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This review deals with the most recent findings on the antimalarial, antimycobacterial, and antifungal properties of fatty acids, with particular emphasis on novel marine fatty acids. The first section deals with the most recent and some background literature on what has been the latest developments with respect to fatty acids as antimalarial agents and the importance of enzyme inhibition, in particular the inhibition of the enoyl-ACP reductase (FabI) of Plasmodium falciparum, the principal agent responsible for malaria. This section of the review also emphasizes the latest antimalarial research with the very long-chain Delta5,9 fatty acids from sponges. The second section of the review deals with the recent literature on the antimycobacterial activity of fatty acids and the importance of enzyme inhibition, in particular the inhibition of the enoyl-ACP reductase (InhA) of Mycobacterium tuberculosis for antimycobacterial activity. The inhibitory activities of the Delta5,9 fatty acids against InhA as well as that of the alpha-methoxylated fatty acids are also discussed. The importance of Delta5,9 fatty acids as topoisomerase I inhibitors and its connection to cancer is also reviewed. The last part of the review, the antifungal section, also emphasizes the most recent research with antifungal fatty acids and the importance of enzyme inhibition, in particular N-myristoyltransferase (NMT) inhibition, for antifungal activity. This last section of the review emphasizes the latest research with the alpha-methoxylated fatty acids but the importance of acetylenic fatty acids is also considered.

Methoxylated lipids have been reviewed emphasizing the alkylglycerol ethers and fatty acids bearing the methoxy group in the alkyl chain. The literature on methoxylated lipids and their derivatives has been divided into four main groups, namely 2-methoxylated alkyl glycerols, omega-methoxylated fatty acids, mid-chain methoxylated fatty acids, and alpha-methoxylated fatty acids. The natural occurrence, biological activity, and synthesis of this interesting group of lipids are discussed. Most of these compounds have been isolated from either bacterial or marine sources, but others are mainly of synthetic origin. Among the interesting biological activities displayed by these compounds the most important are antibacterial, antifungal, antitumor, and antiviral.

The phospholipid fatty acid composition of the sponge Amphimedon complanata was reinvestigated, and the 2-methoxy-13-methyltetradecanoic acid, 2-methoxy-14-methylpentadecanoic acid, and 2-methoxy-13-methylpentadecanoic acid were identified for the first time in nature. Structure characterization was accomplished by means of gas chromatographic retention times and gas chromatography-mass spectrometry. These acids could have originated from bacteria in symbiosis with the sponge.

The lipid composition of a Bacillus sp., isolated from Lake Pomorie in Bulgaria, was unusual and consisted of 26 different fatty acids between C12 and C26, with anteiso C15-C17 saturated fatty acids predominating. The furan fatty acid, 10,13-epoxy-11-methyloctadeca-10,12-dienoic acid, was also identified, a new finding for this genus. The hydrocarbons consisted of 30 different monounsaturated hydrocarbons, between C25 and C30, with the iso-iso, iso-anteiso, anteiso-anteiso, iso-normal, and anteiso-normal methyl branching for odd-numbered chains, and the iso-iso, iso-anteiso, iso-normal, and anteiso-normal methyl branching for even-numbered chains. The double bond positions in these hydrocarbons were determined by dimethyl disulfide derivatization followed by GC-MS, and the double-bond cis configuration was confirmed by infrared spectroscopy. Some previously unknown hydrocarbons in bacteria, such as (Z)-3,21-dimethyl-9-tricosene, (Z)-3,21-dimethyl-10-tricosene, (Z)-2,24-dimethyl-11-pentacosene, and (Z)-2,25-dimethyl-13-hexacosene were identified. Sterols were detected and were based on the sitosterol nucleus.

