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Pharm Decks > Lecture 14 - Intercalation and new targets > Flashcards

Lecture 14 - Intercalation and new targets Flashcards

1
Q

What is TOP-2?

A
  • Topoisomerase II
  • Target of important classes of anticancer drugs
  • a DNA processing enzyme
  • make dsDNA break, to remove twists and knots in duplex DNA molecules
  • Promising target in chemo
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2
Q

What drug targets TOP-2 and what is this type of drug?

A
  • Doxorubicin
  • Intercalator
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3
Q

What is a side effect of doxorubicin?

A
  • formation of secondary malignancies that arise from drug-induced translocations
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4
Q

General overview of how intercalators fit into DNA

A
  • Slot into the gaps in DNA through base pairs
  • Via the neighbourhood exclusion rule where they fill every other gap
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5
Q

What is the structure of Doxorubicin?

A
  • large aromatic core normally 3 rings fused together forming flat planar mass
  • Sugars (multifunctional rings)
  • stacks between the base pairs of DNA
  • stacking of pi systems within the drug and the two base pairs either side
  • very stable, cause a stabilisation of the duplex
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6
Q

What do DNA intercalators prefer to associate with on DNA?

A
  • Protein DNA complexes rather than naked DNA
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7
Q

What do the sugars (multifunctional rings) of doxorubicin do?

A
  • bind into the major groove of DNA
  • form non-covalent interactions with the phosphate backbone of DNA stabilising the complex
  • Important for increasing the potency
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8
Q

What increases potency of doxorubicin?

A

Stronger binding

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9
Q

Mechanism of action of doxorubicin

A
  1. TOP-2 complex is a dimer, with 2 binding pockets
  2. A kink in DNA forms for drug to be dropped into
  3. Drug slots into the two pockets, which are specific to the binding site
  4. Results in stabilisation
  5. Then get covalent modification by the protein of the DNA rather than the drug stuck to the DNA
  6. The TOP-2 protein stuck covalently, representing big challenge to DNA repair mechanism and thus DNA breaks
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10
Q

What intercalator targets TOP-1?

A
  • SN-38 complex
  • similar way to TOP-2
  • interact with the complex TOP-1 and DNA
  • single specific binding socket which opens up and drug fits in and binds tightly
  • lock the complex of TOP-1 with DNA
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11
Q

What is pluramycin and what does it do?

A
  • Intercalator/alkylator
  • Binding of TBP to the TATA box facilitates intercalation of pluramycin
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12
Q

Overview of how doxorubicin works?

A
  • stabilisation of a complex with eventual alkylation via a protein forming strand breaks at that site
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13
Q

How is SN-38 formed from natural products?

A
  • Natural product camptothesin
  • formed via hydrolysis of Irinotecan by carboxylesterases and metabolized via glucuronidation at the phenol
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14
Q

More than just alkylating DNA - principle of intercalators…

A
  • Intercalators –> large molecule in the minor groove of DNA stabilises it, making it difficult for enzymes to pull apart and get into the DNA to repair it
  • once complex formed itself may change the DNA
  • Can form dimers with drugs, as they get bigger though they become less stable
  • Secondary structures are also important within DNA
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15
Q

What do telomerases do?

A
  • Take DNA and create a repeat end at the end of DNA to form telomeres
  • adds DNA sequence repeats, “TTAGGG” to the 3’ end of DNA strands in the telomere regions
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16
Q

What forms at the end of telomeres by telomerases?

A
  • G-quartet (complex between 4 guanines)
  • Guanine tetraplex/quadruplex
17
Q

Structure of a g-quartet?

A
  • 4 guanines, 4 hydrogen bonds
  • flat, planar structure
  • metal in the centre to stabilise
18
Q

What are telomeres?

A
  • telomeres contains non-coding DNA material at end of chromosomes
  • prevents constant loss of important DNA from chromosome ends
  • regenerated by telomerase
19
Q

Why could we target telomerases in cancer?

A
  • They are active in cancer cells to maintain telomere length during uncontrolled cell divison
20
Q

How could we target telomerases?

A
  • Form telomerase inhibitor which fits across guanine quadruplex
21
Q

What is name of best telomerase inhibitor and briefly how does it work?

A
  • Telomerstatin
  • stacks above guanine tetramers stabilising it and causing disruption
  • sequester newly formed G-quadruplexes
22
Q

What other 2 drugs can target the telomere/telomerase complex?

A

Perylene and cationic porphyrins

23
Q

What do perylene and cationic porphyrins do?

A
  • They are G-quadruplex-interactive drugs
  • Which inhibit helicases or facilitate formation of new quadruplexes
24
Q

General principle of Doxorubicin?

A
  • Binds to sites up and downstream of TOP-2 interaction sites, in specific binding pockets
  • damage done by formation of stable complex of drug, protein and DNA which sits with covalent modifications by the PROTEIN not the ligand
  • Result in protein bound to DNA not the ligand
  • Cell cannot process this damage and get SSB and DSB
25
Q

How is the damage actually done by doxorubicin?

A
  • Wasn’t the drug which alkylated DNA
  • BUT the formation of a stable complex of drug, protein and DNA which sits in a way with covalent modifications by the protein not the ligand
  • Protein bound to DNA not the ligand
  • cell cannot process ssDNA and dsDNA breaks
26
Q

What are the repair pathways for TOP-2 mediated DNA damage?

A
  • double strand break repair pathways
  • other pathways specific for removal of protein DNA adducts
27
Q

Example of Intercalators which target TOP-2

A
  • Doxorubicin
  • Mitoxantrone
28
Q

What is the intercalator SN-38 and cancer used in?

A
  • irinotecan analog
  • topoisomerase I inhibitor
  • primarily used in the treatment of colorectal cancer
29
Q

Mode of action of pluramycin

A
  • binds peripherally to the TATA-binding protein (TBP)–TATA box complex
  • Alkylation by pluramycin enhanced by TBP binding to the TATA box, and as a result TBP is immobilized on the DNA
30
Q

Anticancer drugs which target TOP-1

A
  • SN-38 (analogue of irinotcean)
  • topotecan
31
Q

Disadvantages of TOP-1 inhibitors

A
  • side effects
  • low solubility
  • adverse drug interactions
32
Q

What is the equilibrium between dsDNA and G quadruplexes dependent on?

A
  • helicases that unwind the quadruplex and chaperone proteins that are required for its formation
33
Q

What can G-quadruplex-interactive drugs do (telomerase inhibitors)?

A
  • inhibit helicases or facilitate formation of new quadruplexes (perylene and cationic porphyrins)
  • OR sequester newly formed G-quadruplexes (telomestatin)
34
Q

Side effect of Doxorubicin

A
  • cardiotoxicity by iron-related free radicals and mitochondrial disruption
35
Q

Mode of action of SN-38

A
  • SN-38 binds to and inhibits topoisomerase I by stabilizing the cleavable complex between topoisomerase I and DNA
  • resulting in DNA breaks, inhibition of DNA replication, and apoptosis

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