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Good Morning
Bayani Bash
Lecture 6
Dr. Dana Ameen
Pharmaceutical Chemistry
HMU / College of Pharmacy
N-oxidation
N-oxidation of Secondary Aliphatic
Amine to Nitrone metabolite
Methemoglobinemia toxicity
Primary and Secondary Amines
Secondary amines (either parent compounds or
metabolites) are susceptible to oxidative Ndealkylation, oxidative deamination, and Noxidation reactions.
N-dealkylation of secondary amines proceeds by
the
carbinolamine
pathway
to
the
corresponding primary amine metabolite.
OH
O
H2C
C
H
CH
C
H2
CH2
HN
CH
OH
O
O
CH
C
H2
CH3
CH3
Propranolol
H2
C
CH2
HN
Oxyprenolol
C
CH H
3
CH3
The primary amine metabolites formed from oxidative
dealkylation are susceptible to oxidative deamination,
which involves an initial α-carbon hydroxylation
reaction to form a carbinolamine intermediate, which
then undergoes subsequent carbon-nitrogen
cleavage to the carbonyl metabolite and ammonia.
O
H2
C
CH
CH3
H2
C
CH2
NH3
C
O
NH2
HN
CH3
Methamphetamine
CH
CH3
H2
C
Amphetamine
Phenylacetone
CH3
If α -carbon hydroxylation can not
occur, then oxidative deamination is not
possible for example: norketamine.
Dealkylation of secondary amines is believed to occur
before oxidative deamination, direct deamination of the
secondary amine also has occurred.
OH
OH
Direct
Oxidative
O
CH
C
CH2 Deamination
H2
HN
CH3
CH
C
H2
CH
H
HN
CH
O
O
CH
C
H2
CH3
C
H
Aldehyde Metabolite
NH3
O
OH
OH
CH
CH2
HN
C
H3C
CH3
CH3
O
CH3
Carbinolamine
H2N
O
Carbinolamine
Propranolol
C
H2
CH
CH3
CH3
O
O
OH
O
Oxidative
Deamination
Through Primary Amine
CH
C
H2
CH2
HN
CH
H
Primary Amine Metabolite
(Desisopropyl Propranolol)
CH3
CH3
Secondary alicyclic amines, like their tertiary amine
analogs, are metabolized to their corresponding lactam
derivatives,
for
example:
anorectic
agent:
Phenmetrazine.
C6H5
O1
2
3
H3C
N
H
Phenmetrazine
C6H5
H3C
1
O
2
3
N
OH
H
Carbinolamine
Intermediate
C6H5
1
O
2
N 3 O
H
3-oxophenmetrazine
H3C
Alfa Carbon Hydroxylation
N-Oxidation of secondary aliphatic and alicyclic amines
leads to several N-oxygenated products. N-hydroxylation of
secondary amine generates the corresponding Nhydroxylamine products are susceptible to further oxidation
to
the
corresponding
nitrone
derivatives:
N-phenylamphetamine and Phenmetrazine. N-oxidation
occurs for secondary amines much less than oxidative
dealkylation and deamination.
-
OH
NH
N
CH3
Secondary Amine
CH3
Hydroxylamine
O
+
N
CH2
Nitrone
N-Oxidation of Secondary Aliphatic Amine
to Nitrone metabolite
H2
C
CH
H2
C
H2
C
CH3
CH
HN
CH2C6H5
N-benzylamphetamine
CH3
CH
-
N
N
O
Nitrone
Metabolite
HO
CH2C6H5
Hydroxylamine
Metabolite
CH3
+
CHC6H5
N-oxidation of Secondary Alicyclic Amine to Nitrone
metabolite
C6H5
H3C
O
N
H
Phenmetrazine
C6H5
O
C6H5
H3C
N
H 3C
OH
N-hydroxyphenmetrazine
O
(Z)
N
+
_
O
Nitrone
Metabolite
Primary amine metabolites arising from
N-dealkylation or decarboxylation
reactions are also undergo deamination.
N
Br
CH
CH2
CH
H2C
CH2
H2C
Brompheniramine
N
H3C
CH
CH3
NH2
Bisdesmethyl
Metabolite
CH2
HOOC
3-(p-Bromophenyl)-3pyridyl-propionic acid
N-Hydroxylation of primary aliphatic amine generates the
N-hydroxylamine products that are susceptible for further
oxidation to the corresponding nitroso and nitro derivatives.
