Biological Activity of Carboxylic Acids

Considering the variety of reactions that carboxylic acids can undergo, it is no wonder that they are very important, not only as synthetic intermediates in the laboratory, but also in biological systems. This section will provide a glimpse of the enormous structural and functional diversity of natural carboxylic acids. A discussion of amino acids will be deferred to Chapter 26. 

As Table 19-1 indicates, even the simplest carboxylic acids are abundant in nature. Formic acid is present not only in ants, where it functions as an alarm pheromone and chemical weapon, but also in plants. For example, one reason why human skin hurts after it touches the stinging nettle is that formic acid is deposited in the wounds. 

Acetic acid is formed through the enzymatic oxidation of ethanol produced by fermentation. Vinegar is the term given to the dilute (ca. 4-12%) aqueous solution thus generated in ciders, wines, and malt extracts. Louis Pasteur in 1864 established the involvement of bacteria in the oxidation stage of this ancient process. 

Fatty acids are derived from coupling of acetic acid 

A conceptually more straightforward mode of multiple coupling is found in the biosynthesis of fatty acids. This class of compounds derives its name from its source, the natural fats, which are esters of long-chain carboxylic acids (see Section 20-4). Hydrolysis or saponification (so called because the corresponding salts form soaps sapo, Latin, soap—see Real Life 19-1) yields the corresponding fatty acids. The most important of them are between 12 and 22 carbons long and may contain cis carbon-carbon double bonds. 

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Specific biological activity of carboxylic acids peroxide derivatives in compaiison with their oxidation ability and ionization degree in aqueous solutions has been considered. Peroxyoctanoic, diperoxynonandioic and diperoxydecandioic acids give the most intense bactericidal effect among researched cai boxylic acids peroxide derivatives. The perspectives of use of the aliphatic middle-chain peracid C8-C9 as anti-infective agents have been discussed. 

Almquist, R. G., Chao, W. R., Jennings-White, C. Synthesis and biological activity of carboxylic acid replacement analogues of the potent angiotensin converting enzyme inhibitor 5(S)-benza-mido-4-oxo-6-phenylhexanoyl-L-proline. J. Med. Chem. 1985, 28, 1067-1071. 

Due to the biological activity of bisphosphonic acids, a vast array of derivatives and precursors have been generated including bile salts (Scheme 4.166) [255]. The overall process started with protection of the alcohols on the parent bile salt through the addition of formic add. Once suitably protected, the addition of thionyl chloride converted the carboxylic acid into an add chloride. Since these conversions are typically carried out using an excess of the thionyl chloride, the ranoval of unreacted material can be particularly troublesome. In these reactions, the ranoval of the excess thionyl chloride was achieved through repeated trituration with benzene. The final steps in the synthesis entailed... 

It is worthy of note that a-sulfanyl phosphonic acids, which can now be obtained enantioselectively from corresponding a-hydroxyphosphonates, are analogues of the a-sulfanyl carboxylic acids, which, for some of them, are metallo- -lactamases inhibitors [ 112]. To our knowledge, it does not seem that biological activities of a-sulfanyl phosphonic acids have been examined so far. 

Wong and co-workers have prepared various quaternary cx-nitro-cx-methyl carboxylic acid esters by the palladium-catalyzed allylic alkylation of a-nitropropionate ester (Eq. 5.59). The products can be kinetically resolved by using cx-chymotrypsin and are converted into optical active a-methyl cx-amino acids. Such amino acids are important due to the unique biological activity of these nonproteinogenic a-amino acids.82... 

Method E, which assumes the N(7)-C(7a) bond formation in the cyclization step, is also rarely used in the synthesis of thienopyridines. For example, the method (1997H255, 1998JMC(E)33, 1998PS21) for the preparation of 4-oxo-4,7-di-hydrothieno[2,3-Z>]pyridine-5-carboxylic acid esters 54 is based on intramolecular /V-nucleophilic substitution of (E/Z)-aminomethylene derivatives of (2,5-dichloro-3-thenoyl)acetic acid esters 52 in the presence of a strong base. Esters 52 and products of their alkaline hydrolysis 56 have an antibacterial action the influence of the substituents on the biological activity of the resulting compounds was studied. 

Rogers, I. H., Manville, J. F., and Sahota, T. (1974). Juvenile hormone analogs in conifers. II. Isolation, identification, and biological activity of c/s-4-[r(R)-5 -dimethyl-3 -oxohexyl]-cyclohexane-1-carboxylicacidand(+)-4(R)-[l (R)-5 -dimethyl-3 -oxohexyl]-1-cyclohex-ene-1-carboxylic acid from Douglas-fir wood. Can. ). Chem. 52, 1192-1199. 

Very recently, a dihydrofullerene carboxylic acid has been shown to photo-chemically kill certain cells and cause guanosine-specific damage to DNA. Tests suggested that this action was caused by singlet oxygen [103]. This is only one of the recent reports of interesting biological activity of dihydrofullerenes [104], a field which is poised to explode. 

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