Download Oxidation involving CO System ( O

Metabolic Changes of Drugs
Prof. Faris T. Abachi ( PHD Pharmacy)
3rd Year Pharmacy
2017
Oxidations involving carbon-heteroatom

Oxidations involving carbon-heteroatom systems. N 2
and O 2 functionalities are commonly found in most of
the drugs and foreign compounds. Sulfur functionalities
occur occasionally. Metabolic oxidation of carbonnitrogen, carbon –oxygen and carbon-sulfur systems
involves two basic types of biotransformations . 1.
Hydroxylation of -carbon atom attached directly to the
heteroatom (N, O, S). Oxidative N, O & S dealkylation as
well as oxidative deamination reactions fall under this
mechanistic pathway.
Oxidation of Alcohols








Primary alcohol ( RCH2OH)
CH3CH2OH---- CH3CHO…. CH3COOH
Acetaldehyde non- toxic
CH3OH ------ H-CO-H…… H-COO-H
Formaldehyde
highly toxic
Then to carboxylic acid
Secondary alcohol R2CHOH
(CH3 )2 CH-OH .. CH3COCH3 Ketone
Oxidation involving C-O System
( O-Dealkylation )Ethers
H
R1
C
OH
CYP450
O
R3
R1
R2
C
Spontaneous
O
R3
R1
C
R2
O
+
HO
R3
R2
■
Converts an ether to an alcohol plus a ketone or aldehyde
■
Steric hindrance discussion similar to N-dealkylation
OH
O
H3C
H 3C
H3C
O
O
NH2
N
NH2
CY
P4
50
O
O
N
us
eo
tan
on
Sp
H 3C
O
CH2
CH3
OH
N
NH2
N
NH2
H 3C
H 3C
Trimethoprim O-Dealkylation
O
O
N
NH2
N
NH2
CH3
N
H3C
O
H
N
O
O
OH
CH3
CH3
N
O
O
O
OH
O
CH3
Codeine
H3C
H3C
O
CH3
Cl
Phenacetin
N
NH2
OH
O
N
N
O
Indomethacin
N
O
O
H3C
Prazosin
O
H
N
CH3
Metoprolol
■
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
H3C
C
H
OH
CYP450
OH
H3C
C
H
Spontaneous
OH
H3C
C
H
CH3
O
Oxidation involving C-S System
H
■
S-Dealkylation
R1
C
OH
CYP450
S
R3
R1
R2
C
S
R3
Spontaneous
R1
C
R2
R2
Steric hindrance discussion similar to N-dealkylation
O
S
■
Desulfuration
R1
C
R1
R2
C
R2
O
■
R1
S-Oxidation
S
R1
R2
S
O
R2
R1
S
N
N
N
H
6-(Methylthio)-purine
N
S
CH2 OH
N
N
N
N
H
R2
O
Sulfone
Sulfoxide
CH3
S
O
SH
CH2
N
N
N
H
6-Mercaptopurine
N
O
+
HS
R3
O
H3C S
COOH
H
N
O
S CH2C6H5
S
N
O
H
Methitural
CF3
2-Benzylthio-4trifluoromethyl benzoic acid
H3C
H3C
O
S
P
O
O
Parathione
NO2
O
H
H
N
N
O
S
N
O
H
Pentobarbital
N
O
H
Thiopental
H3C
O O
P
O
H3C
O
Paraoxone
NO2
N
O
N
S
S
CH3
S
Ring Sulfoxide
N
CH3
CH3
S
Thioridazine
N
CH3
N
S
N
CH3
S CH3
O
Mesoridazine
N
O S
O
N
CH3
CH3
S
Ring Sulfone
N
N
CH3
S
S
CH3
O O
Sulforidazine
Oxidative Dehalogenation
H
R
C
OH
CYP450
Cl
R
Cl
■
C
O Spontaneous
O
R C
R C
+H2O
Cl
OH
+
+
Cl
Cl
Requires two halogens on carbon
H
■
With three there is no hydrogen available to
replace
■
With one, the reaction generally won’t proceed
■
The intermediate acyl halide is very reactive
OH
OH
O2N
OH
NHCOCHCl2
O2N
Chloramphenicol
O2N
OH
O2N
Q. What is Gray Baby Syndrome?
Cl
OH
HCl
OH
NHCOCCl2
OH
H
Cl
OH
NHCOC OH
O
Oxamic Acid
Derivative
OH
NHCOCCl
O
Oxamyl Chloride
Derivative
Tissue
Nucleophiles
Covalent Binding
(Toxicity)
Hepatic Microsomal Flavin Containing
Monooxygenases (MFMO or FMO)
■
Oxidize S and N functional groups
■
Mechanism is different but end products are similar to those