The delta 5,9 fatty acids (5Z,9Z)-5,9-hexadecadienoic acid, (5Z,9Z)-5,9-nonadecadienoic acid, and (5Z,9Z)-5,9-eicosadienoic acid were synthesized for the first time in four steps (9-12% overall yield) starting from commercially available 2-(2-bromoethyl)-1,3-dioxolane. The synthetic approach provided enough material to corroborate the structure and stereochemistry of (5Z,9Z)-5,9-nonadecadienoic acid which was recently identified in the flowers of Malvaviscus arboreus (Malvaceae). The novel phospholipids 1-hexadecanoyl-2-[(5Z,9Z)-5,9-eicosadienoyl]-sn-glycer o-3-phosphocholine and 1-octadecanoyl-2-[(5Z,9Z)-5,9-eicosadienoyl]-sn- glycero-3-phosphocholine were also synthesized from commercially available L-alpha-phosphatidylcholine (egg yolk) and characterized by positive ion electrospray mass spectrometry. These are the first examples of unsymmetrical phospholipids with saturated fatty acids at the sn-1 position and delta 5,9 fatty acids at the sn-2 position.

The fatty acid composition of a Pseudomonas sp. (Alteromonas) and its host, the dinoflagellate Ostreopsis lenticularis, vectors in ciguatera fish poisoning, has been studied. The major fatty acids in O. lenticularis were 16:0, 20:5n-3, and 22:6n-3, but 18:2n-6, 18:3n-3, and 18:n-3 were also identified. In contrast to other dinoflagellates, 1 8:5n-3 was not detected in O. lenticularis. Even-chain fatty acids such as 9-16:1, 11-18:1, and 13-20:1 predominated in the Pseudomonas sp. from O. lenticularis, but 1 6-20% of (E)-11-methyl-12-octadecenoic acid was also identified. The chirality of the latter was confirmed by total synthesis (28% overall yield) starting from oxacyclotridecan-2-one. The fatty acid compositions of two other Pseudomonas species, from the palytoxin-producing zoanthids Palythoa mamillosa and P. caribdea, were also studied and were similar to that of the Pseudomonas sp. from O. lenticularis. The possibility of using some of these fatty acids as chemotaxonomic lipids in identifying marine animals that consume toxic dinoflagellates or zoanthids is discussed.

The fatty acid composition of a new strain of Vibrio alginolyticus, found in the alga Cladophora coelothrix, was studied. Among 38 different fatty acids, a new fatty acid, 9-methyl-10-hexadecenoic acid and the unusual 11-methyl-12-octadecenoic acid, were identified. Linear alkylbenzene fatty acids, such as 10-phenyldecanoic acid, 12-phenyldodecanoic acid and 14-phenyltetradecanoic acid, were also found in V. alginolyticus. The alga contained 43% saturated fatty acids, and 28% C16-C20 polyunsaturated fatty acids of the n-3 and n-6 families.

The dimethyl disulfide derivatization of ethyl (9Z,12Z)-9,12-octadecadienoate and ethyl (9E,12E)-9,12-octadecadienoate was studied. These methylene-interrupted dienes were reacted with dimethyl disulfide and I2 for 72 h at 50 degrees C and the tetrahydrothiopyran, thietane, and tetrahydrothiophene derivatives thus obtained were analyzed by gas chromatography-mass spectrometry. Each configurational isomer displayed a unique gas chromatography trace for the 4-, 5- and 6-membered ring cyclization products thus obtained. Therefore, the cis-cis and trans-trans double bond stereochemistry of 9,12-octadecadienoates can now be determined by dimethyl disulfide derivatization.

The phospholipid fatty acid composition of the Caribbean gorgonians Pseudopterogorgia acerosa (Pallas), Pseudopterogorgia americana (Gmelin), Pseudopterogorgia bipinnata (Verrill) and Pseudopterogorgia rigida (Bielschowsky) is described for the first time. The main phospholipids identified were phosphatidylethanolamine, phosphatidylcholine and phosphatidylserine. All four gorgonians presented a similar phospholipid fatty acid composition. The main fatty acids were 16:0, 18:3(n-6), 18:4(n-3), 20:4(n-6), 22:6(n-3), 24:5(n-6) and 24:6(n-3). In all of the studied Pseudopterogorgia gorgonians, high amounts of the tetracosapolyenoic fatty acids 24:5(n-6) and 24:6(n-3) were identified. In the four gorgonians studied, n-6 polyunsaturated fatty acids predominated. These results suggest that the occurrence of tetracosapolyenoic fatty acids in the Gorgoniidae is more general than previously recognized.

