Oxidation at Allylic Carbon Atoms

H H H H H OH
R1 C C C C R3 R1 C C C C R3
R2 H R4 R2 H R4

7
CH3 7CH2OH CH3 CH3
1 HO HO
6 2
OH OH OH OH
5 3
4
H3C + H3C + H3C
H3C
O C5H11 O C5H11 O C5H11 O C5H11
CH3 CH3 CH3 CH3

∆1-THC 7-Hydroxy-∆1-THC 6α-Hydroxy-∆1-THC 6β-Hydroxy-∆1-THC

H2C H2C
3
2 OH
H
HO HO
N N
1
H3CO H3CO

N N
Quinine 3-Hydroxyquinine
 O-Glucuronide Cojugate

O O O
CH3 CH3 CH3

2' 3' O O
O O O O OH O
CH3 CH3 CH3

3'-Hydroxyhexabarbital 3'-Oxohexabarbital
Hexabarbital

Pentazocine
 Hydroxylation at C α to C=O and C=N
CH 3 CH 3 H O
O O N
N N
O H O H OH
3 OH N-demethylation
Cl N
R C C R' R C C R' Cl N Cl N

H OH

(3S) N-Methyloxazepam Oxazepam

The benzodiazepines Diazepam
or 3-Hydroxydiazepam
are classic examples
(CH3 CH 2 )2 NCH2 CH 2 CH 3
with both functionalities N
O
N
O

3 3

Cl N O2 N N

Flurazepam Nimetazepam

CH2 CH 3 CH2 CH 3
HO
4 3 C6 H5 C6 H5
The sedative hypnotic 4
1
glutethimide possesses
O N O ON O
C α to carbonyl function H H
Glutethemide 4-Hydroxyglutethemide
 Aliphatic hydroxylation
H H H
R1 C C C OH ■  Catalyzes hydroxylation of the ω and ω-1
H H H
ω
H H H carbons in aliphatic chains
R1 C C C H ■  Generally need three or more unbranched
H H H H OH H
carbons
R1 C C C H
H H H

O H O H
N CYP450 N
Pentobarbital Metabolism O O
N N
O H OH O H

CH3
CH3 CH3
O
O O

CYP450 OH
Ibuprofen Metabolism OH OH +
H3C CH3
HOOC CH3
H 3C CH3
OH
 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

OH
O O O O O O
S S
N N CYP450 N N
H H H H
H3C H3C

O O
Acetohexamide Metabolism
 Oxidation Involving Carbon-
Heteroatom Systems
■  C-N, C-O and occasionally C-S
■  Two basic types of biotransformation processes:
1.  Hydroxylation of α-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:
H
H O O
R X Cα R X Cα R XH +

Usually Unstable
Oxidative N-, O-, and S-dealkylation as well as oxidative deamination
reaction fall under this category
2.  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:
1.  CYP mixed-function oxidases: α-C hydroxylation and N-oxidation
2.  Amine oxidases or N-oxidases (non-CYP, NADPH dependent flavoprotein
and require O): N-oxidation

■  3 o Aliphatic and alicyclic H

amines are metabolized by H O O
oxidative N-dealkylation R1 N Cα R1 N Cα R1 NH +
(CYP)
R2 R2 R2
■  Aliphatic 1o, 2o amines are 3o or 2o amine Carbinolamine 2o or 1o amine
susceptible to oxidative
deamination, N-dealkylation H
and N-oxidation reactions H O
O
Cα Cα + NH3
■  Aromatic amines undergoes
NH2 NH2
similar group of reactions as
o
aliphatic amines, i.e., both N- 1 amine Carbinolamine Carbonyl Ammonia
dealkylation and N-oxidation
 N-Dealkylation (Deamination)
H OH
CYP450 Spontaneous
R1 C N R3 R1 C N R3 R1 C O + HN R3
R2 R4 R2 R4 R2 R4
■  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 (α) 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 α-H may be removed, e.g., allyl, benzyl. Quaternary carbon
cannot be removed as contain no α-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

OH
CH3 CYP2C19 CH2 H
N N N N Spontaneous N N
CH3 CH3 CH3

Imipramine N-Dealkylation
 Alicyclic Amines Often Generate Lactams

N OH N O
N
CH3 CH3
CH3 N N
N
Carbinolamine Cotinine
Nicotine

N N O
1 CH3 CH3
C6 H 5 O C6 H 5 O C6 H 5 O
2 Cyproheptadine Lactum metabolite
3
H 3C N H 3C N OH H 3C N O
H H H
Phenmetrazine Carbinolamine 3-Oxophenmetrazine
intermediate

COOCH 3 COOH COOH

Hydrolysis

HN HN HN

O
Methylphenidate Ritalinic Acid 6-Oxoritalinic Acid
 CH3
3oAmine drugs H3C CH3
N N
CH3
H CH3
CH3 CH3
N C
N CH3 NH2 N
H3C O
O
CH3 CH3 O

