hydroxy-9-octadecenoic acid) which characterizes castor oil (from Ricinus communis). It was discovered in 1848 (Saalmüller L, Ann 1848, 64, 108). Goldsobel AG (Ber 1894, 27, 3121) showed that ricinoleic acid has the actual molecular structure. This acid is the only one hydroxylated fatty acid used in oleochemical industry. The seed oils of Jatropha gossypifolia and Hevea brasiliensis (Euphorbiaceae living in South America and India) were found to contain high content of ricinoleic acid (about 18%). 

While known chiefly as a purgative, few decades ago, this fatty acid affords now a wide range of reactions enabling the formation of several derivatives. These chemicals are on a par with petrochemical products for use in several industrial applications. Castor oil and its derivatives are used in food (additive), textile (surfactants, pigment wetting agents), paper (defoamer, water proofing additive), plastics (Nylon-11, polyamide resin known as Rilsan used for coating metals, plasticizers, coupling agents), perfumes and cosmetics (emulsifiers, deodorant), electronics (capacitor fluids, polyurethane and polyamide resins), pharmaceuticals, paints, inks, adhesives and lubricants. The production of conjugated linoleic acid by dehydration and isomerization of ricinoleic acid has been described (Villeneuve P et al., JAOCS 2005, 82, 261).
Castor oil can be reacted with sulfuric acid to make Turkey-Red Oil, the first synthetic detergent or surfactant after ordinary soap, a predecessor to sodium lauryl sulfate. These properties are the result of the sulfonation of ricinoleic acid. Turkey-Red Oil is also used in the dyeing of cotton texture.
The limited amount of castor oil as natural source of ricinoleic acid has led chemists to develop suitable processes for the preparation of hydroxy fatty acids from commercial plant oils (Dahlke B et al., JAOCS 1995, 72, 349).

A fatty acid isomeric with ricinoleic acid, 9-hydroxy-12c-octadecenoic acid, has been shown to be of general occurrence (between 9 and 15%) in the seed oils of the genus Strophantus (Apocynaceae) (Gunstone FD et al., J Sci Food Agric 1959, 10, 522) but was also found in Holarrhena, Nerium and Wrightia of the same family. This fatty acid was named strophantus acid.

As castor seed production presents some problems (toxicity of the seed, allergic reactions), Lesquerella species were proposed as a valuable source in the USA (up to 70% in the oil) of ricinoleic acid but also of lesquerolic acid, the C20 homologue of ricinoleic acid (14-hydroxy-11-eicosenoic acid). In these species, two other hydroxylated fatty acids are found : densipolic acid (12-hydroxy-9,15-octadecadienoic acid) and auricolic acid (14-hydroxy-11,17-eicosadienoic acid) (Smith CR et al., J Org Chem 1962, 27, 3112).

9-Hydroxyacid : another unusual hydroxylated fatty acid which may have many potential oleochemical applications has been discovered in munch seed oil (Dimorphotheca pluvialis) : b-dimorphecolic acid (9-hydroxy,10t,12t-18:2) (Smith CR et al., J Am Chem Soc 1960, 82, 1417). This compound which is also a conjugated diene seems to be a versatile raw material for applications in chemical, pharmaceutical, flavor and fragrance industries since it can be readily dehydrated to a mixture of conjugated triene acids. The 10t12c form of the 9-hydroxy-18:2 (isomeric with dimorphecolic acid) is present in the seed oil of Xeranthemum annuum, Dimorphotheca, Tragopogon, Tagetes, Bidens and Cosmos. This compound was shown to be a partial agonist at PGEl and PGD2 receptors on human platelets (Henry DY et al., Eur J Biochem 1987, 170, 389).
Dimorphecolic acid has been isolated in relatively pure state by supercritical carbon dioxide extraction of munch seed oil (Cuperus FP et al., JAOCS 1996, 73, 1675).
Another isomeric form of dimorphecolic acid, coriolic acid (13-hydroxy-9c,11t-octadecadienoic acid), was reported to be present at high level (70%) in the seed oil of a Coriaraceae Coriaria myrtifolia (Hanseen KS et al., Acta Chem Scand 1967, 21, 301) but also in a Polygonaceae Monnina emerginata (30%) (Phillips BE et al., Biochim Biophys Acta 1970, 210, 353). 

