Alkylate cellular nucleophiles

Wiessler (15) suggested that the nitrosoimmonium ion could act as the electrophile which alkylates cellular nucleophiles. 

These nltrosated amides, In contrast to the nltrosamlnes, do not require metabolic activation in order to alkylate cellular nucleophilic targets. Thus, many of these substances are directly acting mutagens and also carcinogens (38. ... 

The very unstable hydroxy nitrosamine then loses formaldehyde to form the primary alkynitrosamine, which rapidly rearranges to the alkyl diazonium ion. The latter, being a powerful electrophile, alkylates various cellular nucleophiles, including the nucleic acids. 

The alkylating agents can transfer an alkyl radical to a suitable receptor site. Alkylation of DNA within the nucleus represent the major interactions which will lead to cell death. These agents react chemically with sulfhydryl, carboxyl, amino and phosphate groups of other cellular nucleophiles in the cells which make them unavailable for the normal metabolic reactions. Alkylating agents react with nucleic acid and inhibit... 

As a class, the alkylating agents exert their cytotoxic effects via transfer of their alkyl groups to various cellular constituents. Alkylations of DNA within the nucleus probably represent the major interactions that lead to cell death. However, these drugs react chemically with sulfhydryl, amino, hydroxyl, carboxyl, and phosphate groups of other cellular nucleophiles as well. The general mechanism of action of these drugs... 

Ethyleneimine is an extremely reactive alkylating agent that undergoes ring opening reactions with cellular nucleophiles. 

Mechlorethamine is the only aliphatic nitrogen mustard currently on the U.S. market (Fig. 42.3). Its use is limited by extremely high reactivity, which leads to rapid and nonspecific alkylation of cellular nucleophiles and excessive toxicity. It is a severe vesicant, and if accidental skin contact occurs, the drug must be inactivated with 2% sodium thiosulfate (Na2S203) solution. This reagent reacts with the mustard to create an inactive, highly ionized, and water-soluble thiosulfate ester that can be washed away (Fig. 42.4). The affected tissue also should be treated with an ice compress for 6 to 12 hours. 

Pre-treatment of rats with phenobarbitone, which is known to increase the P450 content of microsomal enzymes, increased the mutagenic response to vinyl chloride monomer in vitro (Bartsch etal. 1975). In an aqueous solution at pH 7.4 and 37 °C the epoxy compound had a half-Ufe of 1.6 min, and its rate of hydrolysis followed a first order kinetic. Chloroethylene oxide, but not 2-chloroacetaldehyde, showed a strong alkylating activity as determined by its reaction with 4-(p-nitrobenzyl)pyridine (Malaveille etal. 1975). 2-Chloroacetaldehyde is a chemically reactive and toxic compound (Lawrence et al. 1972), and is covalently bound to cellular nucleophiles. It reacts at pH 3.5-4.5 and 37 °C with adenosine or cytidine to give fluorescent products, which have been characterised as 3- 3-D-ribofuranosyl-imidazo-(2,l-i)pur-ine or 5,5-dihydro-5-dihydro-5-oxo-5- 3-D-ribofu-... 

The role of active site polarity in enhanced enzyme-catalyzed alkyl transfers has not been investigated in detail. It is clear that indiscriminate alkylation of cellular nucleophiles is incompatible with life therefore enzyme-catalyzed alkyl transfer must be strictly regulated vivo. Fig. 3 shows rate data for the... 

The reversibility of QM adducts also creates numerous challenges. For example, measuring the full burden of DNA alkylation by a QM can be obscured by the loss of its labile products during or before chemical identification can be completed. Results from a deoxynucleotide model system indicated that only a small fraction of the possible adducts could be measured after the interval required for analysis of DNA. Perhaps the kinetic products of QMs also contribute to the cellular activity of these intermediates although this has yet to be explored. QM equivalents can be envisioned to migrate from one reversible nucleophile such as the N1 of adenine in such cofactors as ATP to another until quenched by a compound such as glutathione that is present in cells as a defense against undesirable electrophiles. 

CN is considered less than lethal or nonlethal because it has a large safety ratio. That is, its effective dose or concentration ECtfo is low compared to its lethal dose or concentration (LCtfo). In the body, CN is converted to an electrophilic metabolite. It is an SN2 alkylating agent that reacts with SH groups and other nucleophilic sites of biomolecules. Alkylation of SH-containing enzymes leads to enzyme inhibition with disruption of cellular processes. CN was found to inhibit human plasma cholinesterase via a non-SH interaction, and some of the toxic effects may be due to alkylation of SH-containing enzymes. 

The ability of quinazoline to enter the xanthine oxidase active site, and the presence of an active site nucleophile near the alkylating center, very likely accounts for enzyme inactivation by these hydroquinones. The quinone (696) acts as an oxidizing suicide substrate. It is able to enter the xanthine oxidase active-site, and by the enzyme reductive action and HCl elimination it becomes a reductive alkylating agent (698) targeted towards cellular structures important to the cancer cell <88JOC6099>. 

During the oxidation of nitrosamines, the hydroxylated derivative formed cleaves spontaneously into highly reactive metabolites capable of alkylating nucleophilic sites in the cellular components. 

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