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Med Chem Final > Second set of slides > Flashcards

Second set of slides Flashcards

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1
Q

under normal conditions, acetaminophen is a substrate for which phase 2 metabolic reactions?

A

glucuronidation
sulfation (contains phenol)

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2
Q

if too much is taken, acetaminophen can cause ____ toxicity

A

hepato

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3
Q

when given a structure, what’s the very first thing you should look for?

A

polar functional groups

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4
Q

true or false

when acetaminophen is ingested, it goes through both sulfation and glucuronidation right away

A

true

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5
Q

substrate for sulfation

A

phenol

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6
Q

under normal conditions, does acetaminophen undergo phase 1 metabolism?

A

NO - only if too much is taken

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7
Q

what is a typical michael acceptor

A

an alpha-beta unsaturated carbonyl (or equivalent)

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8
Q

michael acceptors (alpha beta unsaturated carbonyls) are excellent substrates for which conjugation pathway?

A

GSH because they are chemically reactive

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9
Q

true or false

michael acceptors are very reactive

A

TRUE

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10
Q

explain the different pathways of acetaminophen metabolism

A

under normal conditions: phase 1 is bypassed and acetaminophen immediately undergoes both glucuronidation and sulfation

if too much is taken and the system becomes saturated, there are other pathways.

  1. arene oxide formation (oxidation) and formation of DIOL, to form a “catechol metabolite”
  2. oxidized to 1,4 Imidoquinone intermediate. this has THREE POTENTIAL FATES:
  3. Cleared through GSH conjugation
  4. unknown pathway that leads to cell death
  5. it itself binds to liver tissue macromolecules OR gets hydrolyzed and that compounds covalently binds to liver tissue macromolecules (both cause cell death)
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11
Q

if the toxic metabolite (1,4 imidoquinone) undergoes GSH conjugation, what are the 4 potential conjugates?

A

cysteine, mercapturic acid, methylthio, and methylsulfoxide conjugates

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12
Q

what are the michael acceptor(s) in the metabolism of acetaminophen?

A

the 1,4 imidoquinone intermediate and the compound that results from the hydrolysis of this intermediate

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13
Q

explain how phenacetin is metabolized

A

does NOT have a sufficiently polar functional group (like acetaminophen), so it must undergo phase 1.

the 2 phase 1 reactions that occur are N-hydroxylation and Hydrolysis to form a primary amine (which gets N-hydroxylated) to form HYDROXYLAMINE

hydroxylamine then gets oxidized to nitroso, and nitroso gets reduced back to hydroxylamine - back and forth. this is coupled with HEMOGLOBIN. THUS, as nitroso gets reduced, Ferrous gets oxidized to FERRIC (Fe3+)

ferric is BAD - “methemoglobin” which is not as efficient as typical hemoglobin – leads to oxygen deficiency

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14
Q

how is phenacetin toxic?

A

2 ways:

  1. amines can lead to nephrotoxicity
  2. The oxidation-reduction of nitroso <-> hydroxylamine is coupled with hemoglobin. This causes Ferrous to get oxidized to Ferric +3 (methemoglobin)
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15
Q

hydrazine

A

N-N

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16
Q

what can you say about the metabolism of hydrazines

A

they are very nasty and toxic when metabolized

produce radicals and carbocations

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17
Q

How can oxidative N-dealkylation be toxic?

A

the unstable carbinolamine intermediate can be DEHYDRATED IF R SUBSTITUENTS ARE BULKY – go back and forth between a schiff base (C=N+) reactive species which can readily be hydrated or pick up any nucleophile – potential toxicity concern

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18
Q

Arene oxide can form….

A

a diol or a phenol

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19
Q

teratogenic drugs often exist due to _______ producing molecules

A

ARENE OXIDE

arene oxides are usually readily intercepted, but if not it’s a teratogenic concern

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20
Q

true or false

furan can form an arene oxide

A

TRUE

arene oxides can be heteroaromatic as well as aromatic

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21
Q

chloroform formula

A

CHCl3

22
Q

chloroform was once used for what?

A

decaffeinated coffee

23
Q

explain why chloroform isnt used anymore

A

can form phosgene – a chemically reactive acyl halide. has 2 good leaving groups.

24
Q

carbon tetrachloride was introduced to replace chloroform on what basis? was it successful?

A

carbon tet has no available hydrogen, so it was thought that oxidation would not occur and thus the toxic phosgene (acyl chloride) would not be generated

however, carbon tet can still generate toxic radical species upon reduction

25
Q

true or false

halogenated alkyls are toxic upon oxidation, but safe via reduction

A

FALSE - toxic either way

phogene generated via oxidation and radical species generated via reduction

26
Q

is methylene chloride safe?

