Metals In Medicine 🩺 Flashcards
1
Q
What does an s orbital look like?
How many p orbital shapes?
How many d orbital shapes?
How many f orbital shapes?
A
spherical
like 2xS, 3
5
7
2
Q
What do s block elements have?
A
their electron of highest energy level in the s block
3
Q
What are 5 characteristics of s-block elements?
far left: H, Li,…
A
- Most abundant metal ions in biology - occur in most cells at high concentrations (~mM)
- Difficult to monitor
- Trigger wide range of biochem processes (Ca, Mg)
- Activators of enzyme action (K, Mg)
- Stabilisers of biomolecular structures (Mg, Ca)
4
Q
What are the 5 s-block elements essential for life?
A
H, Na, K, Ca, Mg
5
Q
What are 2 characteristics of p-block elements?
A
- Constituents of living matter
- C, H , N, and O comprise 99% of human body
6
Q
Characteristics of d-block elements:
- Usually prevalent in _____ quantities
- ____er to monitor
- Highly relevant in the function of metalloproteins
- Key participants in e_______transfer reactions, r__________ chain, _2 storage and transport
A
- Usually prevalent in trace quantities
- Easier to monitor
- Highly relevant in the function of metalloproteins
- Key participants in electron transfer reactions, respiratory chain, O2 storage and transport
7
Q
What are 4 chemical interactions?
A
- covalent bond
- ionic bond
- Hydrogen bond
- Van der Waals
8
Q
What is a covalent bond? Name 2 examples
A
sharing of electrons
- peptide bonds
- ligand to metal bonds
9
Q
What is an ionic bond? Name 2 examples
A
Association of positively and negatively charged species
- salt bridges
- association of hard cations
and hard ligands
10
Q
What is a hydrogen bond? Name 2 examples
A
H atom shared between two highly electronegative atoms
- Base-base interactions in DNA
- α-helixes in proteins
11
Q
What are Van der Waals forces? Name 1 example
A
Large number of atoms reinforcing transient weak polarising effects
- Intercalation between DNA base pairs
12
Q
What type of bond exists between a metal centre and ligands?
A
coordinative/dative bond
13
Q
6 questions to cover when dealing with ligands and qs?
A
- type of bond
- Oxi state
- Any ligands?
- What ligands?
- Hm ligands?
- Shape?
14
Q
What is a coordinative/dative bond?
A
Covalent bond in which both electrons come from the same “donor” atom/ligand
15
Q
- Where is the coordinate/dative bond coming from in [Co(NH₃)₆]Cl₃?
A
coordinate/dative bond comes from NH₃
Co -:N
16
Q
- How do you determine the oxidation state of the metal centre?
A
- Determine the overall charge of the complex
- Assign charges to the ligands (most are usually neutral, can be -)
- Determine the difference in charge between
the overall cation and the ligands
17
Q
e.g. Determine the oxidation state of Co in [Co(NH₃)₆]Cl₃.
A
- Cl₃ = 3- charge outside
- inside must add up to 3+ to balance
- NH₃ are neutral
- therefore Co = 3+
18
Q
Determine the oxidation state of Fe in [Fe(CN)₆]4⁻.
A
- Entire complex adds up to -4
- 6 Ligands that are single negative (CN-) = -6
- therefore Fe must be +2
19
Q
Determine the oxidation state of Co in [Co(SO₄)(NH₃)₅]Cl.
no pic
A
- Entire complex adds up to +1, as outside is balanced by Cl (-1)
- 5 neutral NH₃ ligands
- 1 SO₄ = -2
- Cobalt must therefore = +3
20
Q
Oxygen atoms from what compounds can act as donor centres/ligands?
A
- H₂O
- OH⁻
- OR⁻
- NO₃⁻
- RCO₂⁻ (including side-chains of glu, asp, tyr, ser, thr)
21
Q
What can act as donor centres/ligands? (4)
A
- O atoms
- Single charged anions
- Neutral ligands
- Sulphur atoms
22
Q
Name 3 single charged anions that can act as donor centres/ligands
A
Cl⁻, F⁻, CN⁻
23
Q
Name 2 examples of neutral ligands
A
NH₃, CO
24
Q
Sulphur atoms from residues like what compounds can act as donor centres/ligands?
A
RSH
R₂S (including cys and met)
25
Mg²⁺ cation prefers what type of donor centre? Name an example
O donors strongly preferred e.g. phosphate groups in DNA, RNA
26
Ca²⁺ prefers what type of donor centre? Name an example
Only O donors e.g. Ca binding proteins
27
Zn²⁺ prefers what type of donor centre? Name an example
N, O, S favours his, glu, asp, cys
| e.g. Zn-dependent endopeptidases, metallothionein
28
What is the coordination number?