18-Hydroxy acid : kamlolenic acid with the following structure, 18-hydroxy, 9c, 11t, 13t-18:3, is found in kamala oil, a product extracted from the seeds of Kamala tree  (Mallotus phillipinensis, Euphorbiaceae) (Calderwood RC et al., J Sci Food Agric 1954, 5, 382). The kamala oil can be used as a substitute for tung oil, obtained from Aleurites spp., in the production of rapid-drying paints and varnishes. The seed oil is also used as a fixative in cosmetic preparations. The oil is also used as a fixative in cosmetic preparations and for coloring foodstuffs and beverages. 

Very-long-chain fatty acids (C28–C34) containing a hydroxy group at the n-18 position have been identified in the microalgae from the genus Nannochloropsis (Gelin F et al., Phytochemistry, 1997, 45, 641). That constant position likely indicates that the series results from chain-elongation of a particular hydroxy fatty acid. 

Unsaturated oils can contain small amounts of hydroxy derivatives on storage, probably through enzymatic and/or non-enzymatic oxidation.

A wide range of hydroxylated fatty acids is found in sediments but unfortunately these compounds have received little attention from organic geochemists. Long-chain up to C24 and a- and b-monohydroxy acids were observed in a 5000 year-old lacustrine sediment from the English Lake district (Eglinton G et al., Tetrahedron 1968, 24, 5929), and were attributed to microbial oxidation of monocarboxylic fatty acids.

Analytical works on the seed oil of Ongokea gore (Olacaceae) have demonstrated the existence of a variety of hydroxylated diynoic acids (review in Badami RC et al., Prog Lipid Res 1981, 19, 119). Some of them have no other double bond as 8-hydroxyoctadeca-9,11-diynoic acid, others have in addition one double bond as isanolic acid or two double bonds as 8-hydroxyoctadeca-13,17-dien-9,11-diynoic acid. 

POLYHYDROXY FATTY ACIDS

A long-chain dihydroxy fatty acid has been found in an Euphorbiaceae Baliospermum axillare seed oil and characterized as 11,13-dihydroxy-tetracos-9t-enoic acid (Husain S et al., Phytochemistry 1980, 19, 75). It was named axillarenic acid.
Two dihydroxy fatty acids have been isolated from floral oils produced by various flowers (Mariza R et al., J Chem Ecol 2007, 33, 1421). These fatty acids (3,7-dihydroxy-eicosanoic and docosanoic acids) were named tetrapedic acids. One of them (3,7-dihydroxy-docosanoic acid) may be di-acetylated, and was named byrsonic acid. These fatty acids were also found acylating a mono-acylated glycerol molecule. These oily compounds are produced by special flower devices (elaiophores) and attract pollinating insects.
Two dihydroxy fatty acids, 15,16-dihydroxy-30:0 and 16,17-dihydroxy-33:0, have also been identified from the acid hydrolysis of the cell residue of Nannochloropsis.

The seed oil of Cardamine impatiens (Cruciferae, Brassicaceae) contains a series of long-chain vicinal dihydroxy fatty acids which make up of about 25% of the oil (Mikolajczak KL et al., JAOCS 1965, 42, 939). This peculiar structure remains unique in phytochemistry. One example with a C18 chain is shown below. Other members of the series have a C20, C22 or a C24 chain but with the hydroxyl groups remaining at the same position with respect to the terminal methyl group. 9,10-dihydroxyoctadecanoic acid was also found at 11% in the seed oil of a Rutaceae Feronia elephantum (Badami RC et al., J Oil Tech Assoc India 1972, 4, 59).

An isomeric form of the previous one but not with vicinal hydroxy groups has been described in the seed oil of a Rutaceae Peganium harmala, 9,14-dihydroxyoctadecanoic acid (Ahmad I et al., Phytochemistry 1977, 16, 1761). 
Cutin is known to be a polyester polymer which is insoluble and can be hydrolyzed mainly into a mixture of long-chain C16 and C18 w-hydroxyacids having frequently hydroxyl or epoxy groups in secondary positions. Phellonic acic, 22-hydroxydocosanoic acid, was also detected in cork suberin. Several studies led to tentative models of cutin based on the inter-esterification of w-hydroxyacids, both head-to-tail in a linear form , and cross-linked via the secondary hydroxyls. In some plant species cutin, 16-carbon dihydroxy and 18-carbon trihydroxyacids were detected (Graca J et al., Phytochemistry 2002, 61, 205).   
Suberin is a similar type of polyester polymer which contains among other fatty acids a,w-diacids as  long-chain monomers esterifying glycerol (Graca J et al., Chem Phys Lipids 2006, 144, 96). Moreover, these diacids (C16, C18, C18:1, and C22) are further esterified by another glycerol molecule or by a hydroxylated fatty acid.

