Nucleophilic cell components

Nucleophilic cell components, e.g. the amino groups of the guanine bases in DNA, are alkylated by the aziridinium ion as a result of a nucleophilic ring-opening. In the case of bis(2-chloroethyl)amine, the reaction can be repeated on a guanine base of the other DNA strand of the double helix. This results in cross-linking of the two DNA strands and consequently blocks replication (see p 31). 

Different types of aldehydes are shown in Figure 6. The electrophilic character of aldehydes is a consequence of the deficit of electrons on the carbonyl atom which enables the aldehydes and aldehyde releasing compounds to react with nucleophilic cell components as is demonstrated in Figure 7. 

Mierobieides disposing of sueh a toxophoric structural element - as already mentioned, acrolein and a-bromo-einnamaldehyde do that - may add to nucleophilic cell components (Figure 8.) and release their antimicrobial effect in this way. However, sueh substances are only suitable for practical applications, e.g. as non-persistent slimieides, if the aetivated vinyl group is part of a resonance-stabilized system (which has been mentioned already in eonneetion with the stability of BCA). Without stabilisation by a resonance system the substances are too reaetive and unstable, i.e. polymerisation and reactions with components in the surrounding medium, reactions with ammonia and amines taking preeedence (Paulus, 1976). 

Figure 18 Reaction of organometallic compounds with nucleophilic cell components.

Figure 13 Reaction of an active N-haloalkylthio compound with a SH group bearing cell component (nucleophile).

Benzyl bromoacetate acts as an electrophilic active compound due to its electron attracting power (electronegativity) the bromo atom may be substituted nucleophilically, i.e. by nucleophilic active components of the microbe cell. 

The experiments presented above definitively established the fact the Lipson s HPD-forming procedure gives dimeric and trimeric porphyrin esters as the high-molecular weight component which is eminently better localized and retained in tumor cells and is responsible for most of the photodynamic activity associated with HPD. Mechanistically, the formation of ester linkage is not only understandable but expected as well. Under the alkaline condition employed in the synthesis of HPD, the nucleophilic substitution reaction illustrated in the following scheme is very similar to the... 

The final type of chemical toxicity that will be presented are the vesicants, chemicals that cause blisters on the skin. There are two classes of blisters that implicate different mechanisms of vesication. Intraepidermal blisters are usually formed due to the loss of intercellular attachment caused by cytotoxicity or cell death. The second class occurs within the epidermal-dermal junction (EDJ) due to chemical-induced defects in the basement membrane components. The classic chemical associated with EDJ blisters is the chemical warfare agent sulfur mustard (bis-2-chloroethyl sulfide HD). HD is a bifunctional alkylating agent that is highly reactive with many biological macromolecules, especially those containing nucleophilic groups such as DNA and proteins. 

The carboxyperoxyl radical anion thus produced should be similar in reactivity to the hydroperoxyl radical, HO. The nucleophilic activity of the superoxide ion towards carbonyl groups in acid chlorides, esters and ketones is well documented The reaction between superoxide ion and the Py-Py" cation radical, which leads to destruction of the latter, would seem more likely to mitigate the long-term effects of the Py-Py rather than promote damage to components of the cell d . The occurence of Rh(bipy) -mediated photoreduction of alkenes with NADH models and... 

As mentioned previously, the biotransformation of lipophilic xenobiotics by Phase I and Phase II reactions might be expected to produce a stable, water-soluble, and readily excretable compound. However, there are examples of hepatic biotransformation mechanisms by which xenobiotics are converted to reactive electrophilic species. Unless detoxified, these reactive electrophiles may interact with a nucleophilic site in a vital cell constituent, leading to cellular damage. There is evidence that many of these reactive substances bind covalently to various macromolecular constituents of liver cells. For example, carbon tetrachloride, known to be hepatotoxic, covalently binds to lipid components of the liver endoplasmic reticulum (Reynolds and Moslen 1980). Some of the reactive electrophiles are carcinogenic as well. 

Examples of nucleophilic reaction partners in the cell are amino and thiol groups, as well as the amide groups of amino acids or proteins (Fig. 15). These in turn are components of enzymes, which are inactivated by the reaction of their nucleophilic groups with aldehydes. 

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