produced by S and N oxidation by CYP450
■
FMO’s do not work on primary amines
■
FMO’s will not oxidize substrates with more than a single charge
■
FMO’s will not oxidize polyvalent substrates
H3C
S
NH
N
H
N
H
N
N
C
MFMO
H3C
CH3
S
NH
N
Cimetidine MFMO S-Oxidation
Q. What is the difference with MFO?
N
O
H
N
H
N
N
C
CH3
N
Non-Microsomal Oxidation Reactions
■
Monoamine oxidase (outer membrane of mitochondria, flavin containing enzyme )
■
Dehydrogenases (cytoplasm)
■
Purine oxidation (Xanthene oxidase)
Monoamine oxidase
H
R1
C
N
R2 R3
H
R1
C
R2
O
+
H
N
H
R3
■
Two MAOs have been identified: MAO–A and MAO–B. Equal amounts are found in
the liver, but the brain contains primarily MAO–B; MAO–A is found in the adrenergic
nerve endings
■
MAO–A shows preference for serotonin, catecholamines, and other monoamines
with phenolic aromatic rings and MAO–B prefers non–phenolic amines
■
Metabolizes 1° and 2° amines; N must be attached to α-carbon; both C & N must
have at least one replaceable H atom. 2° amines are metabolized by MAO if the
substituent is a methyl group
■
b–Phenylisopropylamines such as amphetamine and ephedrine are not metabolized
by MAOs but are potent inhibitors of MAOs
Alcohol dehydrogenase
R2
R1
C
Aldehyde dehydrogenase
R2
OH
R1
H
C
R1
C
O
O
R1
C
H
O
OH
Metabolizes 1° and 2° alcohols and aldehydes containing at least one “H” attached to a-C; 1°
alcohols typically go to the aldehyde then acid; 2° alcohols are converted to ketone, which
cannot be further converted to the acid. The aldehyde is converted back to an alcohol by
alcohol (keto) reductases (reversible), however, it goes forward as the aldehyde is converted to
carboxylic acid; 3° alcohols and phenolic alcohols cannot be oxidized by this enzyme; No “H”
attached to adjacent carbon
H2
C
Ethanol Metabolism
H3C
Alcohol
Dehydrogenase
OH
H3C
Aldehyde
Dehydrogenase
H
C
OH
H3C
O
C
O
Purine oxidation
O
O
N
HN
N
N
H
Hypoxanthine
Xanthine
oxidase
N
HN
O
N
H
Xanthine
Molybdenum Containing
O
O
N
H
Xanthine
oxidase HN
O
N
H
N
HN
O
OH
N
H
N
H
Uric acid
(hydroxy tautomer)
O
N
H
N
H
Uric acid
(keto tautomer)
Reductive Reactions
■
Bioreduction of C=O (aldehyde and keton) generates alcohol
(aldehyde → 1o alcohol; ketone → 2o alcohol)
■
Nitro and azo reductions lead to amino derivatives
■
Reduction of N-oxides to their corresponding 3o amines and
reduction of sulfoxides to sulfides are less frequent
■
Reductive cleavage of disulfide (-S-S-) linkages and reduction
of C=C are minor pathways in drug metabolism
■
Reductive dehalogenation is a minor reaction primarily differ
from oxidative dehalogenation is that the adjacent carbon does
not have to have a replaceable hydrogen and generally
removes one halogen from a group of two or three
Reduction of Aldehydes & Ketones
H
R
C
O
H
Aldehyde
R
C
H
OH
H
1 alcohol
R
C
O
R2
Ketone
R1
C
OH
R2
2 alcohol
■
C=O moiety, esp. the ketone, is frequently encountered in drugs and
additionally, ketones and aldehydes arise from deamination

