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Med Chem Final > Lecture 2 > Flashcards

Lecture 2 Flashcards

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1
Q

Explain the classifications of P-450 inhibition

A

-reversible inhibition
-metabolic intermediate complexation inhibition
-irreversible inhibition

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2
Q

name some things that present REVERSIBLE p450 inhibition

A

nitrogen heterocycles

imidazole functional group for example, which is contained in antifungal drug classes.

(go back to this and go over nitrogen heterocycles. azo?)

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3
Q

give an example of irreversible p450 inhibition

A

-heme alkylation
-covalent binding of apoprotein

the inhibitor can target either the CATALYTIC or the APOPROTEIN site

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4
Q

Give an example of metabolic intermediate complexation inhibition

A

alkylamines such as SKS-525A

initial binding and At least 1 cycle of metabolic reactions occurs – an intermediate is produced which is then inhibited by an alkylamine (SKF-525A)

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5
Q

what is a standard drug for testing the inhibition of cytochrome p450 in vitro drug metabolism studies?

A

SKF-525A (an alkylamine)

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6
Q

name the 3 phase 1 reactions

A

oxidations
reductions
hydrolyses

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7
Q

name 4 compounds that undergo phase 1 reduction reactions

A
  1. aromatic and heteroaromatic nitrogen compounds
  2. aromatic azo compounds (N=N)
  3. Aromatic sulfoxides (S=O)
  4. carbonyl groups (ketones and aldehydes)
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8
Q

name 5 compounds that undergo phase 1 hydrolysis reactions

A
  1. carboxylic esters
  2. organic phosphate esters
  3. organic sulfate esters
  4. organic nitrite and nitrate esters
  5. amides
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9
Q

what 3 compounds undergo oxidative desulfurization? is this phase 1 or phase 2?

A

phase 1

thioketones
thioamides
thiophosphates

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10
Q

what is the issue with drugs that undergo oxidative desulfurization?

A

toxic sulfur is produced from these reactions (SO42-)

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11
Q

true or false

in the oxidation of primary alcohols, once carboxylic acid is reached no further oxidation is possible

A

true

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12
Q

what happens when a secondary alcohol is oxidized?
what enzyme catalyzes this?
is it reversible or irreversible?
is further oxidation possible?

A

a KETONE is formed
ADH (alcohol dehydrogenase) catalyzes. it is REVERSIBLE

NO FURTHER OXIDATION IS POSSIBLE

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13
Q

TRUE OR FALSE

the oxidation of alcohols is not catalyzed by the p450 system

A

TRUE

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14
Q

explain why the oxidation of a primary alcohol to an aldehyde is reversible, but the oxidation of an aldehyde to carboxylic acid is irreversible

A

ADH (alcohol dehydrogenase) catalyzes the oxidation of a primary alcohol to an aldehyde. this enzyme is found everywhere (bulk in cytosol) and is therefore very plentiful

ALDH (aldehyde dehydrogenase) catalyzes the oxidation of aldehyde to carboxylic acid. the highest capacity of this enzyme is in the mitochondria, and is thus not as plentiful.

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15
Q

explain the difference and similarities between the oxidation of methanol vs ethanol

A

both are primary alcohols.

our body can’t tolerate methanol as much as ethanol.

Methanol will be oxidized to carboxylic acid (formic acid). this can cause acidosis and the buildup of aldehyde (intermediate - formaldehyde) can cause blindness

ethanol is first oxidized to acetaldehyde, and then acetic acid. acetic acid reacts with coenzyme A to give acetyl coA which participates greatly in lipid and carbohydrate metabolism.

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16
Q

What is the coenzyme in the oxidation of alcohols? is it involved in both steps? (in the case of primary alcohols)

A

NADH

involved in both steps
NAD+ reduced to NADH

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17
Q

give the scenarios in which alkyl side chains can be oxidized

A

-terminal carbon oxidation
-w-1 carbon oxidation

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18
Q

explain the product of terminal carbon oxidation

A

a primary alcohol is produced. this has 2 potential fates.
can be:

-oxidized further via ADH and ALDH to aldehyde and then carboxylic acid

-can stay as alcohol and undergo conjugation (ie: glucuronidation)

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19
Q

explain the product of w-1 carbon oxidation

A

a secondary alcohol is produced.

this can be oxidized further to ketone via ADH OR can remain as alcohol and undergo conjugation (since it has a polar functional group)

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20
Q

what is the allylic position?

A

the allylic carbon is the carbon attached to another carbon that is part of a C=C double bond

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21
Q

oxidative deamination is mechanistically identical to what other reaction?

A

n-dealkylation

22
Q

explain the compounds that are able to undergo oxidative deamination

A
  1. primary amines on primary carbon atoms
  2. primary amines on secondary carbon atom
23
Q

Explain the mechanism of oxidative deamination of primary amines on primary carbon atom

A

the molecule is oxidized to its corresponding alcohol.
this forms CARBINOLAMINE which is chemically unstable metabolite and falls apart.
Since amine is a good leaving group, it comes off when =O is formed.
this forms….

