Phase I Functionalization Oxidation of Aromatic

Oxidative Reactions Oxidation of aromatic moieties ------------------------------ Aromatic hydroxylation refers to the mixed – function oxidation of aromatic compounds ( Arenes) to their corresponding phenolic metabolites ( Arenols).

Preferentially the more electron rich ring is hydroxylated Antihypertensive drug clonidine undergo little aromatic hydroxylation and the uricosuric agent probenecid has not been reported to undergo any aromatic hydroxylation Probenecid Clonidine Preferentially the more electron rich ring is hydroxylated Diazepam Chlorpromazine NIH Shift: Novel Intramolecular Hydride shift named after National Institute of Health where the process was discovered. This is most important detoxification reaction for arene oxides

What is NIH mechanism rearrangement where a hydrogen atom on an aromatic ring undergoes an intramolecular migration primarily during a hydroxylation reaction. This process is also known as a 1,2-hydride shift. These shifts are often studied and observed by isotopic labelling. An example of an NIH shift is shown below: An NIH shift is a chemical

Mechanism of NIH

In this example, a hydrogen atom has been isotopically labeled using deuterium (shown in red). As the hydroxylase adds a hydroxyl (the -OH group), the labeled site shifts one position around the aromatic ring relative to the stationary methyl group (-CH3).

Several hydroxylase enzymes are believed to incorporate an NIH shift in their mechanism, including tetrahydrobiopterin- dependent hydroxylases. The name NIH shift arises from the U.S. National Institutes of Health from where studies first reported observing this transformation.

Oxidation of olefinic bonds (also called alkenes) The second step may not occur if the epoxide is stable, usually it is more stable than arene oxide May be spontaneous and result in alkylation of endogenous molecules Susceptable to enzymatic hydration by epoxide hydrase to form trans-1,2-dihydrodiols (also called 1,2-diols or 1,2-dihydroxy compounds) Terminal alkenes may form alkylating agents following this pathway Q. Any similarities or dissimilarities with aromatic – NIH Shift, Conjugation with macromolecules?

Benzylic Carbon Hydroxylation Hydroxylate a carbon attached to a phenol group (aromatic ring) R1 and R2 can produce steric hindrance as they get larger and more branched So a methyl group is most likely to hydroxylate Primary alcohol metabolites are often oxidized further to aldehyde and carboxylic acids and secondary alcohols are converted to ketones by soluble alcohol and aldehyde dehydrogenase Tolbutamide Metabolism Tolmetin sodium Dicarboxylic acid is the major metabolite

Oxidation at Allylic Carbon Atoms

Pentazocine

Aliphatic hydroxylation Catalyzes hydroxylation of the ω and ω-1 carbons in aliphatic chains Generally need three or more unbranched carbons Pentobarbital Metabolism Ibuprofen Metabolism +

Alicyclic (nonaromatic ring) Hydroxylation Cyclohexyl group is commonly present in many drug molecules The mixed function oxydase tend to hydroxylate at the 3 or 4 position of the ring Due to steric factors if position 4 is substituted it is harder to hydroxylate the molecules Acetohexamide Metabolism

Oxidation Involving Carbon-Heteroatom Systems C-N, C-O and occasionally C-S Two basic types of biotransformation processes: Hydroxylation of a-C attached directly to the heteroatom (N,O,S). The resulting intermediate is often unstable and decomposes with the cleavage of the C-X bond: Oxidative N-, O-, and S-dealkylation as well as oxidative deamination reaction fall under this category Hydroxylation or oxidation of heteroatom (N, S only, e.g., N-hydroxylation, N-oxide formation, sulfoxide and sulfone formation) Metabolism of some N containing compounds are complicated by the fact that C or N hydroxylated products may undergo secondary reactions to form other, more complex metabolic products (e.g., oxime, nitrone, nitroso, imino)

C-N systems Aliphatic (1o, 2o, 3o,) and alicyclic (2o and 3o) amines; Aromatic and heterocyclic nitrogen compounds; Amides Enzymes: CYP mixed-function oxidases: a-C hydroxylation and N-oxidation Amine oxidases or N-oxidases (non-CYP, NADPH dependent flavoprotein and require O): N-oxidation 3o Aliphatic and alicyclic amines are metabolized by oxidative N-dealkylation (CYP) Aliphatic 1o, 2o amines are susceptible to oxidative deamination, N-dealkylation and N-oxidation reactions Aromatic amines undergoes similar group of reactions as aliphatic amines, i.e., both N-dealkylation and N-oxidation

N-Dealkylation (Deamination) Deamination and N-dealkylation differ only in the point of reference; If the drug is R1 or R2 then it is a deamination reaction and If the drug is R3 or R4 then it is an N-dealkylation In general, least sterically hindered carbon (a) will be hydroxylated first, then the next, etc. Thus the more substituent on this C, the slower it proceeds; branching on the adjacent carbon slows it down, i.e. R1, R2 = H is fastest. Any group containing an a-H may be removed, e.g., allyl, benzyl. Quaternary carbon cannot be removed as contain no a-H The more substituents placed on the nitrogen the slower it proceeds (steric hindrance) The larger the substituents are the slower it proceeds (e.g. methyl vs. ethyl). In general, small alkyl groups like Me, Et and i–Pro are rapidly removed; branching on these substituents slows it down even more Imipramine N-Dealkylation

Alicyclic Amines Often Generate Lactams

3oAmine drugs Tamoxifen Lidocaine Disopyramide Diphenhydramine Chlorpromazine Benzphetamine Brompheniramine Alicyclic Amine drugs Meperidine Morphine Dextromethorphan