H2 CH3
C
CH3
NH2
Cl
H2 CH3
C
CH3
HN
Cl
OH
N-hydroxychlorphentermine
Chlorphentermine
H2 CH3
C
CH3
Cl
Nitro Metabolite
H2 CH3
C
CH3
NO2
N
Cl
O
Nitroso Metabolite
Aromatic Amines and Heterocyclic
Nitrogen Compounds
CH3
N-oxidation
CH3
O
N
N
CH3
Tertiary Aromatic Amine
N-oxide
O
Carbon
Hydroxylation
H
CH3
CH3
H
CH3
N
N
CH2OH
Carbinolamine
Oxidative Dealkylation
H
Secondary aromatic amines may undergo Ndealkylation or N-hydroxylation to give secondary Nhydroxylamines. Further oxidation leads to nitrone
products, which in turn may be hydrolyzed to primary
hydroxylamines.
CH2R
N
CH2R
N
H
Secondary Aromatic Amine
OH
Hydroxylamine
(secondary)
Oxidation
NH
OH
Hydroxylamine
(primary)
CHR
H2O
+
N
Nitrone
O
N-oxidation of primary aromatic amines generates
the N-hydroxylamine metabolite, then oxidation of
the hydroxylamine derivative to the nitroso derivative
also can occur.
NH2
Aniline-Primary
Aromatic Amine
NHOH
Hydroxylamine
N
O
Nitroso
Antileprotic agent dapsone is metabolized
significantly to their corresponding N-hydroxylamine
derivatives. The N-hydroxy metabolites are further
conjugated with glucuronic acid.
H 2N
S
O2
NH2
Dapsone
H2N
S
O2
NHOH
N-hydroxydapsone
Conjugation with glucuronic acid
Methemoglobinemia toxicity
• Methemoglobinemia toxicity is caused by
several aromatic amines, including aniline and
dapsone, and is a result of the bioconversion of
the aromatic amine to its N-hydroxy derivative.
• The N-hydroxylamine oxidizes the Fe2+ form of
hemoglobin to its Fe3+ form. This oxidized (Fe3+)
state of hemoglobin (called methemoglobin or
ferrihemoglobin) can no longer transport
oxygen, which leads to serious hypoxia or
anemia, a unique type of chemical suffocation.
Diverse aromatic amines (especially azoamino dyes) are known to be
carcinogenic. N-oxidation plays an important role in bioactivating these
aromatic amines (N-methyl-4-aminoazobenzene) to potentially reactive
electrophilic species that covalently bind to cellular protein, DNA, and RNA.
H
N
N
CH3
C6H5
N N
N-methyl-4-aminoazobenzene
OH
C6H5
N
N
+
N
CH3
C6H5
N
Nitrenuim Ion
(E)
CH3
+
N
N
N
N
CH3
N
N
-SO4=
Sulfate Conjugate
(Z)
C6H5
Hydroxyalmin
e
OSO3
N
C6H5
(E)
CH3
DNA, RNA,
and Protein
Covalntly Binding
H3CO
N1
H3CO
C
H2
NH2
N 3
H2N
H3CO
Trimethoprim
O
H3CO
N1
H3CO
H3CO
H3CO
C
H2
H2N
+
NH2
N
1-N-Oxide
N
H3CO
H3CO
C
H2
H 2N
3-N-Oxide
NH2
N 3
O
N-oxidation of the
nitrogen atoms present
in aromatic heterocyclic
moieties of many drugs
occurs to a minor
extent. N-oxidation of
the folic acid antagonist
trimethoprim has
yielded equal amounts
of the isomeric 1-Noxide and 3-N-oxide
metabolites.
Oxidation of Amides
• Amide functionalities are susceptible to:
1. Oxidative carbon-nitrogen cleavage (via αcarbon hydroxylation).
2. N-hydroxylations.
• Oxidative dealkylation of many N-substituted
amide drugs proceeds via an initially formed
carbinolamide, which is unstable and fragments
to the N-dealkylated product.
Diazepam undergoes extensive
N-demethylation to the pharmacologically
active metabolite desmethyldiazepam.
H3C
H2C
O
N
OH
O
N
-H
Cl
(Z)
C6H5
Diazepam
N
Cl
(Z)
N
C6H5
Carbinolamide
Intermediate
O
C
O
H
N
H
Cl
(Z)
N
C6H5
Desmethyldaizepam
O
5
(R)
N
N
OH
CH3
N
Cotinine
O
5
CH3
N
5-hydroxycotinine
In the cyclic amides or lactams,
hydroxylation of the alicyclic carbon α to the
nitrogen atom also leads to carbinolamides
(conversion of cotinine to
5-hydroxycotinine).
