Reductions/Hydrolysis (PHASE 1)

Question 1

what molecules undergo phase 1 reductions?

Answer 1

1. aromatic and heteroaromatic nitro compounds
2. aromatic azo compounds
3. aromatic sulfoxides
4. carbonyl groups (ketones and aldehydes)

Question 2

nitro functional group

Answer 2

-NO2

Question 3

Can nitro be used for phase 2 conjugation reactions?

Answer 3

NO it is not polar. need a polar functional group

Question 4

what is the issue with aromatic nitro compounds?

Answer 4

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

Question 5

can aromatic nitro compounds be administered parenterally?

Answer 5

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

Question 6

what drug has N=N in its structure?

Answer 6

protonsil

Question 7

what molecule undergoes similar oxidation to that of primary alcohols?

Answer 7

sulfide -> sulfoxide -> sulfone

sulfide to sulfoxide is reversible while sulfoxide to sulfone is IRREVERSIBLE

Question 8

TRUE OR FALSE

only aliphatic ketones can undergo reduction of the carbonyl to alcohol.
those ketones with aromatic substituent(s) cannot

Answer 8

FALSE

both can undergo reduction

Question 9

carbonyl -> alcohol
is this reduction or oxidation?

Answer 9

reduction

Question 10

alcohol -> carbonyl is this oxidation or reduction?

Answer 10

oxidation

Question 11

what molecules can undergo phase 1 hydrolysis?

Answer 11

-carboxylic esters
-organic phosphate esters
-organic sulfate esters
-organic nitrite and nitrate esters
-amides

Question 12

what is a carboxylic ester?

Answer 12

has a C=O bond and a C-O bond

Question 13

as mentioned, carboxylic esters can undergo phase 1 hydrolysis.
classify this further

Answer 13

-open chain esters
-cyclic esters (lactones) CANNOT
-thioesters

Question 14

what is a lactone

Answer 14

a cyclic carboxylic ester

Question 15

lactones (cyclic carboxylic esters) are found in some drugs of what class?

Answer 15

cardiac glycosides

Question 16

explain the mechanism of hydrolysis of cyclic carboxylic esters (lactones)

Answer 16

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

Question 17

explain the mechanism of open chain carboxylic ester hydrolysis

Answer 17

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

Question 18

where is carboxyesterase found? what about aryl esterase?

Answer 18

carboxyesterase is found in microsomes of liver cells and in soluble fraction.

amyl esterase is found in plasma

Question 19

true or false

the hydrolysis of lactones is single step

Answer 19

false - multi

Question 20

true or false

cyclic esters cannot be hydrolyzed by human enzymes

Answer 20

true

some can be hydrolyzed by intestinal bacteria, though

Question 21

true or false

almost all esters are known to be hydrolyzed easily

Answer 21

TRUE

there are rare exceptions such as in the case of cardiac glycosides (cyclic carboxylic esters/lactones) which are not known to undergo hydrolysis

Question 22

where are esterases found?

Answer 22

basically everywhere in the human body

Question 23

which are more easily hydrolyzed– thio esters or their corresponding carboxy ester?

Answer 23

thioesters are more easily hydrolyzed because thiol is a much better leaving group

Question 24

what is paraoxon?

Answer 24

an insecticide.
an organic phosphate ester that predictably undergoes phase 1 hydrolysis

Question 25

explain the hydrolysis of organic nitrate and nitrite esters

Answer 25

there is NO DIRECT HYDROLYSIS of nitrate esters. it is converted to nitrite and THEN hydrolyzed.

there IS direct hydrolysis on nitrite esters

Question 26

nitrite

Answer 26

NO2-

Question 27

nitrate

Answer 27

NO3-

Question 28

Which are hydrolyzed quicker – amides or esters?

Answer 28

typically esters are hydrolzyed faster

Question 29

what enzyme(s) hydrolyze amides?

Answer 29

amidases and esterases

Question 30

true or false

it is difficult to predict the hydrolysis of esters. it depends on the structure and the presence of other functional groups

Answer 30

FALSE - this statement is true for AMIDES

Question 31

name 4 types of amides that are hydrolyzed

Answer 31

-open chain
-cyclic
-hydrazides
-urea type

Question 32

specifically which cyclic amides can be hydrolyzed?

Answer 32

lactams and imides

Question 33

name a specific lactam and imide that can be hydrolyzed in phase 1 metabolism

Answer 33

penicillin
phthalidomide

Question 34

name specific hydrazide(s) that can be hydrolyzed in phase 1 metabolism

Answer 34

acetylisoniazide

Question 35

what is the more polar functional group that primary and secondary open chain amides get hydrolyzed to?

Answer 35

carboxylic acid

Question 36

what can you say about the clinical significance of the hydrolysis of lactams?

Answer 36

once hydrolyzed, it is no longer bioactive.

hydrolyzed by a bacterial enzyme called beta lactamase

Question 37

true or false

carboximide bonds are always hydrolyzed

Answer 37

false

amides are difficult to predict
all depends on structure + various other factors

Question 38

explain the hydrolysis of acetylisoniazid

Answer 38

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

Question 39

what is chloropropamide?

Answer 39

an open chain sulfonyl urea that undergoes hydrolysis between the carbonyl and 1st N

Question 40

which undergo a more predictable hydrolysis – cyclic ureas or open chain ureas?

Answer 40

open chain ureas (chloropropamine and carbamazepine) are more predictable

Question 41

the hydrolysis of _____ is very unpredictable until you actually test.
give a specific example of this

Answer 41

carboxamide

5-phenylhydantoin is a cyclic urea that gets hydrolyzed

barbiturates are also cyclic ureas but are stable to hydrolysis

Question 42

explain the hydrolysis reaction of aromatic sulfonamides

Answer 42

STABLE TO HYDROLYSIS

Question 43

true or false

carbamates have predicatable hydrolysis

Answer 43

false

Question 44

name 2 molecules that are stable to hydrolysis

Answer 44

-barbiturates
-aromatic sulfonamides

Question 45

what is produced in the hydrolysis of carbamates? (if it is hydrolyzed – not predictable)

Answer 45

corresponding alcohol + amine + CO2

Question 46

Between reductions, oxidations, and hydrolysis, which are like starting with nothing? which start with a built in polar functional group?

Answer 46

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

Question 47

which is the most diverse-

reduction
oxidation
hydrolysis

Answer 47

oxidations are most diverse