Organic phosphates and carbamates

The substances discussed in this section have become important because of their property of acylating esterases, particularly acetylcholinesterase (AChase). The death of insects correlates well with the inhibition of their AChase, provided that thoracic (but not brain) isoenzyme is tested (Bigley, 1966 Farnham, Gregory and Sawicki, 1966). Similarly the toxicity oforgano-phosphates to mammals is directly proportional to the inhibition of their AChase (Aldridge and Barnes, 1952). 

Effective insecticides have been found among the phosphinic, phosphoric, and phosphonic esters. In a phosphinic ester, both alkyl groups are directly attached to the phosphorus atom in a phosphoric ester, both are attached through oxygen and a phosphonic ester is intermediate in this respect. 

If the inhibited enzyme has not aged , it can be re-activated by the anionic group of a hydroxylamine (see below). The phenomenon of ageing was discovered by Hobbiger (1955), who noted that esters of secondary alcohols evoke this phenomenon faster than those of primary alcohols. The correct interpretation, namely that ageing is proportional to the hydrolysis of an 

In insects poisoned by organic phosphorus compounds, assays for acetylcholinesterase show that this enzyme becomes increasingly inhibited during the first hour and the levels of free acetylcholine rise sharply (Smallman and Fiske, 1958). For further information on the effect of these agents on the nervous system of insects, see Section 6.4.1 (p. 243). 

Acetylcholinesterases isolated from various insect species differ greatly in their susceptibility to phosphorus insecticides (R. O Brien, 1967). Access to this enzyme is more difficult in insects than in mammals hence it is understandable that ionized analogues have proved not to be insecticidal because foreign ions do not readily penetrate membranes (Section 3.2). 

SCHEME 12.1 Inactivation of an enzyme by phosphorylation and its reactivation if not aged . 

It can be seen from Fig. 12.2 that the mouse converts only a small pro- 

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Role of Drugs. The role of drugs as a factor in the enzyme activity changes brought about by the organic phosphates and carbamates has been the subject of several recent papers. Gaines (57) has shown that phenothiazine derivatives potentiate the toxicity of organophosphate... 

Specific Metabolic Inhibitors. The organic phosphates and carbamates interfere with the synaptic chemistry through inhibition of acetylcholinesterase. 

Biochemically Nonspecific Group. Organic phosphates and carbamates inhibit pseudocholinesterase and other esterases. Toxicity and enzymatic inhibitory power are augmented by phenothiazine derivatives but reduced by chemicals which are SER- and esterase-stimulating but not by carbon tetrachloride. 

Why then, since such an abundance of metabolic inhibitors is available, do so few of them find practical application Examples are the folic acid reductase inhibitors, such as aminopterin, the purine and pyrimidine analogs used as cytostatics in cancer chemotherapy and known for their high toxicity in a wide variety of species, and the organic phosphates and carbamates used as insecticides but also highly toxic to mammals. Lack of selectivity in the action of metabolic inhibitors is inherent in their mechanism of action due to the universality of biochemical processes and principles throughout nature. Selectivity in action requires species differences in biochemistry. For the antivitamins, for instance, there is not only a lack of species differences in action in addition, the fact that vitamins often serve as cofactors for a variety of enzymes is a serious drawback to endeavors to obtain agents with species-selective action. 

The action of naturally secreted acetylcholine can be reinforced by drugs which acylate, and hence block, the enzyme acetylcholinesterase (see Section 12.3). The organic phosphates and carbamates do this. Of the carbamates, the alkaloid physostigmine (7.25), also known as eserine, has long been used for therapeutic results which can now be defined as giving the patient a much enhanced effect from his own acetylcholine . Even at a dilution of io" m, it strongly inhibits this enzyme, and is pharma-... 

Wesseling C, Keifer M, Ahlbom A, et al. Long-term neurobehavioral effects of mild poisonings with organic phosphate and N-methyl carbamate pesticides among banana workers. Int J Occup Environ Health 2002 8(1) 27—34. 

Pesticides can be analyzed on a C18 column, the chlorinated hydrocarbon type (chlordane) at 80% An/water UV, 220 nm, the carbamate type (sevin) at 40% An/water UV, 254 nm, and the organic phospahate (malathion) at 50% An/water with UV, 192 nm or with a CAD. The organic phosphate types are hard to detect at low concentration and various phosphate analysis techniques have been evaluated. LC/MS, where available, is the technique of choice for analyzing all of these pesticides, but especially the organic phosphates, in a general gradient HPLC scheme. 