N-hydroxylation of aromatic amides
-SO4=
Sulfate
N-hydroxylation
Conjugation
(E)
+
N
NH
H 3C
O
2-Acetylaminofluorene
(AAF)
H3C
N
OH
OSO3
H3C
O
N-hydroxy AAF
O
O-sulfate ester of
N-hydroxy AAF
-
N+
(Z)
(E)
N
H 3C
H 3C
O
Nitrenium
Species
O
Nu
H
N
Nu= Nucleophile
e.g. DNA
O
Nu
H3C
This occurs to a minor extent, it is of some toxicological interest, since this
biotransformation pathway my lead to the formation of chemically reactive
intermediates.
Oxidation Involving
Carbon-Oxygen System
Oxidation Involving CarbonOxygen System
Oxidative O-dealkylation of carbon-oxygen systems (ethers) involves an
initial
α -carbon hydroxylation to form either a hemiacetal or a hemiketal,
which undergoes spontaneous carbon-oxygen bond cleavage to yield the
dealkylated oxygen species (phenol or alcohol) and a carbonyl moiety
(aldehyde or ketone).
Small alkyl groups (methyl or ethyl) attached to oxygen is O-dealkylated
rapidly.
H
O
H
Carbon
R
O
Ether
C
R
O
C
R
Hemiacetal or
Hemiketal
Phenol or
Alcohol
O
Hydroxylation
OH
+
C
Carbonyl moiety
(aldehyde or ketone)
Morphine is the metabolic product of
O-demethylation of codeine.
CH3
CH3
N
H
H
N
(R)
(R)
H
H
O
(Z)
(R)
+
(Z)
(R)
H
(S)
(R)
(S)
(R)
O
H3CO
O
(S)
(S)
Codeine
OH
HO
Morphine
OH
H
In many drugs that have several nonequivalent methoxy
groups, one particular methoxy group often appears to
be O-demethylated selectively or preferentially. For e.g.,
trimethoprim undergoes
O-demethylation to yield
predominately the corresponding 3-O-demethyated
metabolites.
4-O-demethylation also occurs to a minor extent.
Trimethoprim
H3CO
3
H3CO
4
H3CO
N
C
H2
H2N
NH2
N
Oxidation Involving
Carbon-Sulfur Systems
Oxidation Involving Carbon-Sulfur Systems
Carbon-sulfur functionalities are susceptible to:
1. S-dealkylation (oxidative carbon-sulfur bond cleavage).
2. Desulfuration (oxidative carbon-sulfur bond cleavage).
3. S-oxidation.
S-dealkylation is analogs to O- and N-dealkylation (α-carbon hydroxylation).
S
CH3
N
N
N
H
6-(Methylthio)-purine
N
S
H2
C OH
SH
N
N
N
H
+
N
N
N
CH2O
N
H
6-Mercaptopurine
N
Desulfuration Pathway
O
O
CH2CH3
CHCH2CH2CH3
HN
HN
CH3
S
N
H
Thiopental
O
CH2CH3
CHCH2CH2CH3
CH3
O
N
O
H
Pentobarbital
Oxidative conversion of carbon-sulfur double bonds
(C=S) (thiono) to the corresponding carbon oxygen
double bond (C=O) is called desulfuration. A well known
example of this metabolic process is the
biotransformation of thiopental to its corresponding
oxygen analog pentobarbital.
Desulfuration Pathway
H3CH2CO
S
P
H3CH2CO
O
H3CH2CO
NO2
O
P
O
H3CH2CO
Parathion
Paraxon
An analogous desulfuration reaction also occurs with
the P=S moiety present in a number of
organophosphate insecticides, such as parathion.
Desulfuration of parathion leads to the formation of
paraxon, which is the active metabolite responsible
for the anticholinesterase activity of the parent drug.
NO2
S-oxidation Pathway
S
S
2
N
S
CH2CH2
CH3
N
Mesoridazine
Thioridazine
N
CH3
CH3
S
O
CH2CH2
N
CH3
Organosulfur xenobiotics undergo S-oxidation to yield sulfoxide derivatives.
Phenothiazines are activated by this pathway. Oxidation of the 2-methylthio group
yields the active sulfoxide metabolite mesoridazine (twice as potent as an
antipsychotic agent as thioridazine).
