Reductions/Hydrolysis (PHASE 1) Flashcards
what molecules undergo phase 1 reductions?
- aromatic and heteroaromatic nitro compounds
- aromatic azo compounds
- aromatic sulfoxides
- carbonyl groups (ketones and aldehydes)
nitro functional group
-NO2
Can nitro be used for phase 2 conjugation reactions?
NO it is not polar. need a polar functional group
what is the issue with aromatic nitro compounds?
the undergo rapid single electron reduction to produce a nitroradical. this is quickly reoxidized back in aerobic conditions with the help of molecular oxygen and GSH.
thus, if aromatic nitro compounds remain in 1 compartment for too long, it could cause GSH depletion and tissue toxicity
can aromatic nitro compounds be administered parenterally?
NO. it will never get reduced to nitroso because it can only be done by the microorganisms in the large intestine
however, nitroso can be administered parenterally to easily get reduced to hydroxylamine and then amine
what drug has N=N in its structure?
protonsil
what molecule undergoes similar oxidation to that of primary alcohols?
sulfide -> sulfoxide -> sulfone
sulfide to sulfoxide is reversible while sulfoxide to sulfone is IRREVERSIBLE
TRUE OR FALSE
only aliphatic ketones can undergo reduction of the carbonyl to alcohol.
those ketones with aromatic substituent(s) cannot
FALSE
both can undergo reduction
carbonyl -> alcohol
is this reduction or oxidation?
reduction
alcohol -> carbonyl is this oxidation or reduction?
oxidation
what molecules can undergo phase 1 hydrolysis?
-carboxylic esters
-organic phosphate esters
-organic sulfate esters
-organic nitrite and nitrate esters
-amides
what is a carboxylic ester?
has a C=O bond and a C-O bond
as mentioned, carboxylic esters can undergo phase 1 hydrolysis.
classify this further
-open chain esters
-cyclic esters (lactones) CANNOT
-thioesters
what is a lactone
a cyclic carboxylic ester
lactones (cyclic carboxylic esters) are found in some drugs of what class?
cardiac glycosides
explain the mechanism of hydrolysis of cyclic carboxylic esters (lactones)
NOT KNOWN TO UNDERGO HYDROLYSIS.
metabolically stable. the carbonyl is conjugated so C=O is not as electrophilic. (in the case of cardiac glycosides)
however, other cyclic esters (lactones) can undergo hydrolysis via the INTESTINAL BACTERIA to produce the corresponding -OH and -COOH. multistep reaction
explain the mechanism of open chain carboxylic ester hydrolysis
if R’ is aliphatic (not aromatic), hydrolysis is catalyzed by carboxyesterase. ester splits to produce corresponding carboxylic acid + alcohol
if R’ is aromatic, catalyzed by aryl esterase. produces phenolic alcohol + corresponding carboxylic acid
where is carboxyesterase found? what about aryl esterase?
carboxyesterase is found in microsomes of liver cells and in soluble fraction.
amyl esterase is found in plasma
true or false
the hydrolysis of lactones is single step
false - multi
true or false
cyclic esters cannot be hydrolyzed by human enzymes
true
some can be hydrolyzed by intestinal bacteria, though
true or false
almost all esters are known to be hydrolyzed easily
TRUE
there are rare exceptions such as in the case of cardiac glycosides (cyclic carboxylic esters/lactones) which are not known to undergo hydrolysis
where are esterases found?
basically everywhere in the human body
which are more easily hydrolyzed– thio esters or their corresponding carboxy ester?
thioesters are more easily hydrolyzed because thiol is a much better leaving group
what is paraoxon?
an insecticide.
an organic phosphate ester that predictably undergoes phase 1 hydrolysis
explain the hydrolysis of organic nitrate and nitrite esters
there is NO DIRECT HYDROLYSIS of nitrate esters. it is converted to nitrite and THEN hydrolyzed.
there IS direct hydrolysis on nitrite esters
nitrite
NO2-
nitrate
NO3-
Which are hydrolyzed quicker – amides or esters?
typically esters are hydrolzyed faster
what enzyme(s) hydrolyze amides?
amidases and esterases
true or false
it is difficult to predict the hydrolysis of esters. it depends on the structure and the presence of other functional groups
FALSE - this statement is true for AMIDES
name 4 types of amides that are hydrolyzed
-open chain
-cyclic
-hydrazides
-urea type
specifically which cyclic amides can be hydrolyzed?
lactams and imides
name a specific lactam and imide that can be hydrolyzed in phase 1 metabolism
penicillin
phthalidomide
name specific hydrazide(s) that can be hydrolyzed in phase 1 metabolism
acetylisoniazide
what is the more polar functional group that primary and secondary open chain amides get hydrolyzed to?
carboxylic acid
what can you say about the clinical significance of the hydrolysis of lactams?
once hydrolyzed, it is no longer bioactive.
hydrolyzed by a bacterial enzyme called beta lactamase
true or false
carboximide bonds are always hydrolyzed
false
amides are difficult to predict
all depends on structure + various other factors
explain the hydrolysis of acetylisoniazid
acetylisoniazid is the major metabolite of isoniazid (antituberculosis drug)
acetylisoniazid undergoes hydrolysis between the carbonyl and hydrazide group to produce pyridine with carboxylic acid substituent at para position + the hydrazide group clipped off.
this group undergoes further oxidative metabolism to produce a carbocation or radical species which is known to cause LIVER TOXICITY
what is chloropropamide?
an open chain sulfonyl urea that undergoes hydrolysis between the carbonyl and 1st N
which undergo a more predictable hydrolysis – cyclic ureas or open chain ureas?
open chain ureas (chloropropamine and carbamazepine) are more predictable
the hydrolysis of _____ is very unpredictable until you actually test.
give a specific example of this
carboxamide
5-phenylhydantoin is a cyclic urea that gets hydrolyzed
barbiturates are also cyclic ureas but are stable to hydrolysis
explain the hydrolysis reaction of aromatic sulfonamides
STABLE TO HYDROLYSIS
true or false
carbamates have predicatable hydrolysis
false
name 2 molecules that are stable to hydrolysis
-barbiturates
-aromatic sulfonamides
what is produced in the hydrolysis of carbamates? (if it is hydrolyzed – not predictable)
corresponding alcohol + amine + CO2
Between reductions, oxidations, and hydrolysis, which are like starting with nothing? which start with a built in polar functional group?
oxidation reactions basically start with nothing, like going from benzene to phenol
reductions and hydrolysis reactions start with some polar group (such as nitro in the case of reductions) And go to something more polar
which is the most diverse-
reduction
oxidation
hydrolysis
oxidations are most diverse