Lidocaine Disopyramide Tamoxifen

CH3
N
CH3 CH3 N CH3
O CH3 N N
N
S CH3 N
CH3
CH3
Cl
Br
Diphenhydramine Chlorpromazine Benzphetamine Brompheniramine
CH3 CH3 CH3
Alicyclic Amine drugs N N N
H

O CH3
HO O OH O
O
CH3
Meperidine Morphine Dextromethorphan
 2o & 1o Amines

O
CH3 CH2 NH3
CH3 CH3

HN NH 2 O
CH3
Methampetamine Ampetamine Phenylacetone

Cl Cl
NHCH 3 NH 2
O O

Ketamine Norketamine

Generally, dealkylation of secondary amines occurs before deamination. The rate of

deamination is easily influenced by steric factors both on the α-C and on the N; so it is
easier to deaminate a primary amine but much harder for a tertiary amine.
Exceptions: Some 2o and 3o amines can undergo deamination directly without dealkylation.

OH OH OH
O O O
O H H2 N O
Direct Oxidative
HN CH 3 Deamination CH 3
HN
CH 3 CH 3
Propranolol NH3
Aldehyde
Carbinolamine Metabolite

OH O OH
O Oxidative Deamination
O
H3C CH3 Through Primary Amine

HN CH 3 NH 2

O CH 3
H Primary Amine Metabolite
(Desisopropyl Propranolol)
 N-Oxidation
H H H OH
N N N O
Aromatic amines

1° aromatic amine Hydroxylamine Nitroso

H H H H
H H O
1° amines R C N R C N R C N O R C N
H OH O
H H H H
1° amine Hydroxylamine Nitroso Nitro

H H H
CH3 CH3 CH2
2° amines R C N R C N R C N
H OH O
H H H
2° amine Hydroxylamine Nitrone

H H
CH3 CH3
R C N R C N O
3° amines
CH3 CH3
H H
3° amine N-Oxide
■  The attack is on the unbonded electrons so 3o amines can be oxidized
■  Generally, only occurs if nothing else can happen, so it is a rare reaction
■  Performed by both amine oxidases and hepatic MFO
s
■  Good examples would include amines attached to quaternary carbons since
they cannot be deaminated

H H
H3C H3C
N CYP450 N
H OH
CH3 CH3
Cl Cl
Chlorphentermine N-Hydroxylation Hydroxylamine

H NH2 Nitroso
H3C
N
H
CH3
Nitro
Phentermine
Amantadine
 Amides

C-N bond cleavage via α-C

hydroxylation (formation of
carbinolamide) and N-
hydroxylation reactions
 Oxidation involving C-O System (O-Dealkylation)
H OH
CYP450 Spontaneous
R1 C O R3 R1 C O R3 R1 C O + HO R3
R2 R2 R2

■  Converts an ether to an alcohol plus a ketone or aldehyde

■  Steric hindrance discussion similar to N-dealkylation
OH
CH2
O
O N NH2
H3C
H 3C N
O

Sp
on
NH2

tan
50

eo
P4

us
CY

CH3
O OH
O N NH2 O N NH2
H 3C H 3C
H3C N H 3C N
O O
NH2 Trimethoprim O-Dealkylation NH2
 CH3
O O
N O H3C
H OH
N CH3
N CH3

O
O O OH
O CH3
CH3 Cl
Codeine Phenacetin Indomethacin
OH H
O
O N N
H3C O O N CH3
N
H3C N
O H3C CH3
O Metoprolol
NH2 Prazosin

■  One exception that appears to be a form of O-dealkylation is the

oxidation of ethanol by CYP2E1
■  In this case R3 is hydrogen instead of carbon to form the terminal
alcohol rather than an ether
■  The enzyme involved is CYP2E1 and has been historically referred to
as the Microsomal Ethanol Oxidizing System (MEOS)

H OH
CYP450 Spontaneous
H3C C OH H3C C OH H3C C O
H H H
 Oxidation involving C-S System
H OH
CYP450 Spontaneous
R1 C S R3 R1 C S R3 R1 C O + HS R3
■  S-Dealkylation
R2 R2 R2
Steric hindrance discussion similar to N-dealkylation
S O
■  Desulfuration R1 C R2 R1 C R2

O O

■  S-Oxidation R1 S R2 R1 S R2 R1 S R2
O
Sulfoxide Sulfone
O
CH3 CH2 OH CH2 SH
S S
N N N N
N N
N N N N
N N H
H H
6-(Methylthio)-purine 6-Mercaptopurine
 COOH
O H O H O H
H3C S N S CH2C6H5 N N
S S O
N N N
O H CF3 O H O H
Methitural Thiopental Pentobarbital
2-Benzylthio-4-
trifluoromethyl benzoic acid

NO2 NO2
H3C O S H3C O O
P P
O O
H3C O H3C O
Parathione Paraoxone
 N N N N
S CH3 O S CH3
O
O
CH3 CH3
S S
N N Ring Sulfoxide Ring Sulfone
S CH3

CH3
S
N N N N
Thioridazine
S CH3 S CH3

CH3
S CH3 S
O O O
Mesoridazine Sulforidazine