O-dealkylation reactions

Scheme 23. O-Dealkylation reactions of apoiphines by Cunninghamella elegans ATCC 9245.

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. 

Peroxidase-catalyzed reactions of particular interest are the N- and O-dealkylation reactions via electron transfer. These reactions also require drastic experimental conditions in preparative organic chemistry [91], but are relatively common in the plant cell biochemical factory. N- and O-dealkylation reactions catalyzed by class III plant peroxidases can be summarized [91] as follows ... 

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]. 

The work conclusively indicates that Aspergillus niger could be used as a microbial model for mammalian metabolism in o-dealkylation reactions, as the meehanism of o-dealkylation (as indicated from the quantitative studies) is similar to the cytochrome P450 catalyzed reactions. The work has also resulted in a synthetically viable method of o-dealkylations. 

Kim KH, Isin EM, Yun CH, Kim DH, Guengerich F (2006) Kinetic deuterium isotope effects for 7-alk-oxycoumarin O-dealkylation reactions catalyzed by human cytochromes P450 and in liver microsomes. FEES 1273 2223 2231... 

The concept of microbial models of mammalian metabolism was elaborated by Smith and Rosazza for just such a purpose (27-32). In principle, this concept recognizes the fact that microorganisms catalyze the same types of metabolic reactions as do mammals (32), and they accomplish these by using essentially the same type of enzymes (29). Useful biotransformation reactions common to microbial and mammalian systems include all of the known Phase I and Phase II metabolic reactions implied, including aromatic hydroxylation (accompanied by the NIH shift), N- and O-dealkylations, and glucuronide and sulfate conjugations of phenol to name but a few (27-34). All of these reactions have value in studies with the alkaloids. 

Smith and Rosazza have suggested that microbial transformation experiments could best be carried out by using a series of perhaps 10 metabolitically prodigious microorganisms as microbial models. Microorganisms for such work may be selected on the basis of considerable literature precedence for their abilities to catalyze the desired biotransformation reaction (i.e., O-dealkylation, N-dealkylation, aromatic hydroxylation, and reductions). The alkaloid substrate... 

The O-dealkylation of ethers, while not as frequently encountered as N-dealkylation in drug metabolism studies, is still a common metabolic pathway. Mechanistically it is less controversial than N-dealkylation in that it is generally believed to proceed by the HAT pathway, i.e., a-hydrogen atom abstraction followed by hydroxyl radical rebound, and not a SET pathway (Fig. 4.58). The product of the reaction is unstable, being a hemiacetal or hemiketal depending on the number of hydrogens on the a-carbon, which dissociates to generate an alcohol and an aldehyde or ketone. 

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... 

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. 

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... 

Dealkylation 0-, N-, and S-Dealkylation. Probably the best known example of O-dealkylation is the demethylation of p-nitroanisole. Due to the ease with which the product, /t-nilrophcnol, can be measured, it is a frequently used substrate for the demonstration of CYP activity. The reaction likely proceeds through formation of an unstable methylol intermediate (Figure 7.5). 

The O -dealkylation of organophosphorus triesters differs from that of p-nitroanisole in that it involves the dealkylation of an ester rather than an ether. The reaction was... 

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. 

Figure 7.6 Metabolic dealkylation reactions shown for the removal of CH3 from N, O, and S atoms in organic compounds.

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. 

A particular isozyme can perform several types of reaction, including hydroxylations, reductions, O-dealkylations and epoxidations.65 The most important reactions for CAC are hydroxylations and epoxidations. A CYP isozyme can also catalyse different reactions of different substrates. CYP1A, to give an example, can O-dealkylate ethoxyresorufine or hydroxylate benzo[a] pyrene. 

The conversion of (—)-apomorphine into (+)-apomorphine has been achieved.56 The O-dealkylation of 10,11-dimethoxyaporphine, using sodium thioethoxide in dimethylformamide, has been reported.57 The reactions of the enamine dehydro-nuciferine with dimethyl acetylenedicarboxylate, methyl propiolate, methyl acrylate, and diethyl azodicarboxylate have been investigated, and have resulted in the preparation of a novel series of 7-substituted aporphines.58... 

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