O
S
S
N
S
CH3
N
S
CH2CH2
2
N
S
O
O
CH3
S
CH2CH2
CH3
N
CH3
N
Ring Sulfoxide
CH3
Ring Sulfone
CH2CH2
N
CH3
S
S
N
Thioridazine
Mesoridazine
CH3
S
N
O
CH2CH2
N
CH3
S
O
CH2CH2
Sulforidazine
N
CH3
CH3
O
Sulfoxide drugs and metabolites may be further
oxidized to sulfones (-SO2-). The sulfoxide group
present in the immunosuppressive agent
oxisuran is metabolized to a sulfone moiety.
O
O
O
C
S
C
C
H2
N
Oxisuran
O
S
C
H2
CH3
N
O
CH3
Sulfone Metabolite
Oxidation of Alcohols and Aldehydes
Many oxidative processes (benzylic, allylic, alicyclic, or aliphatic hydroxylation)
generate alcohol or carbinol intermediate. If not conjugated, are further oxidized to
aldehydes (if primarily alcohols) or to ketones (if secondary alcohols). Aldehyde
metabolites resulting from oxidation of primary alcohols or from oxidative
deamination of primary aliphatic amines often undergo facile oxidation to generate
polar carboxylic acid derivatives. As a general rule, primary alcohol groups and
aldehyde functionalities are vulnerable to oxidation.
+
NAD
RCH2OH
Primary
Alcohol
NADH
NAD+
NADH
RCHO
RCOOH
Aldehyde
Acid
Metabolism of cyclic amines to their lactam metabolites has
been observed for various drugs. The soluble or microsomal
dehydrogenase and oxidases are involved in oxidizing the
carbinol group of the intermediate carbinolamine to a carbonyl
moiety, as in the metabolism of medazepam to diazepam, the
intermediate carbinolamine (2-hydroxymedazepam) undergoes
oxidation
of
its
2-hydroxy group to a carbonyl moiety.
H3C
H3C
H3C
OH
N
N
O
N
Oxidation
Cl
(Z)
N
C6H5
Medazepam
Cl
(Z)
N
C6H5
2-Hydroxymedazepam
Cl
(Z)
C6H5
Diazepam
N
Other Oxidative Biotransformation
Pathways
1. Metabolic aromatization:
Metabolic aromatization has been reported for
norgestrel. Aromatization or dehydrogenation of
the ring A present in this steroid leads to the
corresponding phenolic product 17α-ethinyl-18homoestradiol as a minor metabolite in women.
OH
OH
CH2CH3
CH2CH3
(R)
C
(R)
CH
(S)
(S)
A
O
C
A
(Z)
Norgestrel
HO
17x-Ethinyl-18-homoestradiol
CH
2. Dehalogenation:
Many halogen-containing drugs and xenobiotics are
metabolized by oxidative dehalogenation. For example,
the volatile anesthetic agent halothane is metabolized
principally to trifluoroacetic acid.
H
H
F3C
Br
Cl
Halothane
F3C
O
O
O
Br
Cl
Carbinol
Intermediate
-HBr
F3C
Cl
Trifluoroacetyl
Chloride
H2O
F3C
OH +
Trifluoroacetic Acid
HCl
Chloroform also appears to be metabolized
oxidatively by a similar pathway to yield the
chemically reactive species phosgene. Phosgene
may be responsible for the hepato- and
nephrotoxicity associated with chloroform.
H
H
Cl
O
O
Cl
Cl
Chloroform
Cl
Cl
Cl
Carbinol
Intermediate
-HCl
Cl
Cl
H2O
H2CO3 + HCl
Phosgene
Tissue Nucleophile
Covalent Binding
The dichloroacetamide portion of the molecule undergoes
oxidative dechlorination to yield a chemically reactive oxamyl
chloride intermediate that can react with water to form the
corresponding oxamic acid metabolite or can acylate microsomal
proteins. Thus, it appears that in several instances, oxidative
dehalogenation can led to the formation of toxic and reactive acyl
halide intermediate.
OH
O2N
CH
Chloramphenicol
O
H
N C
H
CH2OH
C
H
C
R
Cl
N
H
O
O
H
C
C
Cl
Cl
Cl
Dichloroacetamide Portion
R
N
H
O
O
C
C
- HCl
O
Water
OH
Oxamic Acid Derivative
R
N
H
O
C C Cl
Oxamyl Chloride
Derivative
Tisuue Nucleophile
Covalent Binding (Toxicity?)
Thank You For Your
Attention