Medchem of Cytotoxic Drugs
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Transcript of Medchem of Cytotoxic Drugs
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Intro
Otherwise, the chemo can kill the patient before it kills the cancer
We want to specifically kill cancer cells over normal cells (selective toxicity)
Compared to antibiotics, which exploit differences in biochemical pathways
between us and them
Problem is, cancerous cells tend to use the same biochemical pathways as normalcells
Some normal cells are rapidly dividing (gut, bone marrow, liver) so they are
affected my chemo
But some cancerous cells won't divide rapidly, so chemo won't work well
against them
So we tend to target rapidly dividing cells to target the cancer
Oral forms are desired
Finally, we also want to have them in a form which is easy to administer
Vesicant- a substance which is able to cause blistering. Quite a few chemo drugs tend to
be vesicants. This is why patients need to be told to look out for redness, swelling,
discomfort or pain around the infusion site.
Alkylating agents
Can't copy or transcribe information from DNA
Trigger apoptosis due to damage
Guanine is generally targeted due to its nucleophilic properties (see below)
Designed to interfere with DNA function
Guanine is alkylated, so there's this massive group attached to it
This can lead to the elimination of the group as well (the base comes
off the DNA, see below)
Either way, the DNA can't work this way, so excision repair enzymes
are activated, to cut the DNA to replace these faulty bases
Because repairs can be made, this isn't effective
Modification of DNA bases (mono-alkylation)
See below for the structure a sulphur mustard
Notice it has two chlorines, so it can alkylate twice
Between chains
Within chains (more common)
It can form covalent bonds either:
This will prevent the DNA from coming apart normally for normal
function
Effective
Cross-linking within and between DNA strands (di-alkylation)
Normally, we'd except A goes with T and C goes with G in DNA
But alkylated G can go with T, which is a mistake
This will lead to mutations
Which can lead to a malfunctioning cell, and apoptosis
Nucleotide mispairing
How does it work? (mode of action):
Janus is the Roman god of doors. He has two heads, one pointing inside, and
the other pointing out.
Why is this important? Because alkylating agents will kill cancerous cells BUT
because they interfere with DNA, they can also CAUSE cancer.
Exhibits a 'Janus' effect
Medchem of cytotoxic drugs
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People may have secondary tumours which are completely different
to the original tumour after a few years of treatment
Below is a sulphur mustard, where there's a two carbon bridge between the
S and the chlorines. THIS IS IMPORTANT. RECOGNISE THIS.
Sulphur mustards are gases, due to low intermolecular bond strength (they
don't H-bond to each other) so they are too dangerous to work with
So nitrogen mustards were investigated, because they can H-bond to each
other, so it's not a gas anymore, so it's safer to handle
The alkylating agents will always have a specific moiety
The two nitrogens in the right side ring presents a electron rich region
This makes it nucleophilic, attacking the alkylating agent (seen as R)
Can lead to the ring opening which permanently binds the agent to
the base
Or can cause the entire group to come off as a leaving group from the
DNA
This addition will lead to a positive charge on the nitrogen, which needs to
be removed.
But remember: monoalkylation (shown below) can easily be repaired
Why is guanine (N7 nitrogen) targeted specifically?
The electronegative chlorine atoms will draw electrons towards itself,
causing the adjacent carbons to become slightly positive
Chlorine is a good leaving group as it comes of neutral with respects to
acid-base chemistry (i.e. even though it's negatively charged, it
doesn't have acid base chemistry)
The non-bonding electron pair (NBP electrons) on the nitrogen is attracted
to the positive charges, leading to intramolecular nucleophilic attack (SNi)
Bond angles are strained (at 60 degrees instead of normal 108)
Both carbons are positively charged
The SNi leads to the formation of the aziridium ion, which is a highly reactive
electrophile (i.e. susceptible to nucleophilic attack)
After nucleophilic attack with the nucleophile (which is likely to be guianine),
The mechanism of action of alkylating agents is all the same (and we need to
memorise it)
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Remember: the molecule is bifunctional as it has two carbons, so it
can crosslink DNA (deals more damage)
the base is now alkylated.
