Oxidative O-dealkylation

FIGURE 4.66 P450-catalyzed oxidative O-dealkylation of an ester. 

From these data, it can be estimated that chlorphenoxamine (11.24, R = 4-C1, R = Me) should hydrolyze ca. 17 times faster than diphenhydramine. This decreased stability appears sufficient to drive formation of detectable amounts of the benzhydrol metabolite (11.25, R = 4-C1, R = Me) in the stomach of patients dosed with chlorphenoxamine. Indeed, ether bond cleavage to form this and derived metabolites was a major pathway in humans [49], Whether the reaction was entirely nonenzymatic or resulted in part from oxidative O-dealkylation (Chapt. 7 in [50]) remains unknown. 

Q5.1 The primary metabolic step involves a different mechanism for each of the drugs listed in Figure 5.11. Select the appropriate transformation for each drug from the following list aliphatic hydroxylation, oxidative N-dealkylation, hydrolysis, aromatic hydroxylation, oxidative O-dealkylation. Draw the structure of the primary metabolite in each case. 

Oxidative O-dealkylation of ethers is a common metabolic reaction with a mechanism of dealkylation analogous to that of N-dealkylation oxidation of the a-carbon, and subsequent decomposition of the unstable hemiacetal to an alcohol (or phenol) and a carbonyl product... 

Miwa GT, Walsh JS, Lu AYH (1984) Kinetic isotope effects on cytochrome P-450-catalyzed oxidation reactions. The oxidative O-dealkylation of 7-ethoxy-coumarin. J Biol Chem 259 3000-3004... 

Anilides are simple acetamides of aniline, which may or may not contain a 4-hydroxy or 4-alkoxy group (Figure 13.13). Acetanilide is ring hydroxylated after administration to yield acetaminophen, the active analgesic/antipyretic, whereas phenacetin (rarely used) undergoes oxidative-O-dealkylation to produce acetaminophen. Anilides do not possess carboxylic acid functionality and, therefore, they are classified as neutral drugs and possess little, if any, inhibitory activity against COX. 

Fenoldopam (76) is an antihypertensive renal vasodilator apparently operating through the dopamine system. It is conceptually similar to trepipam. Fenoldopam is superior to dopamine itself because of its oral activity and selectivity for dopamine D-1 receptors (D-2 receptors are as.sociated with emesis). It is synthesized by reduction of 3,4-dimethoxyphenylacetonitrile (70) to dimethoxyphenethylamine (71). Attack of diis last on 4-methoxystyrene oxide (72) leads to the product of attack on the epoxide on the less hindered side (73). Ring closure with strong acid leads to substituted benzazepine 74. O-Dealkylation is accomplished with boron tribromide and the catechol moiety is oxidized to the ortho-quinone 75. Treatment with 9NHC1 results in conjugate (1,6) chloride addition and the formation of fenoldopam (76) [20,21]. 

N-dealkylation, O-dealkylation, oxidative dehalogenation, and oxidation of aryl and alkyl methyl groups. 

Halogen dealkylation mimics O-dealkylation both in terms of mechanism and the commonality of the process. Virtually any drug that contains a carbon-hydrogen bond adjacent to a halogen atom will be subject to P450-catalyzed oxidative dehalogenation (Fig. 4.61). 

By analogy to N- and O-dealkylation reactions, one might expect esters and amides to be susceptible to P450-catalyzed oxidative attack at the a-carbon to oxygen (esters) or a to nitrogen (amides). This is indeed the case and was first established (132) by demonstration that the pyridine diester (Fig. 4.66) was oxidatively cleaved by rat-liver microsomes to yield the monoacid as shown. 

A relatively unique type of reactive metabolite is carbene, i.e., a divalent carbon, which is a proposed intermediate in the oxidation of methylene dioxy-containing compounds. A methylenedioxy group in aromatic compounds is subject to O-dealkylation, e.g., 3,4-methylenedioxyamphetamine, as shown in Figure 8.20. The process generates formic acid and the catechol metabolite as final products. However, in the course of the reaction, a... 

An unusual oxo-transfer to an amine has been observed, besides other products that originate from oxidative N-dealkylation chemistry, when the di-copper(I) complex of hgand 24 was reacted with O2 at 0 °C (Scheme 11) [169]. A labeling experiment showed that the O atom in 25 is derived from molecular dioxygen. 

