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Chemistry and Disease > Metals in medicine > Flashcards

Metals in medicine Flashcards

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1
Q

What is the principle of Paracelsus?

A

‘The dose makes the poison’

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2
Q

What is the therapeutic width?

A

The concentration range of a drug causing advantageous physiological effects.

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3
Q

Define synergism and antagonism and give examples of each

A 
Synergism= 2 components interacting by mutually promoting effects- displacement (Zn2+/Cd2+), deactivation (Cu2+ +S2- -> CuS), chelation (Fe3+/ black tea).
Antagonism= 2 components interacting by competing and suppressing each other's effects- solubilisation (Fe3+/vitamin C).
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4
Q

Give examples of essential main group and transition metals

A

Main group: Na, K, Mg, Ca

TM: V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Mo

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5
Q

What is anaemia?

A

Insufficient oxygen supply due to decrease in haemoglobin levels, oxygen binds to Fe centres in Hb (ie lack of iron).

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6
Q

What are the 1st and 2nd most abundant d-block (TM) metals?

A

1st= Fe, 2nd= Zn

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7
Q

What are some of the consequences of zinc deficiency and the most affected enzymes?

A

Growth retardation, skin lesions, poor appetite. Most affected enzymes are alkaline phosphatase and carboxy peptidase (key metabolic function).

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8
Q

What is the role of copper in the body and what can a deficiency lead to?

A

Important role in the respiratory chain (cytochrome C oxidase) and superoxide deactivation. Deficiency can lead to anaemia, brain and heart disease.

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9
Q

What deficiency is a lack of vitamin B12 attributed to?

A

Co (pernicious anemia)

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10
Q

Why are some inorganic elements (non-bioessential) toxic?

A

High affinity for thiol groups, cysteine (soft, polarisable elements eg Pb/Cd/Hg/Tl). Substitution of essential metals with similar but not identical chemical properties eg Zn/Cd.

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11
Q

List 2 methods, with examples, for therapeutic detoxification

A

Application of antagonists (Ca2+ for Cd2+ poisoning) and chelation therapy (EDTA for Cd2+).

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12
Q

Why are chelate complexes more stable than their non-chelated analogues?

A

Thermodynamic stability: increase in the number of independent molecules in solution causes entropy increase (more disorder)- G= H-TS
Kinetic stability: increase in ‘holding power’, if 1 donor atom dissociates, the metal is still attached to the other donors.

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13
Q

How does the structure of D-penicillamine allow it to form highly stable complexes with toxic heavy metal ions?

A

5-membered chelate ring, has soft (S) and intermediate (N) donors. Has a carboxylic acid group for water solubility.

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14
Q

What are the symptoms and examples of lead poisoning from organometallic compounds and inorganic Pb2+ salts?

A 
Organometallic compounds (eg leaded petrol Et4Pb): disordered nervous system (as able to cross blood-brain barrier) leads to loss of coordination.
Inorganic Pb2+ salts (eg lead acid batteries in cars, old white oil based paints): haematological and gastrointestinal problems.
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15
Q

Why can lead poisoning lead to symptoms of anemia?

A

Pb2+ inhibits aminolevulinic acid dehydratase, a zinc-dependent enzyme that catalyses haem biosynthesis (unreacted aminolevulinic acid in the urine indicates lead poisoning). Pb2+ inhibits heme synthetase (SH groups) so no incorporation of iron.

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16
Q

What is the retention time of lead in the body?

A 
Blood/liver/kidneys= about a month
Bones= up to 30 years
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17
Q

What treatments can be used to treat chronic and acute lead poisoning?

A 
Chronic= almost impossible (bones)
Acute= chelation therapy, eg with BAL or EDTA
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18
Q

What detoxification strategies have organisms developed to remove unwanted substances (eg mercury)?

A

Efflux pumps: removes substances or pumps in antagonists.

Use of chelate ligands that bind well to heavy metals.

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19
Q

Why is RHg+ particularly toxic?

A

As can penetrate membranes. NB all Hg conpounds/elemental Hg is toxic.

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20
Q

What are the symptoms of thallium poisoning and why is it such a toxic substance?

A

Symptoms include nausea/vomiting/headaches/dementia/hairloss ie all very general so hard to diagnose until too late. Its compounds are colourless, tasteless and odourless.

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21
Q

Explain a treatment for thallium poisoning

A

Ion exchange asorbents, eg colloidal Prussian blue- contains cyanide ions (strong crystal field splitting), d6-Fe2 is low spin and kinetically inert so the cyanide ligands are not released. Tl+ replaces K+ in the lattice and is made insoluble hence can’t be re-absorbed by the body and is excreted.

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22
Q

What are two genetic diseases which can lead to iron overload due to the frequent blood transfusions required?

A

Sickle cell disease- valine instead of glutamate gives ‘hydrophobic spot’ leading to lower oxygen binding activity.
Beta-thalassaemia- unbalanced production of alpha and beta side chains in haemoglobin.