ALDEHYDE +NH3 (ammonia)

keep in mind, this aldehyde can be oxidized further to its carboxylic acid or reduced back to its alcohol

24
Q

Explain the concern with big molecules in terms of metabolism

A

many metabolic reactions are possible on a big molecule, but not all will occur.

we want to know all the metabolic reactions possible on a molecule. Some are more likely to happen than others

25
Q

true or false

oxidative deamination is very possible and common

A

true

26
Q

explain the name “oxidative deamination”

A

the initial reaction is the oxidation to alcohol, and then the amine group is kicked off the metabolically unstable intermediate

“oxidative deamination”

27
Q

when is oxidative deamination NOT possible

A

there MUST be at least 1 available hydrogen on the carbon, otherwise oxidation cannot occur.
this is why oxidative deamination is only possible on primary and secondary substituted carbons

28
Q

explain the mechanism of oxidative deamination of primary amines on secondary substituted carbon atom

A

oxidized to its corresponding alcohol, the metabolite is unstable and falls apart to form KETONE + ammonia

29
Q

tertiary alkyl amines typically undergo what kind of reaction?

A

an oxidation reaction – N-dealkylation

mechanistically the same to oxidative deamination

30
Q

explain the mechanism of N-dealkylation

A

occurs on tertiary alkyl amines, so there are TWO ALPHA CARBONS that can potentially be oxidized. it is possible that only 1 can happen in vivo, but we don’t know. we need to recognize the potential oxidations.

mechanistically the same to oxidative deamination (on primary amines on primary and secondary substituted carbon atom) – via carbinolamine intermediate to product a SECONDARY AMINE + the leaving group

31
Q

what is carbinolamine

A

the metabolically unstable intermediate in both oxidative deamination and N-dealkylation of tertiary alkyl amines

consists of an amine and a hydroxyl attached to the same carbon

32
Q

when considering oxidative deamination and N-dealkylation, what is a VERY IMPORTANT CONSIDERATION

A

there MUST be at least 1 available hydrogen for the reaction to take place. has to be there to insert oxygen and for oxidation to occur

33
Q

explain the how to differentiate in naming things deamination or dealkylation

A

if the amine portion is smaller than the alkyl, the term is deamination

if the alkyl portion is smaller than amine portion, the term is dealkylation

both are mechanistically the same and are oxidative reactions

34
Q

tertiary alkyl amines undergo what reaction?

A

N-dealkylation

35
Q

pyridine is…..

A

a tertiary amine.
undergoes oxidative N-oxide formation

36
Q

In the case of pyridine, what reaction occurs?

A

pyridine is a tertiary amine. However, it CANNOT undergo N-dealkylation.
pyridine is aromatic and thus fully substituted. no oxidation can occur on the alpha carbon, therefore N itself is oxidized to form N-oxide

37
Q

which is more popular:

oxidative deamination/dealkylation OR the oxidation of dialkyl amides

A

deamination/dealkylation is more popular

38
Q

what molecules undergo O-dealkylation?

A

ethers with 1 aliphatic (or aromatic) R group

REMEMBER must be at least 1 available hydrogen on alpha carbon

39
Q

explain the mechanism of O-dealkylation

A

occurs on ethers with 1 aliphatic (could be aromatic) R group

the alpha carbon is oxidized. and this forms an oxidative metabolite which is a chemically unstable intermediate (hemiacetal) that falls apart spontaneously to form the corresponding ALCOHOL + ALDEHYDE

these 2 can undergo further reactions

40
Q

thioethers undergo what kind of reaction?

A

oxidation — sulfoxidation

sulfide <-> sulfoxide -> sulfone

thioethers with one R group being methyl:

-alpha carbon undergoes oxidation which produces the unstable intermediate - hemithioacetal which falls apart to produce thiol (R-S-H+ + formaldehyde

41
Q

which is more unstable and why– hemiacetal or hemithioacetal?

which reactions produce what?

A

BOTH ARE UNSTABLE AND FALL APART BUT hemithioacetal is even more unstable because S is a good leaving group

O-dealkylation of ethers produces thioacetal while the oxidation of a thioether (with 1 R group being methyl) produces hemithioeacetal

42
Q

in the case of thioethers, can the R group be aromatic and still undergo oxidation?

A

YES
it doesnt matter if it’s aromatic or aliphatic. just keep in mind that aromatic rings can undergo more reactions

43
Q

What are heteroatoms? what is an important consideration in terms of metabolism?

A

any atom besides C or H (in terms of drugs – N, O, S)

molecules having N, O, or S with an alpha carbon and at least 1 available hydrogen are EXTREMELY POPULAR AND HIGHLY SUSCEPTIBLE TO OXIDATIVE METABOLISM

almost always guaranteed that oxidation will occur in these scenarios

44
Q

between the heteroatoms, which are the MOST FLEXIBLE to undergo oxidation?

A

Nitrogen and sulfur, but MAINLY SULFUR (has extreme electron capabilities - can form double bonds)

45
Q

TRUE OR FALSE

once hemiacetal falls apart, it is possible to return to hemiacetal from the alcohol + aldehyde

A

FALSE - can’t go back. that’s it

46
Q

what reactions produce reactive sulfur? what can you conclude from this?

A

the oxidative desulfurization of thioketones, thioamides, and thiophosphates

though reactive sulfur is short lived, (neutralized to SO42-) it is highly toxic.

thus, these 3 compounds are not usually a good choice for drug design

47
Q

what has been used chemically to lower thyroid activity?

A

C=S

48
Q

how was C=S discovered to be toxic?

A

before cimetadine (tagamet) was found, a leading H2 antagonist had C=S in its structure and was discovered to have toxicity.

the structure was modified to still interact with the binding site but have no toxicity

49
Q

what is commonly used as an insecticide?

A

thiophosphates (P=S)

50
Q

what are azo compounds

A

have N=N

51
Q

true or false

only aliphatic azo compounds can undergo oxidation to azoxide

A

FALSE – both aliphatic and aromatic can

52
Q
A

Med Chem Final (11 decks)

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