A

ch2-cl2

NO.
does the same thing as chloroform just to a lesser extent

27
Q

true or false

all thiols produce sulfenic acid upon oxidation

A

FALSE

mainly the foreign organic thiols produce this toxicity, but natural thiols like GSH and cysteine are safe

28
Q

is there any toxicity concern with thiol?

A

yes - foreign organic thiols can produce sulfenic acid upon oxidation – a very reactive electrophile

29
Q

what enzyme(s) can catalyze the reduction of sulfoxide to sulfide?

A

xanthine oxidase
aldehyde oxidase
cyt p450 reductase

30
Q

-S- <-> -S=O- —> O=S=O

is this any concern?

A

the oxidation (forward reaction) catalyzed by MFO system usually is not, but the reduction of sulfoxide to sulfide can be catalyzed by -
xanthin oxidase
aldehyde oxidase
cytp450 reductase

this is a potential concern for sulfur toxicity

31
Q

allyisopropylacetamide

A

a double bond containing molecule that can irreversibly inhibit Cytochromep450 through heme alkylation

32
Q

besides allylisopropylacetamide, what else can do heme alkylation?

A

alkynes

33
Q

in both scenarios of heme alkylation, what can form?

A

epoxides

in the case of alkynes it is turned into a carboxylic acid

34
Q

is the metabolism of anthracycline quinones any concern?

A

yes

radical oxygen species are formed when molecular oxygen accepts an electron from the oxidation of the molecule (OH to carbonyl) SINGLE ELECTRON TRANSFER – due to cytochromep450 reductase in MFO system

this can generate H2O2, O2. and .OH

35
Q

what is a class of medications that are anthracycline quinones?

A

interculating agents – class of anticancer drugs

36
Q

what specific toxicity occurs from the metabolism of anthracycline quinones

A

cardiotoxicity from reactive oxygen species

37
Q

Is there any way for toxicity NOT to be generated from anthracycline quinones?

A

YES

there is an enzyme - DT-Diaphorase that can supply 2 electrons at once and thus bypass the radical species.

with this enzyme, you can go straight from highly reactive quinone to DIOL – which is chemically safe

38
Q

NADPH -> NADP is this oxidation or reduction?

A

oxidation

39
Q

NADPH is the cofactor involved in….

A

the redox reaction of anthracycline quinones

40
Q

what can provide protection against radical oxygen species?

A

GSH conjugation

41
Q

what is cyclophosphamide

A

an alkylating anticancer drug

42
Q

what is on the right side of the structure of cyclophosphamide

A

a nitrogen mustard (N and 2 carbon chains with chlorine at the end of each)

43
Q

true or false

cyclophosphamide is extremely unstable

A

FALSE

it is stable due to P=O pulling electrons from the nearby N.
no reactive aziridinium species is spontaneously formed

44
Q

what were the potential phase 1 reactions on cyclophosphamide?

A

originally, it was thought to undergo hydrolysis via phosphoramidase, but this did not turn out to be the case

there are 2 potential positions for oxidation — the carbon alpha to nitrogen and the carbon alpha to O.
it turned out that only the 4 position (alpha to nitrogen) was oxidized well.

when oxidized, becomes 4-hydroxycyclophosphamide

45
Q

explain the mechanism of cylclophosphamide metabolism

A

undergoes oxidation at #4 position to form 4-hydroxycyclophosphamide.

this is a carbinolamine like intermediate that is unstable and the ring breaks open to form =O at one edge (aldehyde)
aldehyde and 4-hydroxycyclophosphamide can go back and forth.

the phosphate ester-like structure is a good leaving group. a proton gets pulled off by any base which causes BETA ELIMINATION and fragmentation of the molecule into

ACROLEIN and a penultimate nitrogen mustard that undergoes other reactions to spontaneously cross links DNA.

46
Q

what is acrolein?

A

a metabolite of cyclophosphamide - a highly reactive michael acceptor

47
Q

_____ is notorious for generating kidney toxicity, and lesser so with _____

A

iphosphamide, cyclophosphamide does too but not as bad

due to the generation of ACROLEIN

48
Q

what is the term for when the cyclophosphamide fragments into 2 pieces

A

tautomerization

49
Q

what can the michael acceptor be generated from

A

C=C or C triple bond C connected to N or O or S

50
Q

true or false

acrolein is a michael acceptor

A

true

51
Q
A

Med Chem Final (11 decks)

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