Carboxylic acid inhibitors

Gunata, Y.Z., Sapis, J.C., and Moutounet, M., Substrates and carboxylic acid inhibitors of grape polyphenoloxidases. Phytochemistry 26, 1573, 1987. 

Marciano, D., Benbaruch, G., Marom, M., Egozi, Y., Haklai, R., and Kloog, Y. (1995). Farnesyl derivatives of rigid carboxylic acids-inhibitors of Ras-dependent cell-growth. 

Table V. Carboxylic Acid Inhibitors of the Carboxypeptidase A-Catalyzed Hydrolysis of Esters and Peptides ...

Parker, M.H., Lunney, E.A., Ortwine, D.F., Pavlowsky, A.G., Humblet, C. et al. (1999) Analysis of the binding of hydroxamic acid and carboxylic acid inhibitors to the stromlysin-1 (matrix metalloproteinase-3) catalytic domain by isothermal titration calorimetry. Biochemistry 38 13592-13601. 

Gunata, YZ, Sapis, JC Moutonet, M. Substrates and Aromatic Carboxylic acid Inhibitors of Grape Polyphenol Oxidases. Phytochemistry, 1987 26,1573-1575. 

Fig. 23. Representative protecting groups for phenolic and carboxylic acid-based systems, (a) The polymer-based protecting groups are fisted in order of increasing activation energy for acid-catalyzed deprotection, (b) Acid-labile monomeric dissolution inhibitors, a bifunctional system based on protected bisphenol A. (c) Another system that combines the function of dissolution inhibitor and PAG in a single unit.

Some of the physical properties of fatty acid nitriles are Hsted in Table 14 (see also Carboxylic acids). Eatty acid nitriles are produced as intermediates for a large variety of amines and amides. Estimated U.S. production capacity (1980) was >140, 000 t/yr. Eatty acid nitriles are produced from the corresponding acids by a catalytic reaction with ammonia in the Hquid phase. They have Httie use other than as intermediates but could have some utility as surfactants (qv), mst inhibitors, and plastici2ers (qv). 

Carboxylic Acid Functional Group Reactions. Polymerization is avoided by conducting the desired reaction under mild conditions and in the presence of polymeriza tion inhibitors. AcryUc acid undergoes the reactions of carboxyUc acids and can be easily converted to salts, acryhc anhydride, acryloyl chloride, and esters (16—17). 

Penam Sulfone B-Lactamase Inhibitors. Natural product discoveries stimulated the rational design of p-lactamase inhibitors based on the readily accessible penicillin nucleus. An early success was penicillanic acid sulfone, (2(5)-cis)-3,3-dimethyl-7-oxo-4,4-dioxide-4-thia-l-a2abicyclo [3.2.0]heptane-2-carboxylic acid [68373-14-8] (sulbactam) (25, R = = H, R" = R" = CH ), CgH NO S. The synthesis (118), microbiology (119—121),... 

The reaction is proposed to proceed from the anion (9) of A/-aminocatbonylaspattic acid [923-37-5] to dehydrooranate (11) via the tetrahedral activated complex (10), which is a highly charged, unstable sp carbon species. In order to design a stable transition-state analogue, the carboxylic acid in dihydrooronate (hexahydro-2,6-dioxo-4-pyrimidinecarboxylic acid) [6202-10-4] was substituted with boronic acid the result is a competitive inhibitor of dibydroorotase witb a iC value of 5 ]lM. Its inhibitory function is supposedly due to tbe formation of tbe charged, but stable, tetrabedral transition-state intermediate (8) at tbe active site of tbe enzyme. 

The formation of polymer can be considered as a quasi-living polymerization. After the polymerization is complete, it can be reinitiated with the addition of more monomer to the unquenched polymer. However, the degree of polymerization cannot be predicted by the monomer/initiator molar ratio, the polydispersity is 1.5-2.0, and water, or even carboxylic acids, act as inhibitors and do not terminate the polymerization [10]. 

