Lecture 2 Flashcards
Explain the classifications of P-450 inhibition
-reversible inhibition
-metabolic intermediate complexation inhibition
-irreversible inhibition
name some things that present REVERSIBLE p450 inhibition
nitrogen heterocycles
imidazole functional group for example, which is contained in antifungal drug classes.
(go back to this and go over nitrogen heterocycles. azo?)
give an example of irreversible p450 inhibition
-heme alkylation
-covalent binding of apoprotein
the inhibitor can target either the CATALYTIC or the APOPROTEIN site
Give an example of metabolic intermediate complexation inhibition
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)
what is a standard drug for testing the inhibition of cytochrome p450 in vitro drug metabolism studies?
SKF-525A (an alkylamine)
name the 3 phase 1 reactions
oxidations
reductions
hydrolyses
name 4 compounds that undergo phase 1 reduction reactions
- aromatic and heteroaromatic nitrogen compounds
- aromatic azo compounds (N=N)
- Aromatic sulfoxides (S=O)
- carbonyl groups (ketones and aldehydes)
name 5 compounds that undergo phase 1 hydrolysis reactions
- carboxylic esters
- organic phosphate esters
- organic sulfate esters
- organic nitrite and nitrate esters
- amides
what 3 compounds undergo oxidative desulfurization? is this phase 1 or phase 2?
phase 1
thioketones
thioamides
thiophosphates
what is the issue with drugs that undergo oxidative desulfurization?
toxic sulfur is produced from these reactions (SO42-)
true or false
in the oxidation of primary alcohols, once carboxylic acid is reached no further oxidation is possible
true
what happens when a secondary alcohol is oxidized?
what enzyme catalyzes this?
is it reversible or irreversible?
is further oxidation possible?
a KETONE is formed
ADH (alcohol dehydrogenase) catalyzes. it is REVERSIBLE
NO FURTHER OXIDATION IS POSSIBLE
TRUE OR FALSE
the oxidation of alcohols is not catalyzed by the p450 system
TRUE
explain why the oxidation of a primary alcohol to an aldehyde is reversible, but the oxidation of an aldehyde to carboxylic acid is irreversible
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.
explain the difference and similarities between the oxidation of methanol vs ethanol
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.
What is the coenzyme in the oxidation of alcohols? is it involved in both steps? (in the case of primary alcohols)
NADH
involved in both steps
NAD+ reduced to NADH
give the scenarios in which alkyl side chains can be oxidized
-terminal carbon oxidation
-w-1 carbon oxidation
explain the product of terminal carbon oxidation
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)
explain the product of w-1 carbon oxidation
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)
what is the allylic position?
the allylic carbon is the carbon attached to another carbon that is part of a C=C double bond
oxidative deamination is mechanistically identical to what other reaction?
n-dealkylation
explain the compounds that are able to undergo oxidative deamination
- primary amines on primary carbon atoms
- primary amines on secondary carbon atom
Explain the mechanism of oxidative deamination of primary amines on primary carbon atom
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
Explain the concern with big molecules in terms of metabolism
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
true or false
oxidative deamination is very possible and common
true
explain the name “oxidative deamination”
the initial reaction is the oxidation to alcohol, and then the amine group is kicked off the metabolically unstable intermediate
“oxidative deamination”
when is oxidative deamination NOT possible
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
explain the mechanism of oxidative deamination of primary amines on secondary substituted carbon atom
oxidized to its corresponding alcohol, the metabolite is unstable and falls apart to form KETONE + ammonia
tertiary alkyl amines typically undergo what kind of reaction?
an oxidation reaction – N-dealkylation
mechanistically the same to oxidative deamination
explain the mechanism of N-dealkylation
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
what is carbinolamine
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
when considering oxidative deamination and N-dealkylation, what is a VERY IMPORTANT CONSIDERATION
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
explain the how to differentiate in naming things deamination or dealkylation
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
tertiary alkyl amines undergo what reaction?
N-dealkylation
pyridine is…..
a tertiary amine.
undergoes oxidative N-oxide formation
In the case of pyridine, what reaction occurs?
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
which is more popular:
oxidative deamination/dealkylation OR the oxidation of dialkyl amides
deamination/dealkylation is more popular
what molecules undergo O-dealkylation?
ethers with 1 aliphatic (or aromatic) R group
REMEMBER must be at least 1 available hydrogen on alpha carbon
explain the mechanism of O-dealkylation
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
thioethers undergo what kind of reaction?
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
which is more unstable and why– hemiacetal or hemithioacetal?
which reactions produce what?
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
in the case of thioethers, can the R group be aromatic and still undergo oxidation?
YES
it doesnt matter if it’s aromatic or aliphatic. just keep in mind that aromatic rings can undergo more reactions
What are heteroatoms? what is an important consideration in terms of metabolism?
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
between the heteroatoms, which are the MOST FLEXIBLE to undergo oxidation?
Nitrogen and sulfur, but MAINLY SULFUR (has extreme electron capabilities - can form double bonds)
TRUE OR FALSE
once hemiacetal falls apart, it is possible to return to hemiacetal from the alcohol + aldehyde
FALSE - can’t go back. that’s it
what reactions produce reactive sulfur? what can you conclude from this?
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
what has been used chemically to lower thyroid activity?
C=S
how was C=S discovered to be toxic?
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
what is commonly used as an insecticide?
thiophosphates (P=S)
what are azo compounds
have N=N
true or false
only aliphatic azo compounds can undergo oxidation to azoxide
FALSE – both aliphatic and aromatic can