DeBleecker, J.L. (2006). Intermediate syndrome in organ-phosphate poisoning. In Toxicology of Organophosphate and Carbamate Compounds (R.C. Gupta, ed.), pp. 371-80. Academic Press, Amsterdam. 

Pesticides Carbamate insecticides and herbicides, chlorinated pesticides (for example aldrin, dieldrin, heptachlor, DDT, DDE, HCB, HCH isomers), dithiocarbamate fungicides, organic phosphates, triazine herbicides... 

Many simpler carbamates, as well as organic phosphates, which have this property of blocking acetylcholinesterase, are used in treating glaucoma, also as anthelmintics and insecticides (see Section 13.3). 

The determination of pesticides has become increasingly important in recent years because of the widespread use of these compounds, which is due to their large range of biological activity and a relatively low persistence. The development of biosensors for pesticides is the subject of considerable interest, particularly in the areas of food and environmental monitoring. Several enzymes such as cholinesterase enzymes (AChE, BChE) and urease have been used in the design of direct electrochemical biosensors for the detection of pesticides (Larsen et al., 2007). Analytical devices based on the inhibition of cholinesterase have been widely used for the detection of organic phosphate compounds and carbamate pesticides. 

Uncharged carbamates, such as carbaryl (8.20, sevin), can penetrate the CNS of insects (which do not use AChE in their neuromuscular junction) and they act quite selectively as insecticides with a low toxicity to mammals (median lethal dose [LDjg] in the rat = 540 mg/kg, p.o.). Many useful insecticides can thus be found in this group. Malathion (8.21) is a pro-drug, since the thiophosphate must be bioactivated to the phosphate form—a transformation carried out by insects but not mammals. Additionally, the ester groups of malathion are rapidly hydrolyzed in higher organisms to water-soluble and... 

Recently, organic carbamates have been synthesized by the reaction of amines and alkyl halides with scC02 in the presence of potassium carbonate and an onium salt (Bu4N)Br [52]. In order to ascertain the carbonyl-active species (carbonate or C02 ), the reaction was carried out also with potassium phosphate instead of the carbonate salt the similar results obtained confirmed that scC02 acted in the process not only as a solvent but also as a carboxylating agent. 

Endocrine Effects. Little is known about the effects of aluminum on endocrine systems. The oral administration of sodium aluminum phosphate to male and female Beagle dogs for 6 months did not alter thyroid, adrenal, or pituitary gland weight or microanatomy (Katz et al. 1984 Pettersen et al. 1990). These organs were also normal in male and female Wistar rats fed a diet containing unspecified amounts of aluminum phosphide/ammonium carbamate for 24 months (Hackenberg 1972). 

The hydrosilation reaction is highly compatible with a number of functional groups including ether, epoxide, acetal, ketone, ester, nitrile, amine, amide, nitro, carbamate, isocyanate, phosphate, sulfide, sulfone, and others." As a consequence, it is a very attractive reaction for the construction of complex organic molecules. Sometimes allyUc displacement is observed as a side reaction, especially in the reaction of allyl halides. ... 

AIM soln of MesP in THE (ImL) was added at rt to the azide (Immol) in THE (3mL) when the phosphazene formation (1-2 h, TLC) was complete Z-Cl (or other chloroformates) (1.1-1.2 mmol) was added. A precipitate was formed stirring was continued for 20-60 min and the reaction was quenched by addition of phosphate buffer (pH 7). The carbamates were extracted with CH2CI2, the organic layers washed, dried, and evaporated yield 80-100%. 

Leaving groups in the Tsuji-Trost reaction include acetates, halides, ethers, carbonates, sulfones, carbamates, epoxides, and phosphates. Reviews (a) Tsuji, J. In Handbook of Organopalladium Chemistry for Organic Synthesis, Negishi, E. deMeijere, A., Eds. Wiley-lnterscience New York, 2002 Vol II, Palladium-Catalyzed Nucleophile Substitution Involving Allyl Palladium, Propargyl-palladium and Related Derivatives, pp. 1669-1687. (b) Frost C. G. Howarth, J. Williams, J. M. J. Tetrahedron Asymmetry 1992, 3, 1089-1122. 

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