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Flashcards in Medicines Design - Dr Thompson Deck (27)
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How do Platinum drugs work?

The 2 Cls create a complex with water which is positively charged, so can be attacked by DNA....usually by guanine at N7


This can create both inter and intra-strand breaks


How do mustard drugs work?

The postiviely charged nitrogen that is formed can be attacked by DNA (which is nucleophillic), which causes strand breaks


This DNA alkylation normally occurs at Guanine N7/3 and Adenine N7/3


How does Mitomycin C work?

It reacts with both the N2/7 sites on guanines in the minor groove of DNA


It is attacked by DNA twice, with the first being called the alpha, and the second, beta


The beta reaction will only occur with the correct isomer of Mitomycin C


Known as a conjugate-addition reaction


Explain Base Excision Repair (BER)

The removal of either a single (SP) or multiple damaged (LP) DNA base(s)


The N-glycosydic bond of the damaged base is broken by a DNA glycosylase, creating a abasic (empty) site


The sugar-phosphate backbone of the abasic site is then cleaved


The gap is then filled via a short patch (SP) or a long patch (LP), with PARP being involed in LPs


DNA ligases then fix the backbone via the 5' end


What is Bleomycin?

A mixture of glycopeptides that differ in their terminal amine substituent


They are freely soluble in water


They can bind transition metals (eg, Fe/Cu) and oxygen, allowing them to cause ss and ds strand breaks


Explain Nucleotide Excision Repair (NER)

DNA damage is removed by removing 27-30 bases in which the damage is located


XPC-R23 detects damage and creates a bubble by recruting other proteins that promote DNA unwinding, which creates 2 junctions


2 different DNA endonucleases then cut the DNA at the junctions to remove the damage


The remaining strand is used as a template to synthesize the other complementory strand, which reduces the chance for error


What is the structure of Bleomycins?

Metal Binding Domain --> This is what cuts DNA


What are the 3 ways in which resistance can occur against platinum drugs outside of the nucleus?

The copper transporter CTR1 can be mutated or removed in tumours, meaning drugs cant get into the cell


Glutathione and Metallothioein are upregulated in tumours, which can bind to the platinums and so remove them


Copper exporters (ATP7A/B) and glutathione-drug conjugate exporters are upregulated in cancer, causing the platinums to be pumped out of the cell


What is a Guanine Tetraplex?

4 guanine residues around a single cation (normally K+) which stabilises the complex


Form at the end of DNA strands, stabilising them. They become more stabilised when drugs bind. The increased stability means that DNA polymerase and telomerase cant bind, so DNA can't replicate.


Drugs can only bind to the top or bottom of the stacks, never in-between


Why kind of damage is done by topoisomerase II targetting drugs like doxorubcin?

Double strand DNA breaks




What is the main difference between Adozelesin and Bizelesin (CPIs)?

Adozelesin--> Can form both Watson/Crick base pairing and Hoogsteen base pairing, which makes DNA repair much harder


Bizelesin --> Binds via the A-Track that is formed between the DNA strands. The A-track bends the DNA, making Bizelesin more likely to bind


How does Pluramycin function?

Binds to the TATA-Binding Protein (TBP) -TATA box complex


Alkylation is enhanced by this, meaning that TBP becomes immobilised in the DNA


How did Cyclopropapyrroloindoles (CPIs) cause delayed lethality before they were changed?

Their Ethano bridges cause DNA to overwind, and so eventually cause damage and cell death (these were later removed due to this)


Stereochemistry is vital, especially when it comes to dimerising the drugs, which will increase the potency


What are DNA minor groove binders?

Drugs that have planar poly-aromatic structures and so have a natural twist, allowing them to bind into the DNA minor groove


This causes the DNA and drug to get closer, so DNA alkylation is more likely


How does Temozolomide work?


And how can we reverse this?

It is broken down to methyldiazonium ions, which are a DNA methylating species....which will cause DNA damage



This can be reversed by using a glutahione like molecule called AGT, which guanine at the O6 position, looking for DNA alkylation. If present it removes the methyl group (via its sulphur) and returns the base back to the normal guanine


For CPIs, where does the DNA attack occur?

At the N3 of adenine (the only place thay it will occur)


What are the main concepts currently being considered to prevent platinum resistance?

Increased delivery to the tumour (eg, liposomes)


Resistance Modulators (eg, drugs that will deactivate glutathione)


Targeting Agents (eg, mAbs with the platinum payload)


 Drugs that target the resistance mechanims (eg, oxaliplatin/picoplatin/satraplatin)


How do PBDs work?

A reversible aminal bond between the exo-cyclic NH2 of guanine (the only base it will bind with) and the C11 of the PBD


If the PBD has been duplexed, then it can obviously bind to twice as many guanines


What are the methods of resistance to platinums after DNA has bound?

Loss of DNA mismatch repair


Bypassing of adducts by polymerase B and (n)


Down-regulation of apoptopic pathways


Increased removal from the DNA via more NER occuring


What is the function of telomerase in cancer?

An enzyme that adds tandem repeats (TTAGGG) onto the 3' end of chromosomes (telomere region) to stop them from dying naturally, and as allow them to continue causeing cell division


These are always present in cancer cells, so cells never die! As when the telomere repeat sequences are almost fully degraded, the telomerase just adds some more....whereas in healthy cells they would just die off


What are the following....





DACH --> Gives increased resistance to cells producing more glutathione


Aroplatin --> A liposomal formulation of cisplatin-like agents


ProLindac --> A cisplatin-drug that is conjugated to a water-soluble biocompatible co-polymer. This enhances permeability and retention (EPR) effects of macromolecules in tumours


How does Doxorubicin (an anthroycycline) intercalate DNA?

Follow the neighbour exclusion rule, so cant bind next to each other


Do bind symetrically, with pie stacking stabilising the structure


Its tails hang down and bind into the minor grooves


It binds to Topoisomoerase II-DNA complex (Cleavable complex), stabilising it....and so making the repair of the DNA damage that it has caused much harder



How do Bleomycins work?

It makes a cut in the DNA


The bithiazole tail then rotates around to the other side, activating the metal-binding region...creating a second break


These can create both flat and staggered DNA breaks


What is SN-38?


And what did it evolve from?

A topoisomerase I targetter


Evolved from Camptothesin, whcih had low water solubility and several ADRs


What kind of DNA crosslinking can PBDs do?

Inter and Intra-stand


This makes repair much harder


How does Double Strand DNA Repair (DSB) work?

Peel the ends back at the break (can be flat or staggered) to create single stranded tails. This creates a bubble which allows DNA repair to occur


Recombination is the only way of doing this that is inherently error free


Explain the development of platinum based drugs

Cisplatin --> First one (1971)


Safety increased to Carboplatin (1982) before development into the first oral drug of Satraplatin (1993)


Picoplantin/Oxaliplatin --> Broader spectrum of activity (1997/1986 respectively)