A trihydroxylated oxo-fatty acid, phaseolic acid (2-oxo-5,8,12-trihydroxydodecanoic acid) was shown to stimulate elongation in pea stem segments (Farmer EE, Plant Mol Biol 1994, 26, 1426). This compounds is reminiscent of animal lipoxins.
The 9,10,18-trihydroxyoctadecanoic acid (phloionolic acid) was isolated from the seed oil of Chamaepeuce afra (Mikolajczak KL et al., Lipids 1967, 2, 261) but was also recognized as an important constituent of cork suberin (Holloway PJ, Chem Phys Lipids 1972, 9, 158). 

A monounsaturated derivative of phloionolic acid was also detected in some seed oil.
Higher plant cutin and suberin can also be a significant source of esterified C16-C22 a-, b-, and w-monohydroxy and C16 and C18 polyhydroxylated fatty acids in sediments (Cardoso JN et al.,Geochim  Cosmochim Acta 1983, 47, 723).

Estolides are dimers formed by a normal fatty acid esterifying a hydroxy fatty acid. They are found mainly in some special triglycerides where they acylate the sn-3 position and formed estolide tetraester triglyceride. They are found in seed oil from Euphorbiaceae. A hydroxy allenic acid (8-hydroxy-5,6-octadienoic acid) was described in an estolide from Sebastiana commersoniana (Spitzer V. et al. Lipids 1997, 32, 549). The w-hydroxyl group was shown to be acylated by a conjugated diene with 10 carbon atoms. 

The allenic acid was shown to have antifungal properties (Ohigashi H et al Agr Biol Chem 1972, 36, 1399), the triglyceride being not recommended for animal diet. 

Estolides are now synthesized from vegetal oils and are used as ingredients in various industrial fields. Thus, these new functional fluids have a rapidly growing importance in cosmetics, coatings, and biodegradable lubricants.

 They are largely synthesized from oleic acid warmed with perchloric or sulfuric acid (Cermak SC et al. JAOCS 2001, 78, 557). The average number of fatty acid units added to the first base fatty acid (named "estolide number") varied as a function of reaction temperature. The secondary ester linkages are more resistant to hydrolysis than those of triglycerides, and the unique structure of the estolide results in materials having far superior physical properties than mineral oils and vegetable and petroleum-based oils. They are said to improve intra-fiber moisture retention, to restore elasticity, and prevent mechanical damage. In skin care systems, they provide significant moisturization benefits. 
Estolides made from vegetal oils have a good oxidative stability and low-temperature properties. Oxidative stability may be improved in removing the unsaturation of oleic acid and the low-temperature performance may be improved in using oleic acid and various short or middle-chain saturated fatty acids (lauric or myristic acid, coconut oil). Other chemical developments are in progress to obtain molecules with required functional fluid conditions (Cermak S et al., Inform 2004, 15, 515).
The analysis of these compounds may be effected by a combination of gel permeation chromatography, TLC, and gas chromatography (Fehling E, JAOCS 1995, 72, 355).

Lipoxygenase activities give rise to important hydroxylated derivatives mainly from arachidonic acid. Lipoxygenation of 20:4(n-6) results in the formation of a variety of mono- and dihydroxy derivatives. The monohydroxy derivatives consist of the positional isomers 5-hydroxy-20:4, 12-hydroxy-20:4 and 15-hydroxy-20:4. The dihydroxy derivatives include products arising from 5- or 15-lipoxygenation. Double lipoxygenation of  20:4(n-6) at c5 or c12 position give rise to 5,12-diHETE.
In addition to 20:4(n-6), linoleic acid (18:2n-6) is also a substrate for lipoxygenases. In leucocytes (neutrophiles), 13-hydroxy-18:2 (coriolic acid) is produced through enzymatic activity. It appears to be also produced by vascular endothelial cells where it prevents platelet attachment and has vasoconstrictor activity.
Allium species (onion and garlic) which are known as folk medicine for the treatment of atherosclerosis and some ulcers, were shown to be rich in two trihydroxylated derivatives of 18:2(n-6) : 9,10,13- and 9,12,13-trihydroxy octadecenoic acids. Furthermore, it was shown that these products have PGE-like activity in in vitro bio-assay tests (Claeys M et al., Prog Lipid Res 1986, 25, 53). Similar products were isolated from roots of Bryone ala, used also for similar medicinal purposes as onion (Panossian AG et al., J Med Plant Res 1983, 47, 17).

