A third example can be found with ezlopitant (113), a drug being developed as a potential substance P receptor antagonist. Metabolism of 113 yields two major metabolites, the benzyl alcohol 114 and the corresponding alkene142 115 (Scheme 11).
5.05.2.1.6.2 Oxidative cleavage of esters and amides
If esters and amides are also susceptible to oxidative attack, one would expect that the site of attack to be the carbon atom a to an oxygen atom (esters) or a to a nitrogen atom (amides) by analogy to O- and N-dealkylations. This is indeed the case. Guengerich etal.143 demonstrated that the pyridine diester 116 was oxidatively cleaved, to yield the mono-acid 117 (eqn ). Subsequently, Peng etal.144 established that oxidative cleavage is a general cytochrome P450 reaction for commonly used esters and amides. The reaction has largely gone unrecognized, probably because of being obscured by hydrolysis, the expected mode of reaction.
5.05.2.1.6.3 Oxidative transformation of nitriles
Cytochrome P450-catalyzed C-C bond cleavage is a relatively rare event. The conversion of aldehydes to alkenes112'113 was presented earlier. A second example is the conversion of a nitrile to a cyanide ion and an aldehyde or ketone. Grogan etal.99 modeled the reaction using a set of 26 structurally diverse nitriles. They found that acute toxicity in the mouse correlated with the ease of hydrogen abstraction a to the nitrile (cyanide release) relative to oxidative attack at other intramolecular sites (no cyanide release).
Cytochrome P450 also appears to generate nitriles from alkyl and arylaldoximes by catalyzing their dehydration.145,146 The reaction was first reported for the conversion of n-butyraldoxime (118) to butyronitrile (119), and found to require reduced cytochrome P450 (heme Fe2 +) and be inhibited by excess O2 (eqn ).145 Subsequently, the reaction was established for both alkyl- and arylaldoximes146 (e.g., benzaldoxime (120) (eqn ), and phenylacetaldoxime (122) (eqn )), suggesting that while it is apparently restricted to the (Z) isomer, it might be general.
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