Forms the aziridium ion too easily then, which will just react with all the cells
it comes into contact with
So we need to tie up those NBP electrons to stop forming the aziridium ion
as easily to reduce toxicity, to reduce side effects
If the nitrogen mustard shown above had an aliphatic R group, it is too toxic to use
in people
Alkylating agents- examples
Mephylan
The NBP electrons on the nitrogen are partially taken up into the aromatic ring
It's actually L-phenylalanine (amino acid) attached to the mustard
The sterochemistry on the carbon is R
But it's still actively taken up by all cells, leading to side effects
They thought the phenylalanine would allow the drug to be taken up into growing
cells because it's an amino acid
If the phenylalanine comes off, it's still active because the mustard is intact
If the amino or carboxylate groups are metabolised, again, the mustard is
still intact and it's still active
This drug has some activity, because the NBPs are somewhat available
This is the really important one because we use it quite often
Cyclophosphamide
It is a prodrug, it must be metabolised first:
R
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In fact, the structure shown on the right can be further broken down to form
just a bare nitrogen mustard, which is thought to have most of the activity
The NBP electrons in Cyclophosphamide are completely taken up into resonance,so no aziridium ion formation can occur, so there is no alkylation.
Need to co-administer with Mesna and make sure to keep the patient very
well hydrated with IV fluids and oral fluids
Mesna (pictured top left below) has a sulfate group purely for solubility and
salt formation, while the active area of the molecule is the thiol (SH) group,
which acts as a nucleophile to bind with the acrolein to form a non-toxic
compound
Problem with cyclophosphamide is acrolein is a side-product which is toxic
Some cancer cells produce a great amount of glutathione (GSH)
Remember: thiol is a nucleophile, the active aziridium ion form is very
attractive
GSH has a thiol group, which can react with the alkylating agent before it
reaches the DNA to deal damage
Therefore, these cells will be resistant to treatment
Thiol groups could also be a hindrance to treatment though
An alkylating agent may be conjugated to a steroid to help it get into specific
cells
It is only effective in cells which have low ALDH (aldehyde
dehydrogenase), which are the well-differentiated blood cells, while
the stem cells of the blood are quite high in ALDH, so they tend to be
protected
Cyclophosphamide is actually quite targeted if you think about it
Lastly, some forms are slightly selective
Alkylating agents- Methansulfonates
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The oxygens are strongly electronegative, causing a great positive charge on
the sulfur and adjacent carbon
Busulfan has two methanesulfonate groups (the two sulfur containing groups on
the sides)
The methanesulfonate group is a good leaving group, so the carbon with thepositive charge is able to attack guanine as well
But because it's got two groups, its able to cross link DNA
Alkylating agents- nitrosoureas
These are the drugs which tend to end in 'mustine'
Very useful for brain cancers, as they are lipophilic enough to pass through the
BBB
Because the non-bonding pairs of electrons on the nitrogen are completely
taken up into resonance, so the aziridium ion can't be formed
Although they look like normal alkylating agents, they don't have the same
mechanism
Instead, through a complicated mechanism, it breaks down to form two positively
charged carbocations which are the active molecules
Platins (alkylating-like agents)
These are not alkylating agents, but shows some similar action (crosslinking of
DNA)
The classical one is cisplatnin
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Cisplatnin is a square planar molecule, with 2 amine and 2 chloride groups in
a cis configuration:
This is because of this equilibrium reaction:
Interestingly, cisplatnin is formulated in normal saline (0.9% NaCl)
If the concentration of chlorine is high (as it is in the blood and in normal saline),
then the equilibrium lies to the left, which is the inactive form
Therefore, platnins are prodrugs
However, if cisplatnin moves into the cells, the chloride concentration is much
lower, the equilibrium moves to the right, and the activated 'aquated' form is
produced (pretty much water chucked on)
The H2O ligand is a very good leaving group
The aquated form is active, because the platinum atom can now attach to the N7
atom of guanine (just like alkylating agents)
However, this is a intra-strand (within strand) crosslink.
