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CHEM FOR BIOMED > Metal complexes as drugs > Flashcards

Metal complexes as drugs Flashcards

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1
Q

What is ALS

A
  • Most common form of motor neuron disease
  • selective death of motor neurons
  • changes in mitochondrial morphology
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2
Q

What is the Cu(II)atsm complex?

A
  • Sqaure planar Cu(II) complex

* ligand is a dianion since sulfur carry a negative charge

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3
Q

Properties of Cu(II)atsm complex

A
  • neutral
  • stable
  • planar
  • low molecular weight
  • lipophilic
  • able to cross the blood brain barrier

Shows significant promise in treatment of ALS

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4
Q

What is Cu(II)atsm complex mode of action

A
  • Cu(II)atsm delivers copper to the brain
  • recall - SOD1 (Cu/Zn) enzyme destroys toxic superoxide radical
  • mutated form of SOD 1 which is Cu(II) deficient - a familial cause of ALS
  • therapeutic activity due to ability of Cu(II)atsm to improve bioavailability of Cu
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5
Q

What is an example of an antitumor drug?

A

• cisplatin

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6
Q

What is the structure of cisplatin?

A

Central Pt with four groups attached

  • 2 NH3
  • 2 Cl
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7
Q

What are labile complexes?

A

Ligands rapidly replaced (approx less than 1 min)

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8
Q

What are inert complexes?

A

Ligands slowly replaced (may take hours)

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9
Q

What are the substitution reactions of cisplatin?

A

Undergo 2 hydrolysis reactions ref. lecture 35, slide 16

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10
Q

What are the 2 important features of DNA?

A

• Helix is right-handed
• 2 grooves are present
- major groove
- minor groove

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11
Q

Describe the 2 grooves in DNA

A
  • Major groove - width 12 Å
  • minor groove - width 6 Å
  • depth about the same
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12
Q

What is the preferred metal binding sites on DNA?

A
  • N-7 of guanine is most electron rich site on nucleotides
  • also N-7 of adenine
  • preferred site for metal binding
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13
Q

What are the reactive sites on DNA?

A
  1. Lone pairs on base nitrogens of guanine and adenine
  2. electrostatic interaction with ionised phosphodiester link
  3. sugar ring: main involvement is in the interaction of DNA with radicals
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14
Q

Why is cisplatin kept in a saline solution

A

• The neutral complex is the active form of the drug.
• It is stored and administered in saline to inhibit
hydrolysis to the inactive aquated form.

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15
Q

What is DNA intercalations and what structural changes occur as a result?

A

The DNA intercalation reaction is one in which a molecule, such as B, slides (inserts) in between the
DNA base pairs.
Structural changes on DNA following intercalation are:
• Increase in length of the DNA helix.
• Unwinding of the DNA helix.

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16
Q

How does cisplatin cause cell death?

A

• cisplatin is a neutral molecule which can cross the lipid membrane
• cisplatin gets hydrolysed - mono- or diaqua species
• cations enters the nucleus and diffuse to DNA helix - causes a bend in the DNA
• forms adducts with DNA
• intrastrang GG crosslink formed
- the dna, if repaired, is resistant to damage
- if not repaired, causes cell death

17
Q

What is used to minimise the side effects of cisplatin?

A

rescue agents

• employed to ameliorate these effects

18
Q

What are the mechanisms of resistance to cisplatin?

A
  • enhanced repair of DNA damage
  • reduced cellular uptake of cisplatin
  • elevation of intracellular levels of thiol and sulfur rich proteins - they bind very well to platinum
19
Q

Why is formation of adducts with DNA the reason of cell death?

A
  • levels of Pt-DNA adducts correlate with disease response

* when DNA repair is deficient then patients are hypersensitive to cisplatin

20
Q

How is the hydrolysis of cisplatin relates to Cl- concentration?

A
  • [cl-] in blood and extracellular fluid is high (100mM)
  • High Cl- concentration suppresses hydrolysis
  • intracellular [Cl-] is 4mM - hydrolysis occurs
21
Q

Intra-strand DNA vs Inter-strand DNA

A

Intra-strand: bonds on the same strand (lead to cell death)

Inter-strand - joined to bases on the 2 different DNA strands

ref. lec 35

22
Q

Is cisplatin going to react with the major or minor groove and why?

A
  • always major groove

* that’s where the N7 of guanine is located

CHEM FOR BIOMED (14 decks)

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