A new brominated fatty acid, 6-bromo-5,9-eicosadienoic acid [1] was identified in the phospholipids (mainly phosphatidylethanolamine) of the anemone Condylactis gigantea and the zoanthid Palythoa caribaeorum. The delta 5,9 fatty acids, 5,9-octadecadienoic acid, 5,9-eicosadienoic acid, 5,9-docosadienoic acid, and 5,9-tetracosadienoic acid, were also identified in both organisms. Structural elucidation was accomplished by spectroscopic and chemical means. Our results further corroborate that delta 5,9 phospholipid fatty acids are not unique to sponges, as recognized previously, but can be found in other marine invertebrates such as anemones and zoanthids. An improved procedure for the synthesis of picolinyl esters is also described.

The fatty acid composition of the tunicate Botryllus schlosseri and of two bacterial strains found within the tunicate, namely Vibrio parahaemolyticus and of an associated but previously unreported gram positive cocci were studied. The polyunsaturated fatty acids 6,9,12-octadecatrienoic acid, 5,8,11,14,17-eicosapentaenoic acid, and 4,7,10,13,16,19-docosahexaenoic acid were particularly abundant in B. schlosseri and were not detected in the two bacterial strains found in the tunicate. The iso/anteiso pair, 13-methyltetradecanoic acid and 12-methyltetradecanoic acid, were the principal fatty acids in the gram positive cocci, and the 9- and 11-hexadecenoic acids were particularly abundant in V. parahaemolyticus. The diunsaturated fatty acid 9,12-octadecadienoic acid was also shown to be present in V. parahaemolyticus. The fatty acid composition of a third bacterial strain, characterized as either a Pseudomonas or an Alteromonas species, and shown to be present only in the sea water from the Black Sea and not in B. schlosseri, is also reported. This is the first investigation on fatty acids from Black Sea bacteria.

The phospholipid fatty acid composition of the Calcarean sponge Leucosolenia canariensis was studied, and no delta 5,9 fatty acids were detected. These results are in contrast to the phospholipids from sponges belonging to the class Demospongiae where delta 5,9 fatty acids are predominant. Odd branched-chain fatty acids between 17 and 19 carbons accounted for 26% of the total fatty acids of L. canariensis, while straight-chain fatty acids between 16 and 22 carbons accounted for 61% of the total fatty acid composition. The sterol composition of L. canariensis is also reported, and only delta 5,7,22 sterols were observed.

The diunsaturated fatty acids 5,9-heneicosadienoic acid, 5,9-docosadienoic acid and 5,9-tricosadienoic acid, the brominated fatty acids 6-bromo- 5,9-heneicosadienoic acid and 6-bromo-5,9-docosadienoic acid, and the polyunsaturated fatty acids 5,9,13-eicosatrienoic acid and 5,9,13-docosatrienoic acid, were identified for the first time in nature in the phospholipids (mainly phosphatidylethanolamine and phosphatidylserine) of the anemone Stoichactis helianthus. Structural elucidation was accomplished by means of mass spectrometry and chemical transformations such as pyrrolidide and dimethyldisulfide derivatization. Other delta 5,9 fatty acids such as 5,9-hexadecadienoic acid, 5,9-octadecadienoic acid, and 5,9-eicosadienoic acid were also identified in the anemone. Our results indicate that delta 5,9 phospholipid fatty acids are not unique to sponges, as previously recognized, but can be found in other marine invertebrates such as an anemone. 24-Methylated sterols predominated in the sterol composition of the anemone investigated.

The phospholipid fatty acid composition of the Caribbean sponge Amphimedon viridis was studied, revealing the presence of the previously unreported substances 5,13-nonadecadienoic acid, 4-nonadecenoic acid, and 15-heneicosenoic acid. In A. viridis the very long-chain 5,9,23-nonacosatrienoic acid and 5,9,23-tricosatrienoic acid predominated in the mixture. The fatty acid composition of the sponge Desmapsamma anchorata was revised and 62 phospholipid fatty acids were characterized. The rare 8,13-octadecadienoic acid and 18-tetracosenoic acid were also characterized in the mixture. The two possible stereochemical isomers of 7-methyl-6-hexadecenoic acid, i.e., 7-methyl-6(Z)-hexadecenoic acid and the 7-methyl-6(E)-hexadecenoic acid were identified in both sponges, but D. anchorata had larger amounts. This is the first time that both stereoisomers have been identified in a sponge. The previously reported 7-methyl-8-hexadecenoic acid was not found in D. anchorata. Unprecedented aldehydes, comprising 15-and 17-docosenal, were also identified in the sponges.

