Metal complexes as drugs Flashcards
What is ALS
- Most common form of motor neuron disease
- selective death of motor neurons
- changes in mitochondrial morphology
What is the Cu(II)atsm complex?
- Sqaure planar Cu(II) complex
* ligand is a dianion since sulfur carry a negative charge
Properties of Cu(II)atsm complex
- neutral
- stable
- planar
- low molecular weight
- lipophilic
- able to cross the blood brain barrier
Shows significant promise in treatment of ALS
What is Cu(II)atsm complex mode of action
- 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
What is an example of an antitumor drug?
• cisplatin
What is the structure of cisplatin?
Central Pt with four groups attached
- 2 NH3
- 2 Cl
What are labile complexes?
Ligands rapidly replaced (approx less than 1 min)
What are inert complexes?
Ligands slowly replaced (may take hours)
What are the substitution reactions of cisplatin?
Undergo 2 hydrolysis reactions ref. lecture 35, slide 16
What are the 2 important features of DNA?
• Helix is right-handed
• 2 grooves are present
- major groove
- minor groove
Describe the 2 grooves in DNA
- Major groove - width 12 Å
- minor groove - width 6 Å
- depth about the same
What is the preferred metal binding sites on DNA?
- N-7 of guanine is most electron rich site on nucleotides
- also N-7 of adenine
- preferred site for metal binding
What are the reactive sites on DNA?
- Lone pairs on base nitrogens of guanine and adenine
- electrostatic interaction with ionised phosphodiester link
- sugar ring: main involvement is in the interaction of DNA with radicals
Why is cisplatin kept in a saline solution
• 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.
What is DNA intercalations and what structural changes occur as a result?
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.
How does cisplatin cause cell death?
• 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
What is used to minimise the side effects of cisplatin?
rescue agents
• employed to ameliorate these effects
What are the mechanisms of resistance to cisplatin?
- 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
Why is formation of adducts with DNA the reason of cell death?
- levels of Pt-DNA adducts correlate with disease response
* when DNA repair is deficient then patients are hypersensitive to cisplatin
How is the hydrolysis of cisplatin relates to Cl- concentration?
- [cl-] in blood and extracellular fluid is high (100mM)
- High Cl- concentration suppresses hydrolysis
- intracellular [Cl-] is 4mM - hydrolysis occurs
Intra-strand DNA vs Inter-strand DNA
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
Is cisplatin going to react with the major or minor groove and why?
- always major groove
* that’s where the N7 of guanine is located
