Heteroatom dealkylation

Figure 24 The mechanism of oxidation of heteroatom-containing compounds by P450 enzymes (a) The one-electron oxidation mechanism of heteroatom oxygenation (b) The one-electron and hydrogen atom abstraction mechanisms of heteroatom dealkylation...

P450 2D6 catalyzes maity of the basic kinds of oxidative reactions of P450s, e.g., aliphatic and aromatic hydroxylations, heteroatom dealkylations, etc. [887]. In early work in this laboratory [888], the observation was made that many of the substrates contained a basic nitiDgen atom situated 5 A away from the site of oxidation, possibly due to a specific anionic charge in P450 2D6. Subsequently more detailed pharmacophore models have been developed [889-892]. All of these are based on the premise that a basic nitrogen atom in the molecule interacts (coulom-bic bond) with an acidic anuno acid in P450 2D6, usually Asp-301 in most studies. (More recent work shows a role for Glu-216, however, vide infra.)... 

The numerous biotransformations catalyzed by cytochrome P450 enzymes include aromatic and aliphatic hydroxylations, epoxidations of olefinic and aromatic structures, oxidations and oxidative dealkylations of heteroatoms and as well as some reductive reactions. Cytochromes P450 of higher animals may be classified into two broad categories depending on whether their substrates are primarily endogenous or xenobiotic substances. Thus, CYP enzymes of families 1-3 catalyze... 

Aryl and alkyl hydroxylations, epoxide formation, oxidative dealkylation of heteroatoms, reduction, dehalogenation, desulfuration, deamination, aryl N-oxygenation, oxidation of sulfur Oxidation of nucleophilic nitrogen and sulfur, oxidative desulfurization Oxidation of aromatic hydrocarbons, phenols, amines, and sulfides oxidative dealkylation, reduction of N-oxides Alcohol oxidation reduction of ketones Oxidative deamination... 

A broad spectrum of chemical reactions can be catalyzed by enzymes Hydrolysis, esterification, isomerization, addition and elimination, alkylation and dealkylation, halogenation and dehalogenation, and oxidation and reduction. The last reactions are catalyzed by redox enzymes, which are classified as oxidoreductases and divided into four categories according to the oxidant they utilize and the reactions they catalyze 1) dehydrogenases (reductases), 2) oxidases, 3) oxygenases (mono- and dioxygenases), and 4) peroxidases. The latter enzymes have received extensive attention in the last years as bio catalysts for synthetic applications. Peroxidases catalyze the oxidation of aromatic compounds, oxidation of heteroatom compounds, epoxidation, and the enantio-selective reduction of racemic hydroperoxides. In this article, a short overview... 

Reductive Dealkylation Reductive dealkylation involves replacement of an alkyl group on a heteroatom by hydrogen. The reaction is considered to be mainly biologically mediated and usually is important in the subsurface for transformation of agrochemicals. 

Fig. 7.1 Heteroatom oxidation of drugs by cytochrome P450 leading to heteroatom oxides or dealkylation products. 

In mammalian liver microsomes, cytochrome P-450 is not specific and catalyzes a wide variety of oxidative transformations, such as (i) aliphatic C—H hydroxylation occurring at the most nucleophilic C—H bonds (tertiary > secondary > primary) (ii) aromatic hydroxylation at the most nucleophilic positions with a characteristic intramolecular migration and retention of substituents of the aromatic ring, called an NIH shift,74 which indicates the intermediate formation of arene oxides (iii) epoxidation of alkenes and (iv) dealkylation (O, N, S) or oxidation (N, S) of heteroatoms. In mammalian liver these processes are of considerable importance in the elimination of xenobiotics and the metabolism of drugs, and also in the transformation of innocuous molecules into toxic or carcinogenic substances.75 77... 

When heteroatom-substituted alkyl groups (Y = electronegative heteroatom) are oxidized, all three mechanisms lead to a common, cationic intermediate, 8.1 (Scheme 8.2). Water either attacks or deprotonates intermediate 8.1 depending on the identity of Y (Scheme 8.3). If water attacks as a nucleophile, an alkyl group will be lost from the parent drug. This process is known as an oxidative dealkylation. Two specific dealkylations of drugs are shown in Scheme 8.4. 

Turn to Appendix A and pick five different drugs to demonstrate the following phase I metabolic processes oxidation (dealkylation, arene/alkene, heteroatom), reduction, and... 

Finally, cytochromes P-450 catalyze the oxidation of heteroatom-con-taining molecules, leading to products that derive either from the transfer of an oxygen atom to the heteroatom (N-or S-oxygenation) or from the oxidative cleavage of a carbon-heteroatom bond (N- or S-dealkylation) [46],... 

The heme-thiolate cytochromes P450 (P450) catalyze regio- and stereospecific reactions under physiological conditions [18-20], including the hydrox-ylation of hydrocarbons (Equation Eq. 1), alkene epoxidation, heteroatom (N,S) oxidation, dealkylation, and (anaerobic) dehalogenation [21]. 

Scheme 1 Typical reactions catalyzed by cytochromes P450 (a) hydroxylation of saturated hydrocarbons (b) heteroatom oxidation and dealkylation (c) olefin epoxidation (d) aromatic hydroxylation (e) desaturation (f) aldehyde deformylation.

Metabolites derived by loss of an alkyl or arylalkyl group from ethers [Eq. (4)], thioethers [Eq. (5)], amines [Eq. (6)], and amides [Eq. (7)] represent common biotransformation pathways (R, R" = H, alkyl or aryl). These processes involve oxidation on carbon adjacent to the heteroatom. The intermediates are generally unstable and readily decompose to the corresponding alcohol, thiol, amine, or amide and an aldehyde. Intermediates formed from amides [Eq. (7)] are more stable and may be detected as excreted metabolites. If a secondary carbon atom is adjacent to the heteroatom, then this portion of the molecule is released as a ketone. The heteroatom may also be located in a cyclic structure (e.g., morpholine, piperazine). Two processes have been adopted for amines, namely, N-dealkylation or deamination, that are essentially the same event. In general, which of the two terms applies depends on the... 

Heteroatom-demethylation reactions catalyzed by peroxidases could be of significant importance in the activation of drugs (xenobiotics) in plants and be responsible for some plant diseases [91]. Likewise, O-dealkylation reactions catalyzed by peroxidases may be important in the metabolism of tetrahydroprotoberberine (XV) and protoberberine (XVI) alkaloids in the plant families Berberidaceae and Ranunculaceae [50]. 

Some of the important reactions catalyzed by the P450 monooxygenase system include aliphatic hydroxylation, aromatic hydroxylation, epoxidation, heteroatom (N-, 0-, and S-)dealkylation, nitrogen oxidation, oxidative deamination, oxidative dehalo-genation, oxidative denitrification, and oxidative desulfuration. Most of these reactions result from the initial oxidation of a carbon atom, another reason that P450 is so important in the oxidative biotrans-formation of lipophilic chemicals. Some P450-cataly-zed oxidation reactions are illustrated in Table 2. 

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