The distribution of C14-C22 fatty acids in the phosphatidylethanolamines isolated from the sponges Agelas sp. and Spongia tampa was investigated. Selective changes with phospholipase A2 (from Agkistrodon halys blomhoffii) followed by thin-layer chromatographic separation of the resulting lysophosphatidylethanolamines and free fatty acids and subsequent methylation with HCl/MeOH and diazomethane, respectively, revealed that the 5,9-octadecadienoic acid and the 9,12-octadecadienoic acid present showed no preference for either position sn-1 or sn-2 in these phosphatidylethanolamines. The other saturated and unsaturated fatty acids with chains between 14 and 22 carbons long were also found to be equally distributed between positions sn-1 and sn-2 in the phosphatidylethanolamines in these sponges. The results contrast with what is known about the distribution in most mammalian phospholipids, such as the phosphatidylcholines from human erythrocytes, where octadecadienoic acid typically occupies the sn-2 position.

The novel alpha-hydroxy fatty acids 2-hydroxy-13-docosenoic acid [1a], 2-hydroxy-14-tricosenoic acid [2a], and 2-hydroxy-15-tetracosenoic acid [3a] were identified in the Caribbean urchin, Tripneustes esculentus. The double-bond positions of the novel alpha-hydroxy fatty acids were determined by derivatization with dimethyl disulfide and shown to correlate with the corresponding non-hydroxylated mono-unsaturated fatty acids, 13-docosenoic acid, 14-tricosenoic acid, and 15-tetracosenoic acid also present in T. esculentus. The total fatty acid composition of the urchins is also reported where cis-5-olefinic fatty acids such as 5,9-octadecadienoic acid and 5,11-eicosadienoic acid were found to predominate in the mixture. Cholesterol was the predominant sterol in T. esculentus.

The previously unreported 27-methyl-5,9-octacosadienoic acid [1] and 26-methyl-5,9-octacosadienoic acid [2] were identified in the phospholipids of the Caribbean sponges Chondrosia remiformis and Myrmekioderma styx. Both sponges also contain the novel 15-methyl-5,9-hexadecadienoic acid [3] in their phospholipids. These results extend the possible chain lengths in delta 5,9 iso/anteiso fatty acids in sponge phospholipids from C17 to C29.

The very long-chain fatty acids, (5E,9Z)-6-bromo-5,9-tetracosadienoic, (5E,9Z)-6-bromo-23-methyl-5,9-tetracosadienoic, (5E,9Z)-6-bromo-5,9-pentacosadienoic and (5E,9Z)-6-bromo-24-methyl-5,9- pentacosadienoic acids, were identified in the phospholipids (mainly phosphatidylethanolamine) of the sponge Agelas sp. Structure elucidation was accomplished by means of mass spectrometry and chemical transformations, including deuteration with Wilkinson's catalyst. All of the sterols from the sponge had the delta 5,7 nucleus, with 24-methylcholesta-5,7,22-trien-3 beta-ol (ergosterol) and 24-ethyl-cholesta-5,7, 22-trien-3 beta-ol being the most abundant.

The long-chain fatty acids (5E,9Z)-6-bromo-5,9-heptacosadienoic acid [2a], (5E,9Z)-6-bromo-5,9-octacosadienoic [3a], (Z)-19-heptacosenoic acid [4], and the novel aldehydes 17-pentacosenal [5] and 17-hexacosenal [6] were identified in the phospholipids (mainly phosphatidylethanolamine and phosphatidylcholine) of the sponge Petrosia sp. Structural elucidation was accomplished by means of mass spectrometry and chemical transformations, including deuteration with Wilkinson's catalyst. The dimethyldisulfide derivatization of delta(5.9) fatty acids is also presented.

