Metabolism aromatic rings

In man, the metabolic pathways of mepirizole were distinct from those in experimental animals, since hydroxylation on each of the aromatic rings did not occur in man. Compound (752) was obtained by oxidation of the 3-methyl group to the carboxylic acid (a similar process occurs with 5-methylpyrazole-3-carboxylic acid, an active metabolite of 3,5-dimethylpyrazole). However, the carboxylic acid metabolite of mepirizole had no analgesic activity and did not decrease blood glucose. 

FIGURE 2.6 The procarcinogen benzo[a]pyrene oriented in the CYPlAl active site (stereo view) via n- n stacking between aromatic rings on the substrate and those of the complementary amino acid side chains, such that 7,8-epoxidation can occur. The substrate is shown with pale lines in the upper structures. The position of metabolism is indicated by an arrow in the lower structure (after Lewis 1996). 

The metabolic potential of yeasts has attracted attention in different contexts, and it has emerged that in contrast to many fnngi, they are able to bring about fission of aromatic rings. Some examples that illnstrate the varions possibilities are given below ... 

In connection with the chemistry of the reactive transient species, nitrene, the chemistry of azepines is well documented u. Also, the chemistry of oxepins has been widely developed due to the recent interest in the valence isomerization between benzene oxide and oxepin and in the metabolism of aromatic hydrocarbons 2). In sharp contrast to these two heteropins, the chemistry of thiepins still remains an unexplored field because of the pronounced thermal instability of the thiepin ring due to ready sulfur extrusion. Although several thiepin derivatives annelated with aromatic ring(s) have been synthesized, the parent thiepin has never been characterized even as a transient species3). 

Kaiser et al. reviewed the microbial metabolism of different nitrogen compounds [320], There is agreement among the authors in suggesting an initial step in the transformation of quinoline (by whole cells) that consists of a hydroxylation at position 2 of the heterocyclic aromatic ring, leading to 2-hydroxyquinoline (see Fig. 21 [321]). 

Aromatic amines are initially metabolized by aromatic and A -hydroxylation (oxidation reactions) and Y-acetylation. Following aromatic ring hydroxylation, the ring structure may be further conjugated with glucuronic acid or sulfate (Parkinson 1996). N-hydroxylation results in the potential methemoglobin-generating metabolite,... 

The typical metabolic reactions of pyrethroids are hydrolysis of an ester linkage and oxidation of an alkyl group or an aromatic ring in either acid or alcohol moiety, as shown in Fig. 6. The oxidative cleavage of the C=C bond of the prop-l-enyl... 

The structure of some phenolic metabolites of 3-nitrofluoranthene (231a) and its 2-nitro isomer have been analyzed by one-dimensional and two-dimensional NMR at 500 MHz. Chemical shifts suggest that the nitro group is not strictly coplanar with the aromatic ring system in solution and that metabolism at a distant site can alter the conformation about the C—N bond of the nitro group492. 

In rats dosed orally with the insect repellent N,N-diethyl-2-phenylacet-amide (4.57), TV-ethyl-2-phenylacetamide (4.58), 2-phenylacetamide (4.59), and 2-phenylacetic acid (4.60) were found as metabolites in the blood, liver, and kidney [35], Hydrolysis of this tertiary amide is, perhaps, facilitated by the presence of the aromatic ring. Indeed, a similar metabolic pattern has been found for the aromatic amide TV,TV-diethyl-3-methylbenz amide (4.82) (see Sect. 4.3.1). 

This subsection is devoted to the metabolic reactivity of the amide bond in anilides, i.e., compounds whose amino moiety is attached to an aromatic ring. Based on the nature of the acyl moiety, a number of classes of anilides exist, three of which are of particular interest here, namely arylacetamides, acylani-lides, and aminoacylanilides. The first group contains several analgesic-antipyretic drugs, the second A4-acyl derivatives of sulfonamides, and the third a number of local anesthetics. Particular attention will be paid to structure-metabolism relationships in the hydrolysis of these compounds. Cases where hydrolysis leads to toxification will be summarized in the last part of the chapter. 

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