Lipoxygenase derivatives of docosahexaenoic acid (DHA), named docosanoids, are known to be formed (mainly 11-OH-DHA) in retinal cells (Bazan N et al., Biochem Biophys Res Comm 1984, 125, 741), but their exact structure and bioactivity were revealed only after 2002.
Thus, lipidomic analysis of exudates, vascular, leukocytes and neural cells treated with aspirin have revealed hat DHA was converted into 17R-hydroxy series of dihydroxy- and trihydroxy-docosanoids termed "resolvins" (formed during the resolution phase of acute inflammatory response) which were able to counter proinflammation signals (Serhan CN et al., J Exp Med 2002, 196, 1025; Serhan CN et al., Prost Lipid Med 2004, 73, 155).

On another hand, brain ischemia was shown to induce a release of DHA from membrane phospholipids which then generates via enzymatic oxygenations novel derivatives named "docosatrienes".
The main member of the series was 10,17S-docosatriene which was proved to be a potent regulator of inflammation (Marcheselli VL et al., J Biol Chem 2003, 278, 43807).

The biosynthetic pathway of that DHA derivative in retinal pigment cells and its protective effects from apoptosis induced by an oxidative stress were reported (Mukherjee PK et al., PNAS 2004, 101, 8491). Moreover, that dihydroxy-containing DHA derivative was termed "neuroprotectin". These compounds may be the basis of new therapeutic approaches to enhance photoreceptor survival in retinal degenerations.
Besides 10,17S-docosatriene, the analogue compound 7,17S-docosatriene was shown to be produced during aerobic oxidation of DHA by soybean lipoxygenase (Butovich IA et al., J Lipid Res 2006, 47, 2462). Enzymatic investigations suggest that these compounds might have anti-inflammatory and anticancer activities, which could be exerted, at least in part, through direct inhibition of 5- and 15 lipoxygenase.

One neuroprotectin and several resolvins have been shown to be biosynthesized by isolated trout brain cells providing the first evidence for the conservation of these structures from fish to humans as chemical signals in diverse biological systems (Hong S et al., Prost Lipid Med 2005, 78, 107).

Vascular endothelial cells treated with aspirin was shown to convert eicosapentaenoic acid (EPA) into an intermediate product which gives a bioactive compound 5,12,18R-trihydroxy-EPE (resolvin E1).

This resolvin was shown to be a potent regulator of PMN cells and inflammation (Serhan CN et al., Prost Lipid Med 2004, 73, 155).
A comprehensive review of the metabolism and properties of resolvins, docosatrienes and neuroprotectins may be consulted (Serhan CN et al., Lipids 2004, 39, 1125).

Hypoxilins, hydroxy-epoxy derivatives of arachidonic acid are described with lipoxygenase products.

SULFUR CONTAINING FATTY ACIDS

Sulfur-substituted fatty acid analogues (thia fatty acids) are actively synthesized as they are reported to have important pharmacological properties (antiatherosclerosis and antioxidant).
They can have a variable number of carbon atoms and the sulfur atom in different position (3-thia or 4-thia).
The most commonly 3-thia fatty acids studied are presently:
dodeca thia acetic acid CH₃-(CH₂)₁₁-S-CH₂-COOH
tetradeca thia acetic acid CH₃-(CH₂)₁₃-S-CH₂-COOH
These fatty acid derivatives are reported to have triglyceride and cholesterol lowering effects in animal models (Skrede S et al., Biochim Biophys Acta 1997, 1344, 115).

FATTY ACID AMIDES

These compounds are found in nature, but are seldom encountered in fats and oils. As many other nitrogen derivatives of fatty acids (amino acids, hydrazides, acid azides, nitriles, isocyanates, amines), they are of considerable interest and economic importance and have, therefore, been the object of much research and industrial attention mainly in the 50s. They are now produced on a large scale, their chemical features resulting in high surface activities. These compounds are useful as fiber lubricants, detergents, flotation agents, textile softeners, antistatic agents, wax additives, and plasticizers.