The free fatty acids of the Mediterranean opisthobranch Haminaea templadoi were isolated and characterized, revealing the presence of the new 10,15-eicosadienoic acid [1] and several unusual cis delta 6 monoenoic acids, such as (Z)-6-tetradecenoic acid, (Z)-6-pentadecenoic acid, and (Z)-6-heptadecenoic acid. These results reveal some previously unrecognized fatty acids in mollusks.

The Caribbean sponge Smenospongia aurea revealed the presence of six novel branched alpha-hydroxy fatty acids: 2-hydroxy-17-methyloctadecanoic acid, 2-hydroxy-21-methyldocosanoic acid, 2-hydroxy-22-methyltricosanoic acid, and 2-hydroxy-22-methyltetracosanoic acid, 2-hydroxy-24-methylpentacosanoic acid, and 2-hydroxy-23-methylpentacosanoic acid. These novel alpha-hydroxy fatty acids were associated with phosphatidylethanolamine. The sponges Aplysina lacunosa and Aplysina fistularis also contained considerable amounts of alpha-hydroxy fatty acids, the very long-chain 5,9,23-tricontatrienoic acid (30:3), and phytanic acid. The sterol composition of the three sponges was also studied. It indicated that A. lacunosa and A. fistularis contained large amounts of aplysterol and verongulasterol, while S. aurea did not show any of these sterols. The results are discussed in terms of the taxonomy of the species.

The novel (5Z)-2-methoxy-5-hexadecenoic acid (1) was identified in the phospholipids of the sponge Tethya crypta while the also novel acid (6Z)-2-methoxy-6-hexadecenoic acid (2) was found in the phospholipids of the Caribbean sponge Spheciospongia cuspidifera. The methoxy-fatty acids were mainly associated with phosphatidylethanolamine. The double bond positions were determined by gas chromatography/mass spectrometry on the corresponding dimethyl-disulfide adducts and the double bond stereochemistry was ascertained by gas chromatography/Fourier transform infrared spectroscopy. The fatty acid composition of the two sponges is reported.

The novel fatty acids (Z)-6-nonadecenoic acid (1) and (Z)-17-pentacosenoic acid (2) were characterized in the sponge Geodia gibberosa. These fatty acids were mainly found in phosphatidylethanolamine and phosphatidylcholine.

1. The phospholipid fatty acid compositions of the sponges Ircinia strobilina, Ircinia felix, Ircinia campana, Ircinia sp., Spongia tubulifera and Dysidea etherea were studied, revealing the presence, besides other common fatty acids, of considerable amounts (2-5%) of the novel 23-methyl-5,9-tetracosadienoic acid (1). 2. The demospongic acids 5,9-tetracosadienoic acid, 23-methyl-5,9-tetracosadienoic acid (1), and 5,9-pentacosadienoic acid, were particularly abundant in sponges of the genus Ircinia, in contrast to the most common 5,9-hexacosadienoic acid found in other species. These findings are discussed in terms of the taxonomy of the Dictyoceratida. 3. The complete characterization of the novel phospholipid fatty acid 23-methyl-5,9-tetracosadienoic acid (1) is presented.

The novel fatty acids 18-methyl-5,9-icosadienoic acid [1] and 19-methyl-5,9-icosadienoic acid [2] were identified in the Caribbean sponge Erylus formosus. Other interesting fatty acids identified were the branched acids 3-methylpentadecanoic acid and 3-methylhexadecanoic acid, which are known to possess larvicidal activity. The most stable conformation of the new acid 19-methyl-5,9-icosadienoic acid is also presented as predicted by Molecular Mechanics (MM2) calculations. The sterol composition of E. formosus is also reported.

The total phospholipid fatty acids from the Caribbean sponge Amphimedon complanata were studied, revealing the presence of the new 11,15-icosadienoic acid [1], the rare 7-methyl-6-hexadecenoic acid [2], and the recently discovered 6,11-icosadienoic acid. These acids were mainly encountered in phosphatidylethanolamine and phosphatidylcholine.