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23
Q

What are the toxic effects of iron accumulation?

A

Fe binding proteins get saturated (transferrin and ferritin) so you get free fe in the system which is redox active hence highly damaging- generates free radicals.

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24
Q

Which radical, generated by Fe accumulation, is particularly toxic in the body and why?

A

Hydroxyl radical- reacts with most organic molecules and attacks cell membranes/proteins/nucleic acids.

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25
Q

What are 2 approaches for the removal of excess iron?

A

Fe chelation therapy (think about ligand design) and biomimetic approach.

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26
Q

What are siderophores?

A

Low molecular weight chelators secreted by micro-organisms to solubilise Fe3 for uptake into the cell.

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27
Q

What is the siderophore of E coli and how does the structure change to encapsulate Fe?

A

Enterobactin: arms rotate upwards to encapsulate Fe (change in H-bonds).

28
Q

What is the trade name for desferrioxamine B and what is it used to treat?

A

Desferal, treatment of Fe overload.

29
Q

Why is desferrioxamine a suitable chelator for the treatment of Fe overload and not enterobactin even though it’s a better Fe binder?

A

Catechols are susceptible to oxidation in the gut 9to quinones) and enterobactin hydrolyses easily, lowering the Fe-binding activity. [Fe(ent)]3- is highly negatively charged so can’t cross cell membranes. Enterobactin is capable of donating Fe to pathogenic bacteria- BIG PROBLEM.

30
Q

List some of the disadvantages of Desferal treatment?

A

Not orally active, only achieves sufficient iron excretion if given subcutaneously over periods of 9-12h several times a week, biotechnological prod leads to batches that vary in quality (can cause allergic reactions) and is very expensive.

31
Q

What does 3,4-HPO stand for and what is it being developed for?

A

3-hydroxypyridin-4-ones, trying to develop and orally active chelator.

32
Q

What are the advantages of using 3,4-HPOs?

A

Isoelectronic and isostructural with catechols, monobasic so form neutral Fe3 complexes which can cross cell membranes, selective chelators for Fe3, orally active, easily synthesised, wide range of MWs and properties so can be tuned.

33
Q

Name 2 biomimetic orally active drugs now on the market and explain how they differ

A

Deferiprone (didentate) and deferasirox (tridentate).

34
Q

Why is chelation therapy for 239Pu4 difficult and how could this be overcome?

A

Due to the similarity between Pu and Fe, but discrimination possible as Pu is bigger so can coordinate 8 (Fe CN=6).

35
Q

What are common features of Alzheimer’s, Parkinson’s and prion disease (neurodegenerative diseases)?

A

Protein misfolding and aggregation leading to formation of amyloid fibres in the brain (stable beta-sheet structure). Changes in metal homeostasis (particularly Cu, Zn, Fe).

36
Q

How do Cu, Zn and Fe ions help the brain to function?

A

Zn- modulates nerve impulses.
Fe- involved in neurotransmitter release.
Cu- controls neuropeptide hormone release.

37
Q

What is a critical requirement of metal chelators used to treat neurodegenerative diseases?

A

Blood-brain barrier permeability (small and lipophillic).

38
Q

Why was clioquinol use discontinued?

A

Due to contamination issues during large scale production.

39
Q

What key properties does deferiprone have?

A

Chelating and antioxidant properties and has multifunctional derivatives.

40
Q

Describe the ‘Trojan horse’ strategy as a solution to drug resistance and give an example.

A

Attach the antimicrobial agent to an essential nutrient that the cell has to take up to survive.
eg siderophore mediated Fe (essential nutrient) uptake:
1. solubilisation
2. transport to the cell membrane (molecular recognition)
3. transport across the cell membrane
4. release inside the cell

Natural Trojan horse sideophore antibiotic= albomycin (secreted by streptomyces to kill competing bacteria)

41
Q

What should the drug not interfere with when thinking about siderophore-drug conjugate design and how can this be achieved?

A

The siderophore’s Fe binding properties and the receptor recognition. Attach the drug to the siderophore backbone and select a drug that is small and uncharged (eg beta-lactam or sulfonamide).

42
Q

Describe the structure of cisplatin

A

cis-[PtCl2(NH3)2], square planar, d8 configuration.

43
Q

What are the disadvantages of cisplatin?

A

Side effects (nephrotoxicity and GI problems), limited water solubility (administered by IV).

44
Q

Name the 3 possible bonding interactions between cis-Pt(NH3)2 2+ and guanosine in dsDNA

A

1,2-intrastrand crosslinking, interstrand crosslinking, chelate coordination.

45
Q

Describe the mode of action of cisplatin

A

Passive diffusion (or cu transporter) into cell, hydrolysis gives PtCl(H2O)(NH3)2]+ which approaches negativeky charged DNA. The H2O ligand is replaced and Pt forms a coordinative bond to the N-donor of nucleobases (N7 guanine, preferred 1,2 intratstrand crosslinking). This produces metallothiones and glutathione which are effluxed. The adduct formation causes the purines to become destacked and the DNA helix to become kinked. This cytotoxic effect leads to the failure of DNA replication and transcription and DNA repair mechanisms.

