Mercury compounds, phosphorylation

The biochemical basis for the toxicity of mercury and mercury compounds results from its ability to form covalent bonds readily with sulfur. Prior to reaction with sulfur, however, the mercury must be metabolized to the divalent cation. When the sulfur is in the form of a sulfhydryl (— SH) group, divalent mercury replaces the hydrogen atom to form mercaptides, X—Hg— SR and Hg(SR)2, where X is an electronegative radical and R is protein (36). Sulfhydryl compounds are called mercaptans because of their ability to capture mercury. Even in low concentrations divalent mercury is capable of inactivating sulfhydryl enzymes and thus causes interference with cellular metaboHsm and function (31—34). Mercury also combines with other ligands of physiological importance such as phosphoryl, carboxyl, amide, and amine groups. It is unclear whether these latter interactions contribute to its toxicity (31,36). 

Phosphoryl radicals [10, 18, 38-42] tend to add to double bonds. Owing to the exceptionally high constants of hyperfine coupling of the unpaired electron with the phosphorus nucleus, phosphoryl radicals can be utilized as paramagnetic reporters [10]. Phosphoryl radicals have been prepared by photolysis of diphosphoryl mercury compounds (Scheme 6.5). 

A systematic study of substitution reactions of oxazole itself has not been reported. Bromination of 2-methyl-4-phenyloxazole or 4-methyl-2-phenyloxazole with either bromine or NBS gave in each case the 5-bromo derivative, while 2-methyl-5-phenyloxazole was brominated at C(4). Mercuration of oxazoles with mercury(II) acetate in acetic acid likewise occurs at C(4) or C(5), depending on which position is unsubstituted 4,5-di-phenyloxazole yields the 2-acetoxymercurio derivative. These mercury compounds react with bromine or iodine to afford the corresponding halogenooxazoles in an electrophilic replacement reaction (81JHC885). Vilsmeier-Haack formylation of 5-methyl-2-phenyloxazole with the DMF-phosphoryl chloride complex yields the 4-aldehyde. 

It is generally accepted that the basis of the biological activity of mercury compounds is their reaction with the thiol groups, but the biological action is rather more complicated. Frank (1955) showed that mercury compounds can influence the effect of enzymes which do not contain thiol groups. Mercury also reacts with the phosphoryl groups of the cell membranes (Bassow et a/., 1961) and with the amino and carboxyl groups of the enzymes (Lipscomb et al., 1968). Webb (1966) lists more than 40 enzymes inhibited by mercury compounds. 

Many pesticides are esters or amides that can be activated or inactivated by hydrolysis. The enzymes that catalyze the hydrolysis of pesticides that are esters or amides are esterases and amidases. These enzymes have the amino acid serine or cysteine in the active site. The catalytic process involves a transient acylation of the OH or SH group in serin or cystein. The organo-phosphorus and carbamate insecticides acylate OH groups irreversibly and thus inhibit a number of hydrolases, although many phosphorylated or carbamoylated esterases are deacylated very quickly, and so serve as hydrolytic enzymes for these compounds. An enzyme called arylesterase splits paraoxon into 4-nitrophenol and diethyl-phosphate. This enzyme has cysteine in the active site and is inhibited by mercury(ll) salts. Arylesterase is present in human plasma and is important to reduce the toxicity of paraoxon that nevertheless is very toxic. A paraoxon-splitting enzyme is also abundant in earthworms and probably contributes to paraoxon s low earthworm toxicity. Malathion has low mammalian toxicity because a carboxyl esterase that can use malathion as a substrate is abundant in the mammalian liver. It is not present in insects, and this is the reason for the favorable selectivity index of this pesticide. 

In contrast to diazomethane, a-diazo- S-carbonyl and - S-phosphoryl compounds cannot be halogenated by the direct methods mentioned above, but the corresponding a-mercury-bis(a-diazo-yff-carbonyl) (9.4) or (a-diazo-a-silver-)ff-phosphoryl) derivatives (9.6) must be synthesized first. The metallated compounds 9.4 and 9.6 react with molecular bromine and iodine or with other halogenation reagents, like sulfuryl chloride or cyanogen chloride. The compounds 9.5 and 9.7 are obtained in a yield of 30-90% (Schollkopf et al., 1968, for ethyl diazoacetate Regitz et al., 1979c, for diazophosphoryl compounds). 

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