Metabolism Part2 1

- C-N, C-O, and C-S oxidation involve two main types.
1- Hydroxylation of the -carbon atom directly attached to

heteroatom, to produce unstable intermediate which decomposes by
cleavage the C-X bond.

2- Hydroxylation of the heteroatom (N,S only) forming N-
hydroxyl, N-oxide, sulphoxide and sulphone.

Carbon-Heteroatom systems oxidation

1- Hydroxylation of the -carbon atom directly attached to heteroatom,
to produce unstable intermediate which decomposes by cleavage of
the C-X bond.


2- Hydroxylation of the heteroatom (N,S only) forming N-hydroxyl, N-
oxide, sulphoxide and sulphone.

Oxime, nitrone, nitroso, imino

- Nitrogen containing compounds are divided into three basic classes:

1- Aliphatic (1 , 2 , 3 ) and alicyclic (2 , 3) amines

2- Aromatic and heterocyclic nitrogen compounds

3- Amides

- Tertiary amines:
- Oxidative removal of alky group (oxidative N-dealkylation) by P-
450. Started by -carbon hydroxylation to form carbinolamine
intermediate, then cleavage of C-N bond to secondary amine and
carbonyl moiety (Aldehyde or ketone).

C-N system oxidation

- Small alky groups are normally removed quickly, and the first is
removed faster.

Methadone to pyrrolidine ring cyclization
- Complete dealkylation reactions will lead to oxidation of primary
amine to carboxylic acid.
- t-butyl moiety is not possible to be removed because no alpha H to
be hydroxylated with the exception of t-butyl-norchlorcyclazine,
which occur through oxidation of terminal CH
3
to carboxylic acid
then decarboxylated to produce H at alpha carbon.

Cl
N
N
Cl
N N
OH
Cl
N N
COOH
Cl
N N

- Tertiary alicyclic amines usually form Lactams (nicotine).

- Secondary amines:
Undergo oxidative N-dealkylation, oxidative deamination, and N-
oxidation reactions.
- Oxidative N-Dealkylation: Carbinolamine pathway which produces
primary amine (the same as for tertiary amines).
- Examples:

propranolol methamphetamine
norketamine
- Secondary amines:
- Oxidative Deamination: process by which a molecule loses the
primary amine group by the same carbinolamine intermediate.

- In general, the first step is N-dealkylation, then deamination

- There is an exception such as propranolol in which the oxidative
deamination can occur directly through the oxidation of the alpha-
carbon of its secondary amine.


- Metabolic oxidation reactions of Propranolol:

- Norketamine does not undergo N-deamination. (why?)

- Norketamine can only undergo oxidative N-dealkylation

- Also some alicyclic secondary amines are transformed to their
corresponding lactams (phenmetrazine, methylphenidate).

- N-oxidation also happens but to less extent to form N-
hydroxylamine that is prone to form nitrone derivative
- Primary amines:
- Primary amines normally undergo oxidative deamination or N-
oxidation. (endogenous compounds such as neurotransmitters
oxidized via monoamine oxidase [MAOs]).

- The possibility of alpha carbon oxidation depends on the availability
of alpha hydrogen (eg. Phentermine).

-Decarboxylation step could happen first then deamination occur (methyldopa).
amphetamine
phentermine

- Primary aliphatic amines which are not possible to be oxidized at
alpha position will be N-hydroxylated and further oxidation
produced nitroso and nitro compounds. (phenteramine, amantadine).


- Primary aliphatic amines with alpha hydrogen can be N-
hydroxylated also.

- N-hydroxylation could occur first then converted to imine by water
loss, then converted to oxime which will be converted to ketone
(amphetamine).

Aromatic amines and heterocyclic Nitrogen compounds

- Tertiary and secondary aromatic amines are not common in
medicinal drugs while the primary amines are abundant (from
enzymatic reduction of aromatic nitro compounds, reductive
cleavage of azo compounds and hydrolysis of aromatic amides).

- Tertiary aromatic amines will undergo N-dealkylation and N-oxide
formation.



- Secondary amines undergo N-dealkylation and N-oxidation to give
N-hydroxyl amines which will oxidized again to give nitrone
derivatives, which they may hydrolyze to primary hydroxylamines.