Oxidation Carbon-Oxygen Systems. Molecules containing ether linkages may undergo oxidative 0-dealkylation. In this process, the carbon atom located a to the oxygen atom is hydroxylated, followed by cleavage of the C-O bond. 

Microsomal oxidations may be subdivided into aromatic hydroxylation aliphatic hydroxylation alicyclic hydroxylation heterocyclic hydroxylation N-, S-, and O-dealkylation N-oxidation N-hydroxylation S-oxidation desulfuration deamination and dehalogenation. 

A characteristic of the liver P4so enzymes is their almost total lack of substrate specificity, distinguishing them from the adrenal gland enzymes which are much more specific (B-74MI11003). In addition to hydroxylation of hydrocarbons, which involves the conversion of C—H bonds to C—OH bonds and C=C bonds to epoxide rings, a multitude of other types of reaction are catalyzed. These include iV-oxidation, 5-oxidation, N-, S- and O-dealkylation, peroxidation, deamination, desulfuration and dehalogenation, as well as... 

Three metabolic pathways were identified (i) O-dealkylation to metabolites Ml and M2, with subsequent glucuronidation to metabolites M3 and M5 (ii) hydrolysis to metabolite M4 and (iii) N-oxidation to metabolite M6 (Fig. 3.13). Additional metabolic pathways maybe operative, as represented by the number of unknown compounds observed. However, as each unknown metabolite represented an average of <2% of the dose, these pathways are considered minor contributors to the metabolic process [52],... 

Phase 1 reactions Oxidative reactions involving N- and O-dealkylation, aliphatic and aromatic hydroxylation, N- and S-oxidation, deamination. Phase 2 reactions Biotransformation reactions involving glucuronization, sulphation, acetylation. 

Chemical transformations carried out by biological reagents such as purified enzyme preparations and by intact organisms such as fungi and bacteria have done much to ease the lot of the synthetic chemist in recent years. Regio- and stereoselective reactions such as C-hydroxylation (1, 2), S-oxidation (3, 4), carbonyl reduction (5, 6) and oxidation (7, 5), N- and O-dealkylation (9), N-oxidation (10), and hydrolytic reactions carried out by biological systems have been widely used in many areas of organic chemistry (11, 12). 

The enzymes reductively activate dioxygen using NADPH as an electron source. One oxygen atom is then reduced to water and the other atom is transferred to a substrate, resulting in the hydroxylation of alkenes and arenes, the epoxidation of alkenes and the formation of N-oxides and S-oxides from amino and sulphur compounds. Other P-450 reactions include N-dealkylation, O-dealkylation and reductase-like dehalogenation of halocarbons. Typical P-450 reactions are summarised in Ihble 5-4. 

The second type of oxidative biotransformation comprises dealkylations. In the case of primary or secondary amines, dealkylation of an alkyl group starts at the carbon adjacent to the nitrogen in the case of tertiary amines, with hydroxylation of the nitrogen (e.g., lidocaine). The intermediary products are labile and break up into the dealkylated amine and aldehyde of the alkyl group removed. O-dealkylation and S-dear-ylation proceed via an analogous mechanism (e.g., phenacetin and azathioprine, respectively). 

Epoxidation and hydroxylation A-Dealkylation O-Dealkylation -Dealkylation -Oxidation A-Oxidation P-Oxidation Desulfuration Dehalogenation Nitro reduction Azo reduction Cytochrome P450 (CYP) Aflatoxin, aldrin, benzo[a]pyrene, bromobenzene, naphthalene Ethylmorphine, atrazine, dimethylnitrocarbamate, dimethylaniline p-Nitroanisole, chlorfenvinphos, codeine Methylmercaptan Thiobenzamide, phorate, endosulfan, methiocarb, chlorpromazine 2-Acetylaminofluorene Diethylphenylphosphine Parathion, fonofos, carbon disulfide CCLt, CllCb Nitrobenzene O-Aminoazotoluene Flavin-Containing Monooxygenase (FMO)... 

HRP catalyzes the oxidative dehydrogenation of a wide range of electron-rich aromatic compounds. The result of this radical formation pathway is dimerization and subsequent oligomerization of the substrates [76-78]. Peroxidases have been used to catalyze polymerizations of phenols (e.g. p-cresol and guaiacol) and aromatic amines (e.g. aniline, and o-phenyldiamine) [79, 80]. N- and O-dealkylations are also useful electron transfer reactions catalyzed by peroxidases. These reactions are used in industrial wastewater treatment and may have synthetic applications [81]. 

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