The simple amides may be considered to be products resulting from replacement of the hydroxyl of the carboxyl group  with an amino group, RCONH₂. The first preparation of  stearamide was made in 1882 (Hofmann AW, Ber. 1882, 15, 977) using the procedure of thermal dehydration of ammonium salts discovered by the famous French chemist Dumas (Dumas J, Ann chim phys 1830, 44, 29).

Fatty acid alkanolamides are industrially produced from fatty acids (largely from coconut oil) and alkanolamines, such as ethanolamine, by heating at about 150°C for 6-12 h (Feairheller SH et al., JAOCS 1994, 71, 863).

R-CO-NH-CH₂-CH₂-OH

These compound have a broad spectrum of uses, e.g., in shampoos, detergents, cosmetics, lubricants, foam control agents, and water repellents (Sanders HL, JAOCS 1958, 35, 548).

Simple amides of fatty acids (alkylamides) were shown to be very potent bio-effectors. For example, in chicken chorioallantoid membrane and rat cornea, it was shown that amide of 13-cis-docosenoic acid (erucamide) discovered in the bovine mesentery is an angiogenic factor (Wakamatsu K et al., Biochem. Biophys. Res. Commun., 1990, 168,423). Angiogenic activity (induction of capillary development) was demonstrated by synthetic primary amides of 13-t-docosenoic acid, 18:0, 20:0, 22:0, 20:4n-6, and to a lesser extent of 16:0, 18:1n-9.
The amide of 9-octadecenoic acid (oleamide) was isolated from the cerebrospinal fluid of sleep-deprived cats.

This compound is recognized now to be the endogenous factor inducing sleep in mammals (Cravatt, B F et al., Science, 1995, 268, 1506). Rats treated  with oleamide  fall asleep. It seems that oleamide may have many other physiological functions, including thermoregulation and sensitivity to pain.
Oleamide is synthesized by the brain cells from oleic acid and ammonium (Sugiura, T et al., Biochem. Mol. Biol. Int., 1996, 40, 93) and its level is regulated by a fatty amide hydrolase which degrades the amide to oleic acid. Apart from its effect on the central nervous system, oleamide modulates the function of the immune cells.

Many bioactive lipids containing a fatty acid linked to an amine-containing compound are found in  animal organisms and are described in the simple lipid section. Much attention has been given to that  class of compounds. Briefly, the origins of this research can be traced to 1957 when Kehul FF et al. (J Am Chem Soc 1957, 79, 5577) identified N-palmitoylethanolamine as an anti-inflammatory factor present in egg yolk, soybeans, and peanuts. Renewed interest in this and similar N-acylethanolamines arose with the discovery of N-arachidonoylethanolamine (anandamide). An overview of the biochemistry and pharmacology of anandamide has been released (Hansen HS et al., Eur J Lipid Sci Technol 2006, 108, 877).

Thus, simple lipoamino acids with an amide link between one fatty acid and one aminoacid (serine, ornithine, thyrosine, glycine, proline or leucine) or domamine or aminoalcohol (anandamide) are described. 

Other amide-containing lipids (complex lipoamino lipids) are found containing a fatty acid N-linked to an aminoacid (lysine, ornithine, alanine, proline) linked itself to an alcohol (ester link). 

A review on the role played by these molecules in pain modulation has been released by Walker JM et al. (Prost Lipid Med 2005, 77, 35). 

Fatty acid amides are found in grasses and microalgae. Hexadecanamide and octadecanamide were isolated from the shoots of marine grass Zostera marina (Kawasaki W et al., Phytochemistry 1998, 47, 27). 9-octadecenamide was identified and quantified (about 2.3% of total fatty acids) among others in the green alga Rhizoclonium hieroglyphicum (Dembitsky VM et al., Phytochemistry 2000, 54, 965). The cyclopropyl fatty amide, grenadamide, was detected from the cyanobacterium Lyngbya majuscula (Sitachitta N et al., J Nat Prod 1998, 61, 681) and a branched-chain fatty amide was isolated from the dinoflagellate Coolia monotis (Tanaka I et al., J Nat Prod 1998, 61, 685). 