- Primary aromatic amines first produce hydroxyl derivative, then to
nitroso.

- Aromatic N-oxidation is considered a minor constitute compared to
N-acetylation and aromatic hydroxylation.

- Methemoglobinemia is a common side effect of aromatic amines
(dapsone) when they are converted to N-hydroxyl derivatives. The
N-hydroxyl derivatives are able to oxidize the Fe
+2
to Fe
+3
in
hemoglobin which will prevent oxygen transport (suffocation).


- Aromatic amines are considered carcinogenic: activated by N-
oxidation to make them highly electrophilic and alkylated by DNA,
RNA.
N
N
NH
N
N
N
OH
N
N
N
OSO
3
-
N
N
N
+
nitreniumion
N
N
N
GLG
- N-oxidation of N atoms inside heterocycle occur less common to
produce N-Oxide metabolite, (trimethoprim, cotinine and
metronidazole).

- Oxidative C-N cleavage (- carbon hydroxylation) and N-
hydroxylation reactions.
- Oxidative dealkylation occur through carbinolamide intermediate,
unstable, fragmentation to form N-dealkylated product (Diazepam).

Amides
Amides
Flurazepam
chlorpropamide

- Lactams, in the same way by forming carbinolamide that lead to C-N
breakage (Cotinine).

Amides
Cotinine

- Cyclophosphamide has many metabolites, see book page 73.
- Aromatic amides, minor extent, toxicological importance, 2-acetyl
aminoflourene (AFF) [N-oxidation, sulfonation, then nitrinum ion
production].
Amides
Cyclophosphamide

-Aromatic amides, minor extent, toxicological importance, 2-acetyl
aminoflourene (AAF) [N-oxidation, sulfonation, then nitrinum ion
production].
Amides
- Acetaminophen:
Amides
HN CH
3
O
O
H
Renal excretion
HN CH
3
O
O
N-acetylamindoquinone
HN CH
3
O
O
HN CH
3
O
O
Glucuronide
SO
3
O
-
Cause covalent binding with livercells, necrosis
- Performed via microsomal mixed function oxidases.
- Oxidation involve -oxidation to form hemiacetal or hemiketal,
followed by C-O bond breakage (phenol, alcohol) and (ketone or
aldehyde).

C-O System Oxidation
R
1
H
OH
OR
2
R
1
R
3
OH
OR
2
Hemiacetal hemiketal

-Small alkyl groups removed first.

morphine
- Mescaline where the 3-O demethylation is favored.

- Undergo S-dealkylation, desulfuration, and S-Oxidation. The first
two involve C-S bond cleavage.
- S-dealkylation is proceeded in the same way as C-O and C-N
dealkylation by oxidizing the -carbon.

- Examples are 6-(methylthio)-purine produced 6-mercaptopurine.

C-S System Oxidation
N
N
N
H
N
S
N
N
N
H
N
SH

HN
N
H
S
O
O
S
COOH
CF
3
S
- Desulfuration: Conversion of thiono (C=S) or (P=S) to (C=O) or P=O
respectively.
-Thiopental to pentobarbital

-and parathion to paraoxon.

- S-Oxidation reactions:
- Sulfide to sulfoxide to sulphone.

- Alcohol is produced from different metabolic pathways such as
oxidation of benzylic, allylic, alicyclic or aliphatic oxidation.
- If the OH is not conjugated, it will further oxidized.
- Primary alcohol and aldehydes give facile oxidation to carboxylic
acid.
- Less important, secondary alcohol to ketone, not that important
as it may be reduced again to alcohol as it is easier to be
conjugated.
- The enzyme called alcohol dehydrogenase perform reversible
reaction that converts alcohol to aldehyde and ketone, using
NAD
+
as a coenzyme.
- Further oxidation of aldehyde to COOH, is done by aldehyde
oxidaze and xanthine oxidize.
Oxidation of Alcohols and Aldehydes
- Oxidative aromatization, as in norgestrol.

Other Oxidation Reactions

-Chloroform produce phosgene (hepato and nephrotoxicty).

- Normally dehalogenation reactions produce toxic acylhalides.

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- C-N, C-O, and C-S oxidation involve two main types.

1- Hydroxylation of the -carbon atom directly attached to

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