This will cause the DNA to have a 90 degree kink due to the shape of
cisplatnin (square planar)
This irregular shape means the DNA is now useless
Because there are two chloride groups, the same process will happen again, whichcauses DNA to become cross-linked
GSH will also bind to platnins to make them useless
We can try to shield the platnin with a bulky group, but this is ineffective
Again, another huge problem is with glutathione
Therefore, we have newer, second generation platnins which are less
reactive/toxic but still just as effective
Cisplatnin is too reactive, it is quite toxic
It has a bi-dentate ligand instead of the two chorines
This slows down the aquation of the platinum, leading to reduced toxicity
Pictured above is oxaliplatnin, a second generation platnin
Antimetabolites
Self directed learning
Up to now, we've looked at compounds which deliberately damage DNA
But antimetabolites will cause DNA damage by preventing the synthesis of DNA,
either by producing false metabolites, or interfering with the enzymes responsible
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Therefore, this class of drugs are S phase specific for the cell cycle
for production
Responsible for producing thymine from uracil, uses tetrahydrofolate (THF)
as a co-factor
Disruption will mean thymine synthesis cannot occur, and the cell will
apoptose due to a thymineless death
The primary target enzyme is thymidylate synthase
Antimetabolites- 5-fluorouracil
5-flurouracil has a strongly electronegative group on the 5 position, which makes it
quite attractive to the enzyme
Note: he doesn't think it's a prodrug, because prodrugs tend to be
catabolised (broken down) to its active form. 5-FU is anabolised (built up) to
its final form due to the addition of ribose and phosphate
It is a prodrug (even though Schmerer disagrees), it must first be converted to its
deoxyribonucleotide form (pretty much just attach some phosphates to it to makeit look something like a nucleotide)
Normally the THF would react with the uracil to form thymine, but this can't
happen due to electrical repulsion between the fluorine and the nitrogen 10
of THF
When it enters the thymidylate synthase enzyme, it causes the formation of a
false complex with tetrahydrofolate (THF) and thymidylate synthase
This effectively prevents thymidylate synthase from being regenerated, which
stops thymine production
This causes the elongation of DNA to be stopped, leading to apoptosis
Additionally, these false nucleotides may also be incorporated into the DNA and
RNA
Anti-metabolites- folate metabolism
As stated above folate (as THF) is an important co-factor for thymidylate synthase
It needs to be reduced back to THF to be used again
After thymine is produced from uracil, the THF is oxidised to dihydrofolate (DHF)
It is able to be inhibited
Also causes a thymineless death
May be used as a synergistic drug with 5-FU, as they both target the same
process
The enzyme folate reductase is responsible for this function
Increases the electron density on the nitrogen at the bottom of the
ring, which is essential for binding
Therefore it will be able to outcompete folic acid
Better substrate compared to the endogenous substrate, folic acid due to
the amine group
Methotrexate will inhibit folate reductase
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Bleomycin
This is a problem, as it is hard to scale up to get large yields
Massive molecule which is synthesised by bacteria
Although a part of the molecule is cut off, DNA binding sites lie to the right
of the molecule shown below. However, it is unable to intercalate with DNA
due to too much 3D structure (need to be flat to intercalate)
The important bit is the iron in a square planar structure
Notice how the oxygen is bound to the iron, it displaces the carbamate
group
The oxygen is reduced to oxygen free radicals, which then damage the DNA
The action of bleomycin is to bind to the DNA and cause DNA breakages
The molecule is enzymatically cleaved by hydrolase, which reduces DNA binding
and damage
The copper is removed to inactivate the molecule to reduce toxicity (it will
find iron to chelate to in the body)
Normally, it comes as a blue copper complex (the copper sits where the iron is
sitting below)
It is amazing to see such a large molecule being able to enter the nucleus. The
sugars may be used as a recognition site to gain access to the nucleus
Because it converts oxygen into free radicals, the compound is associated with
oxygen toxicity, leading to pulmonary fibrosis. Need to monitor patients carefully
Actinomycin
Flat ring system which isn't fully aromatic. It is still able to intercalate to the
DNA
Composed of three basic parts:
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Two large lactones made of 5 amino acids, they may differ or be the same
Planar rings allow pi-stacking
Lactones will bind via hydrogen bonding (contains amino and carboxyl
groups) and Vander Waals' forces (because it's big)
The entirety of the molecule will be able to bind to the DNA, causing it to bend out
of shape completely
Bending it out of shape this badly prevents topoisomerase II from unwinding the
DNA properly, so the cell can't replicate or transcribe DNA, leading to death
Anthracyclines
Doxorubicin
Epirubicin
There are a few anthracyclines in use e.g.
Although they have 4 rings, they are not tetracyclines
Tip: rubor is redness, can't forget it's red now
They are red coloured compounds, and they are renally excreted, causing urine to
go red
Note: formaldehyde naturally formed by the body will attack the sugar,
which can cause covalent bonding of the anthracycline to the DNA
That is a good thing
The 4 flat rings allow for intercalation into the DNA, while the daunosamine sugar
(seen at the bottom of the image) will aid with binding to the DNA
Prevents transcription and duplication of DNA
After intercalating with the DNA, it stabilises the interaction of topoisomerase II
with the DNA, preventing it from doing anything else
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Causes free radical formation, which does have some effect against DNA,
but the problem is it also occurs in the cytosol of cells
This is why it might be causing cardiotoxicity, as the cells of the heart cannot
divide to form new cells, so the cells will take gradual damage over use
Therefore, there is a maximum cumulative lifetime dose for all the
molecules in the anthracycline family
They are also a target for reductase enzymes, this is a major issue