Ketones tend to be converted to alcohols which can then be glucuronidated.
Aldehydes can also be converted to alcohols, but have the additional
pathway of oxidation to carboxylic acids
■
Reduction of ketones often leads to the creation of an asymmetric center
and thus two stereoisomeric alcohols are possible
■
Reduction of a, b –unsaturated ketones found in steroidal drugs results not
only in the reduction of the ketone but also of the C=C
■
Aldo–keto oxidoreductases carry out bioreductions of aldehydes and
ketones. Alcohol dehydrogenase is a NAD+ dependent oxidoreductase that
oxidizes alcohols but in the presence of NADH or NADPH, the same
enzyme can reduce carbonyl compounds to alcohols
O
H
O
+
C
R1
O
H
H
HO
H2N
R2
Chiral Alcohol
O
OH H2C
HO
OH H 2C
CH3
H
O
O
CH2
O
O
OH
OH H2C
CH3
H
O
R,R (+)-Warfarin
O
OH
C6H5
CH3
N
OH
OH
H3C
Naloxone
H
O
N
O
Ox Nicotinamide moiety
+
+
of NADP or NAD
+
R,S (+)-Warfarin
R (+)-Warfarin
O
N+
C 6H5
H
HO
+
H
CH3
C6H 5
O
R2
H2N
R
R
Red Nicotinamide moiety
of NADPH or NADH
Ketone
C
R1
N
H
O
O
H3C
OH
O
OH
O
H2 N
OH
Daunomycin
HO
O
O
Naltrexone
CH3
CH3
OH
C
O
OH
H
C
CH
CH
H
HO
Norethindrone
H2
C
CH3
CH
H
H2
C
C
NH2
O
Amphetamine
Phenylacetone
OH
C
OH
H
H
C CH3
NHCH3
(-)-Ephedrine
C
3b,5b-Tetrahydronorethindrone
CH3
H2
C
CH3
CH
OH
1-Phenyl-2-propanol
OH
H
C
CH3
O
1-Hydroxy-1-phenylpropane-2-one
C
H
CH
CH3
OH
1-Phenyl-1,2-propandiol
Reduction of Nitro & Azo Compounds
H
R
C
N
R
O
H
N
C
N
R
O
H
R2
R1
H
H
N
R
H
N
H
N
R
N
N
Azido
NH
H
1 amine
NH2
+
H2N
Two 1 amines
Hydrazo
Azo
R
NH2 + N
Amine
H
N
H
R1
R2
C
OH
Hydroxylamine
Nitroso
N
C
H
Nitro
R1
H
H
O
N2
N
R2

R1 and R2 are almost always aromatic

Usually only seen when the NO2 functional group is attached directly to an
aromatic ring and are rare

Nitro reduction is carried out by NADPH-dependent microsomal and soluble
nitroreductases (hepatic)

NADPH dependent multicomponent hepatic microsomal reductase system
reduces the azo

Bacterial reductases in intestine can reduce both nitro and azo
O
H2N
O
S
O
N
H2
O
S
N N
NH2
H2N
Prontosil
N
H2
H2N
+
NH2
NH2
Sulfanilamide
1,2,3-Triaminobenzene
H
N
O
O
O2N
S
N
Cl
HO
N
O
N
N N
O
Clonazepam
N
H
O
O2N
O
NNa
O
OH
Sulfasalazine
N
Dantrolene
Reduction of Sulfur Containing Compounds
O
O
Sulfoxide reduction (Cannot reduce a sulfone)
R1
S
R1
R2
S
X
R2
Sulfoxide
R1
S
R2
O
Sulfone
Disulfide reduction
R1
S
S
R2
H3 C
SH
+
N
S
S
N
HS
R2
H3C
CH3
S
H3C
R1
S
H3C
CH3
N
SH
S
N,N-Diethylthiocarbamic
Acid
Disulfiram
O
F
OH
CH3
H
H3 C
S
O
Sulindac