Endogenous nucleophiles

In conclusion, it is clear that a variety of stereoelectronic (internal) factors and external conditions favor a substantial positive charge in the transition state of diol epoxides as they undergo hydration or react with nucleophiles [115-118], Interpreting the reactivity of diol epoxides (or of numerous other electrophilic metabolites) in terms of toxification vs. detoxification is particularly difficult since toxicity depends as much on the nature of the endogenous nucleophile as on the intrinsic reactivity of the metabolites. 

The formation of another metabolite, l-hydroxybut-3-ene-2-one (10.109), postulated to arise by dehydrogenation of the secondary alcoholic group, could be demonstrated only indirectly. l-Hydroxybut-3-ene-2-one is believed to react with glutathione and other endogenous nucleophiles, to be oxidized to 2-oxobut-3-enoic acid (10.110), and to break down to form unidentified products. 

In summary, a growing body of evidence suggests that at least part of the chronic toxicity of buta-1,3-diene is caused by reactive metabolites that bear an epoxy or ,/Tunsaluralcd carbonyl group. These metabolites form adducts with protective (glutathione) or critical (e.g., nucleic acids) endogenous nucleophiles [163] [166] [167],... 

Examples for GSH as a transporter of reversibly bound electrophiles are conjugates of isocyanates, isothiocyanates, alpha and beta unsaturated aldehydes, and aldehydes. These compounds form labile conjugates that may again disassociate to the parent electrophile and glutathione. The electrophile can then react with endogenous nucleophiles to form more thermodynamically favored adducts. 

Scheme 19.11 Phenoxybenzamine s (35) irreversible interaction with its targeted biological surface, namely that for treating pheochromacytoma. Note that while this is analogous to the mechanism of the nitrogen mustards displayed in Scheme 19.10, in this case the rate of formation of the aziridinium species has been attenuated by the steric features of the N-benzyl group. This feature, in turn, allows 35 to first associate with its target biological surface (A). Once bound at this intended destination, formation of an aziridinium does occur (B) and this is rapidly followed by a reaction with an endogenous nucleophile located within this immediate locale (C). Ultimately, this biological surface is selectively shut down (D).

Oxidation of the 3-methyl group occurs either directly via deoxygenation or via epoxidation of the 2,3-double bond leading to 2,3-epoxy-3-methylindole, the reactive intermediate that ean be trapped by endogenous nucleophiles, such as glutathione. 

The Diels-Alder reaction is defined as a [4-1-2] cycloaddition between a conjugated diene and a substituted dienophile (alkene or alkyne) to form a (hetero-)cyclohexene system. Based on the electronic effects of the substituent on the diene and dienophile, Diels-Alder reactions can be classified as normal electron-demand (electron-rich diene reacts with electron-deficient dienophile) or inverse electron-demand (iEDDA, electron-deficient diene reacts with electron-rich dienophile) reactions (Scheme la). In a normal electron-demand Diels-Alder reaction, the electron-deficient dienophile, typically a Michael acceptor, is likely to be attacked by endogenous nucleophiles such as free amino and thiol groups in vivo. For this reason, the use of this reaction in bioorthogonal chemistry apphcations poses a challenge. 

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