A method for the isolation of C18 fatty acid amides from lipid extracts and their analysis by mass spectrometry was reported (Sultana T et al., J Chromatogr A 2006, 1101, 278).

Several benzyl alkylamides (macamides) were isolated from maca (Lepidium meyenii) lipid extract. Tubers of that plant, used as food in Peru and as dietary supplements ("Peruvian ginseng") elsewhere, contain macamides which could have promising biological activities. The simplest structure, described in 2002 (Zhao J et al., Chem Pharm Bull 2002, 50, 988) is shown below.

Analogous structures with various chain lengths, unsaturation or substitutions (methoxy or keto group) were also described in the same material (Zhao J et al., J Agric Food Chem 2005, 53, 690).

Similar structures, 11-Cyano or 11-thiocyanato undecanoic acid phenylamide, have been synthesized as corrosion inhibitors to prevent the corrosion of metals in acidic media (Yildirim A et al., Eur J Lipid Sci Technol 2008, 110, 570). These molecules generate a protective layer by adsorption to the metal surface via electrons present on their heteroatoms (0, S, N).

More complex fatty acid amides (one of them is shown below) were discovered in leaves of Chrysanthemum morifolium (Compositae). These isobutylamides, having one or two acetylenic bonds and three or four double bonds, were associated with host-plant resistance against a major insect pest facing greenhouse industry (Frankliniella occidentalis) (Tsao R et al., J Nat Prod 2003, 66, 1229).

The N-alkylamides dodeca-2,4-dienoic acid (1) and dodeca-2,4,8,10-tetraenoic (2) acid isobutylamides from the plant purple coneflower Echinacea were shown to be likely responsible for the early treatment for colds and as immunostimulants (Gertsch J et al., FEBS Lett 2004, 577, 563). 

These alkylamides represent a new class of cannabinomimetics which are able to modulate tumor necrosis factor a mRNA expression in human monocytes/macrophages via the cannabinoid type 2 receptor and have immunomodulatory activities (Raduner S et al., J Biol Chem 2006, 281, 14192).

A comprehensive review on fatty acid amides may be found on the site of Biochimica (Moscow). Their pharmacological properties were discussed by di Marco V (Biochim Biophys Acta 1998, 1392, 153).

Fatty hydroxamic acids may be regarded as derivatives of both fatty acids and hydroxylamine. Their general formula is  R-CO-NHOH.

These compounds are receiving a lot of attention due to their biological activity as inhibitors of cyclooxygenase and 5-lipoxygenase with potent topical antiinflammatory activity (Hamer RR et al., J Med Chem 1996, 39, 246), metal chelators, agent for removing impurities from mineral ores, efficient surfactants in the detergent industry (Masuyama A et al., JAOCS 1987, 64, 764). 
Contrary to some short chain hydroxamic acids, fatty hydroxamic acids are not commercially available and are synthesized chemically (Blatt A, Organic synthesis, 1963, 67, vol 2, J Wiley) or by lipase-catalyzed reaction (Suhendra D et al., J Oleo Sci 2005, 54, 33).

METHOXY and ACETHOXY FATTY ACIDS

Fatty acids may be naturally derivatized with a methoxy or an acetoxy group.

METHOXY FATTY ACIDS

Naturally occurring a-methoxy fatty acids were identified in phospholipids from various sponge species living in warm waters : saturated, monounsaturated and diunsaturated 2-methoxylated fatty acids (19 to 24 carbon atoms) were described (Ayanoglu E et al., Lipids 1983, 18, 830; Carballeira NM et al., Lipids 1992, 27, 72; Carballeira NM et al., J Nat Prod 1998, 61, 675).

Among them, 2-methoxy-5-hexadecenoic acid, 2-methoxy-6-hexadecenoic acid and 2-methoxy hexadecanoic acid were identified in phospholipids of Caribbean sponges.

These monounsaturated fatty acids were shown to have antimicrobial activity.
All these compounds were postulated to originate from bacteria in symbiosis with sponges.

Several other saturated and unsaturated 2-methoxylated fatty acids were isolated from phospholipids of a Caribbean sponge (Callyspongia fallax) (Carballeira NM et al., J Nat Prod 2001, 64, 620). The saturated were identified as 2-methoxytetra-, penta- and octadecanoic acids, the monounsaturated as 2-methoxy-6-tetra-, penta- and hexadecenoic acids.