In addition, Pfister and coworkers investigated 3-hydroxyflavone-6-carboxylic acids as histamine induced gastric secretion inhibitors. After condensing 3-acetyl-4-hydroxybenzoic acid (45) with a variety of aldehydes 46 to deliver the chalcones 47, these purified chalcones were then subjected to the standard AFO conditions to afford flavonols 48 in 51-80% yield. Subsequent alkylation of 48 with methyl iodide or isopropyl iodide followed by saponification of the corresponding esters gave the target compounds. 

Chloro-oxazolo[4,5-/i]quinoline-2-carboxylic acid methyl ester was the most active compound in tests for inhibitors of antigen-induced release of histamine in vitro from rat peritoneal mast cells (IC50 of 0.3 p,M) and as inhibitors of IgE-mediated passive cutaneous anaphylaxis in the rat (ED50 (intraperitoneal) of 0.1 mg/kg in dose 0.5 mg/kg as an inhibitor of the test)—10 times and 60 times more potent, respectively, than the disodium salt of cromoglycic acid (85JMC1255). 

Organic or inorganic inhibitors This distinction is based on the chemical nature of the inhibitor. However, in their inhibitive action many compounds that are organic in nature as, for example, the sodium salts of carboxylic acids, often have more similarities with inorganic inhibitors. 

In addition to effects on biochemical reactions, the inhibitors may influence the permeability of the various cellular membranes and through physical and chemical effects may alter the structure of other subcellular structures such as proteins, nucleic acid, and spindle fibers. Unfortunately, few definite examples can be listed. The action of colchicine and podophyllin in interfering with cell division is well known. The effect of various lactones (coumarin, parasorbic acid, and protoanemonin) on mitotic activity was discussed above. Disturbances to cytoplasmic and vacuolar structure, and the morphology of mitochondria imposed by protoanemonin, were also mentioned. Interference with protein configuration and loss of biological activity was attributed to incorporation of azetidine-2-carboxylic acid into mung bean protein in place of proline. 

Unfortunately, the pharmacology of chloride channels is poorly developed. Specific and highly useful inhibitors or modulators (e.g. strychnine, picrotoxin, diazepams) are only available for ligand-gated chloride channels (but these are covered in a different chapter). There are several chloride channel inhibitors such as the stilbene-disulfonates DIDS and SITS, 9-antracene-carboxylic acid (9-AC), arylaminobenzoates such as DPC and NPPB, niflumic acids and derivates, sulfony-lureas, and zinc and cadmium. All of these inhibitors, however, are not veiy specific. Several of these inhibitors (e.g. DIDS) inhibit many chloride channels only partially even at millimolar concentrations and have effects on other types of transport proteins. 

PhsSnflV)] carboxylates and of some 1 1 addition compounds of PhsSnCl and 2,3-disubstituted thiazolidin-4-ones indicate that the carboxylates in the solid state are monomeric with a Sn atom = 2.14—2.54 mm s the only exception being the furan-2-carboxylic acid derivative, which is polymeric. The PhsSnCl adducts are Thp (I Ag p I = 2.97-3.08 mm s ) with the three Ph groups in a not coplanar eq plane. These complexes are effective inhibitors of C. The 2,3-disubstituted... 

Further, Wasserman and coworkers developed a direct acylation of stabilized phosphonium ylides by carboxylic acids in presence of the EDCI/DMAP (way c). This last method allows the introduction of a-aminoacid structures into the resulting P-oxo phosphorus ylides [19-25],opening the way to the total synthesis of depsipeptide elastase inhibitors [22,24] or cyclic peptidic protease inhibitor EurystatinA [20]. 

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. 

Methyl groups attached to benzene rings can be reacted with oxygen to produce aromatic carboxylic acids. Benzoic acid, the parent aromatic acid, finds wide use as a food preservative and in metal corrosion inhibitors. Aspirin and saccharin are derivatives of benzoic acid. 

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