46
Q

Which cancer is particular hypersensitive to cisplatin?

A

Testicular cancer (due to the DNA-repair deficiency).

47
Q

Why do the second generation cisplatin analogues have reduced side effects?

A

They have the same effectivity but lower dosage.

48
Q

Name 3 second generation cisplatin analogues and explain why their structure leads to reduced side effects

A

Carboplatin, oxaliplatin and nedaplatin. All are square planar, have amine groups (H-bond donors and trans effect) and no Cl (old LG). The Cl has been replaced by bidentate ligands which are more stable due to the chelate effect- ie are substitutionally more inert.

49
Q

Describe the development of 3rd generation cisplatin analogues and name 3.

A

Sterically hindered Pt-complexes to avoid the problem of tumour resistance. Picoplatin, quinoplatin, phenanthriplatin. Also, use of Pt4 complexes whiches are more inert (d6 low spin) hence have v slow ligand exchange. Pt4 is reduced to Pt2 in the cell prior to the reaction with DNA ie is PRODRUG style.

50
Q

What is an advantage of using Pt4 over Pt2?

A

Octahedral rather than square planar so has to extra ligands which can be used to tune the properties of the complex.

51
Q

What is the aim for future development of cisplatin analogues?

A

To develop more soluble, orally active drugs and to target specific types of cancer cells.

52
Q

Describe the advantages of using ruthenium-based anticancer agents

A

Different modes of action, Ru2 has low spin (slow exchange) and similar kinetics to Pt2. But using Ru3 (d5, low toxicity), gets reduced to Ru2 in hypotoxic tumours and is a cancer resistance pathway inhibitor.

53
Q

What is rheumatoid arthiritis?

A

Autoimmune reaction causing inflammation of the tissue surrounding the joints. Damage is caused by hydrolytic enzymes (leaking out from lysosomes).

54
Q

Describe the hypothesis for the mode of action of gold-containing anti-rheumatic drugs

A

Au (soft metal) has high affinity for thiols, eg cysteine in serum albumin and selenocysteine. Auranofin inhibits thioredoxin reductase (reducing enzyme, high levels at inflammation sites) and the Au-containing drug is accumulated in the joints.

55
Q

Describe 2 methods for producing high quality images of locations in the body and give examples

A

Measuring the absorption of externally applied radiation (X-ray, MRI) or administering a radioactive compound and detecting the radiation escaping from the body (radioscintigraphy).

56
Q

What does MRI stand for?

A

Magnetic resonance imagine

57
Q

How do positive contrast agents work?

A

Appear bright on the MRI image, often paramagnetic metal complexes. H20 signal intensity depends on proton relaxation rate, which increases when H20 is close to a highly paramagnetic centre.

58
Q

Define relaxivity

A

Relaxation enhancement of water protons in the presence of the paramagnetic complex at 1mM concentrations.

59
Q

Discuss Gd3 complexes as contrast agents

A

Gd3 is toxic on its own, but stable chelate complexes are not.
Large magnetic moment (paramagnetic).
Relaxation rates of bound H20 increase if the exchange rate increases (want a labile complex) and if the tumbling rate decreases (ie bigger= slower, want to be as close to the Larmour frequency of the MRI machine as possible). Complexes have to be stable, with regards to Gd3 dissociation, for the time they are in the body.

60
Q

Discuss the future challenges of diagnostic imaging

A

To target tumours selectively, to detect disease related enzymatic activity and to monitor metal ion concentrations.

61
Q

How can you tune a compound to increase its relaxtion rate?

A

Use R: can reduce the tumbling rate by having a big R as larger molecules have lower tumbling rates. Can bind to zinc.

62
Q

Describe the different emitters used in radiopharmaceuticals

A

alpha-/beta- emitters: used in radionucleotide therapy.

beta+/gamma emitters: used in diagnosis.

63
Q

What does SPECT stand for and what emitter is used for it?

A

Single photon emission computer tomography, gamma emitters.

64
Q

What does PET stand for and what emitter is used for it?

A

Positron emission tomography, beta+ emitters.

65
Q

What is the most widely used diagnostic radiopharmaceutical and what is it produced as?

A

99mTc, produced as [99mTcO4]- and has to be reduced to oxidation state +5 with Sn2+.

66
Q

Describe some of the nuclear properties of 99mTc.

A

Gamma ray emission energy suitable for most hospital facilities, half life of 6h (long enough to perform imaging but short enough to minimise the radiation dose), readily available, can make 3D images.

67
Q

What are 11In3+ and 68Ga3+ used in?

A 
11In3+ = SPECT
68Ga3+ = PET

Chemistry and Disease (7 decks)

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