The 2-methoxy-13-methyltetradecanoic acid was identified, together with other 2-methoxylated C15-C16 fatty acids, in the sponge Amphimedon complanata from Puerto Rico (Carballeira NM et al., Lipids 2001, 36, 83). This fatty acid is the methoxylated analog of the bacterial 2-hydroxy-13-methyltetradecanoic acid and was shown to be highly cytotoxic to human cancerous cells (Carballeira NM et al., Chem Phys Lipids 2003, 126, 149). These methoxylated fatty acids could have originated from bacteria in symbiosis with the sponge.

Several saturated 2-methoxylated fatty acids (from C10 to C14) were synthesized and were shown to display some degree of inhibition of Mycobacterium tuberculosis (Carballeira NM et al., Lipids 2004, 39, 675).

Fatty acids methoxylated at other positions have been identified from a few natural sources. The marine cyanobacterium  Lyngbya majuscula contain 7-methoxy-4-tetradecenoic acid (Cardellina JH et al., Phytochemistry 1978, 17, 2091), 9-methoxypentadecanoic acid and 15-methoxytricosanoic acid were identified in the red algae Schizymenia dubyi (Barnathan G et al., Phytochemistry 1998, 47, 761). Other acids have originated from bacteria, such as 11-methoxyheptadecanoic and 11-methoxynonadecanoic acids identified in Helicobacter pylori from human gastric mucosae (Inamoto Y et al., J Gastroenterol 1995, 30, 315). 10-methoxyoctadecanoic, 11-methoxyeicosanoic and 13-methoxynonadecanoic acid were detected in the bacterium Thiobacillus (Kerger BD et al., FEMS Microbiol Lett 1986, 38, 67).
Unusual long-chain methoxylated fatty acids were detected in the fungi Blumeria graminis (the causal agent of wheat powdery mildew) (Muchembled J et al., Phytochemistry 2005, 66, 793). They were identified as 3-methoxydocosanoic and 3-methoxytetracosanoic acids.

ACETOXY FATTY ACIDS

The phospholipids of the sponge Polymastia gleneni were shown to contain saturated long chain (C-22 to C-30)-acetoxy fatty acids (Ayanoglu E et al., Lipids 1985, 20, 141).
In plants, several 3-acetoxy fatty acids with 14, 16 or 18 carbon atoms are constituents of the partially acetylated acylglycerols found in floral oils of several species of Diascia (Srophulariaceae) (Dumri K et al., Phytochemistry 2008, 69, 1372). In Calceolaria and Lysimachia, a diacylglycerol, (1,2-di-(3-acetoxy-11-octadecenoy)-sn-glycerol) is the major floral lipid. 

1,2-di-(3-acetoxy-E-11-octadecenoy)-sn-glycerol

From Byrsonima intermedia (Malpighiaceae) floral oil, a di-acetylated fatty acid was isolated, 3,7-diacetoxy-docosanoic acid (bryonic acid) (Reis MG et al., J Chem Ecol 2007, 33, 1421). Several partially acetylated dihydroxy fatty acids could be identified in the floral oil secreted by Malpighia coccigera (Malpighiaceae) (Seipold L et al., Chem Biodiv 2004, 1, 1519). These fatty acids had a chain of 20, 22 or 24 carbon atoms and two hydroxyl groups in various positions, one of them being acetoxylated. 
Unexpectedly, these compounds characterize non-volatile oils produced in flowers by special anatomical adaptations (elaiophores) which are collected by pollinating bees, mainly in tropical areas of North and South America (neotropic ecozone). The bees seem to use these lipid secretions (instead of nectar) as provision for their larvae. These structures, generating a "floral syndrome", were described for the first time by Vogel S in 1969 (XI Proc Intl Bot Congress, Seattle, 1969, p. 229. Abstr). In 1987, a review on the ecology of oil flowers and their bees (more than 400 species) listed more than 2400 species of flowering plants (10 families) offering fatty oils (Buchmann SL, Ann Rev Ecol Syst 1987, 18, 343).  

A group of unusual triglycerides, in which one of the acyl groups is a vicinal dihydroxy acid with one of the hydroxyl groups acetylated, has been isolated from Cardamine impatiens (Cruciferae) seed oil. Several species were identified : C-18, C-20, C-22, and C-24 hydroxy acetoxy fatty acids (Mikolajczak KL et al., Lipids 1968, 3, 215).

KETO FATTY ACIDS

Keto fatty acids are rare but one is well known, 9-keto-2t-decenoic acid, which is an active constituent of the royal jelly (milky substance produced by the worker honey bee).

This fatty acid which has a pheromone role, is produced by the mandibular glands of the queen, it attracts and controls the activities of the workers in suppressing the queen-rearing behavior of the worker bees. Several other examples of similar chemicals participate in animal chemoreception (Winston M et al., Am Scientist 1992, 80, 374).
9-keto-2-decenoic acid could be a stimulant of the antibiotic activities against harmful bacteria and fungal infestations.
A new keto fatty acid, 9-keto-13-18:1(26%), was isolated from the seed oil of Smilax macrophylla (Liliaceae) (Daulatabad CD et al., Phytochemistry 1996, 42, 889).
Rosaceae are characterized by some unusual fatty acids, among them the triunsaturated licanic acid, 4-keto-9c11t13t-octadecatrienoic acid, which was described for the first time in oiticica oil extracted in Brazil from Licania rigida (Brown WB et al., Biochem J 1935, 29, 631). This keto derivative of eleostearic acid is present at high concentration (about 60%) in Licania seed oil (Mendelowitz A et al., Analyst 1953, 78, 704). This oil is used as a drying oil for varnishes, and as a component in the manufacture of alkyd resins.
Three long-chain keto fatty acids have been reported at levels from 3 to 13% in the seed oil of a Bignoniaceae Cuspidaria pterocarpa : 15-keto-18-tetracosaenoic, 17-keto-20-hexacosaenoic and 19-keto-22-octacosenoic acids (Smith CR, Lipids 1966, 1, 268). The seed oil of a Papaveraceae Argemone mexicana was shown to contain about 1% of 9-keto- and 11-keto-octacosanoic acids, and a 30 carbon chain keto fatty acid, 11-keto-triacontanoic acid (Gunstone FD et al., Chem Phys Lipids 1977, 20, 331).  

OXO FATTY ACIDS

There are a number of aldehydic fatty acids (w-oxo acids) in plants which derive from fatty acid hydroperoxides and play important cell signaling roles.
These molecules form the well known "traumatin" family which includes traumatin (12-oxo-9Z-dodecenoic acid, the precursor of traumatic acid), and autoxidation derivatives (9-hydroxy- and 11-hydroxy-traumatin). Traumatic acid is considered as a plant growth hormone.

t

 Traumatin hydro-derivatives were shown to be formed by a non-enzymatic oxidation process (Noordermeer MA et al., Biochem Biophys Res Comm 2000, 277, 112). Traumatin and other w-oxo acids were shown to be the products of the successive actions of lipoxygenase and hydroperoxide lyase on linoleic and linolenic acids (Gardner HW, Lipids 1998, 33, 745).
These substances are likely to play a role in defense against fungi, bacteria and arthropods (Farmer EE, Plant Mol Biol 1994, 26, 1423). 

The homolytic cleavage of fatty acid peroxides by hydroperoxide lyase gives an alcohol (or hydrocarbon) and a w-oxo acid (aldehydic fatty acid) (Gardner HW et al., Plant Physiol 1991, 97, 1059).
In mushrooms (Psalliota), the production of 10-oxo-8E-decenoic acid from linoleic acid was demonstrated (Wurzenberger M et al., Lipids 1986, 21, 261).

In algae, the cleavage of 13-hydroperoxides of linoleic and linolenic acids produced 13-oxo-9Z-11E-tridecadienoic acid (Vick BA et al., Plant Physiol 1989, 90, 125).

This compound was  shown to be also produced by soybean cotyledons (Kondo Y et al., Biochim Biophys Acta 1995, 1255, 9).
The heterolytic cleavage of 9- and 13-hydroperoxides in higher plants leads to the production of traumatin and 9-oxononanoic acid (Delcarte J et al., Biotechnol Agron Soc Environ 2000, 4, 157).

It was shown that in mammal (rabbit liver) another enzymatic pathway (P-450 and reductase) was also able to generate 13-oxo-9-11-tridecadienoic acid as in algae (Rota C et al., Biochem J 1997, 323, 565).