Number of ligands surrounding a metal centre in a complex
29
What does the coordination number determine?
the complex geometry and spatial distribution
30
What is the geometry of a metal with 3 ligands?
trigonal planar
31
What are the potential geometries of a metal with 4 ligands?
tetrahedral or square planar
32
What is the geometry of a metal with 6 ligands?
octahedral
33
What are the potential geometries of a metal with 5 ligands?
trigonal bipyramid or square pyramid
34
What is a trace element?
a dietary element that is needed for the proper
| growth, development, and physiology of the organism.
35
How does the biological function of an organism change with the concentration of that element in diet?
Death->deficient->optimum->toxic->death
rise then fall
always have optimum window
36
What is an example of a metalloprotein that transports O2? Describe the structure
Haemoglobin:
metal centre = Fe
4 big units which each contain a central Fe atom which holds O2, allowing it to be transported in respiration events
37
What happens when there's too little and too much Fe?
Too little = anaemia
| Too much = damage to heart + liver
38
What happens when there's too little Zn?
growth failure, scaly skin inflammation, reproductive failure, impaired immunity
39
What happens when there's too much Cu?
damage to liver, discolouration of skin, hair, hyperactivity in children
40
State the following of haemoglobin:
Metal centre, ligands, geometry, structure (how many units, what group?), function
- metal centre: Fe(II)/Fe(III)
- ligands: 4xN on the plane,1xN histidine below, 1xO₂ above
- geometry: octahedral when O₂ bound
- structure: 4 subunits, each including a haeme group (heterocyclic porphyrin)
- function: O₂ transport, gases transport: CO₂, NO
41
State the following of cytochrome P450:
Metal centre, ligands, geometry, structure (what group?), function
- metal centre: Fe(II)/Fe(III)
- ligands: 4xN on the plane,1xN histidine below, 1 active site above
- geometry: octahedral
- structure: a haeme group (heterocyclic porphyrin)
- function: metabolic oxidation
42
State the following of cobalamin vitamin B12:
Metal centre, ligands, geometry, structure (what ring?), function
- metal centre: Co
- ligands: 4xN on the plane,1xN dimethylbenzimidazole, 1 active site above (X = -CN, -OHM
- geometry: octahedral
- structure: corrin ring
- function: coenzyme for isomerases, methyl-transferases and dehalogenases; key in synthesis of myelin, DNA synthesis!!, amino acid metabolism
X could be -CN, -OH, -CH₃
43
State the following of carbonic anhydrase:
Metal centre, ligands, geometry, function
- metal centre: Zn
- ligands: 3xN histidine side chains, 1x active site above
- geometry: tetrahedral
- function: catalyses conversion of CO₂ and water to bicarbonate
44
State the following of superoxide dismutase:
Metal centre, ligands, geometry, struture (how many subunits in each form?) function
- metal centre: Cu/Zn (SOD1), Mn (SOD2)
- ligands: 3xN histidine side chains, 1xO from water, 1xO carboxilate
- geometry: trigonal bypry
- structure: SOD1 = 2 subunits, SOD2 = 4 subunits
- function: antioxidant in cells, turning O₂ radical into H₂O₂
45
Where are the 2 forms of superoxide dismutase found?
SOD1: cytoplasm
SOD2: mitochondria
46
What are 4 different mechanisms of reactions that can occur in metal centres
- Substitution reactions (Ligand exchange)
- Addition reactions
- Elimination reactions
- Oxidative/reductive addition
47
What happens in a substitution reaction w a metal centre?
1 step
In an octahedral with 5 ligands = L and 1 = X, X could be substituted for Y
?
ML5X -> ML5Y
48
What are 2 types of substitution reactions that can occur?
- green: 2 separate steps where the intermediate ML₅ is formed and Y is added in second step
SN1
- blue: 1 step where XY coexist in a transition state
SN2
49
What does the energy profile look like for green (2 step) substitution reactions?
```
2 peaks (transition states) in energy between reacs and products
trough between them = intermediate
```
X leaving as Y arriving
50
What does the energy profile look like for blue (1 step) substitution reactions?
X leaves at same time Y arrives
| 1 peak/ transition state
51
What is the most common example of a substitution reaction?
hydrolysis - Y ligand that replaces X is H₂O molecule
52
in substitution reac, what is name of process occuring? (common when X=halogen)
acquation = hydrolisis
53
Write a general addition reaction with M and L as the reactants
M + L → ML
54
Write a general elimination reaction with ML₂ as the reactant
ML₂ → ML + L
55
Write a general oxidative/reductive reaction with Y-ML₄-X as the reactant
aim of reaction is to bring X and Y close enough to they generate X-Y (M used as template)
Y-ML₄-X -> ML4 + X-Y
56
Write the 2 equations summarising the changes in oxidation state between superoxide dismutase, oxygen and hydrogen in the catalysis of hydrogen peroxide
Mn³⁺+O₂⁻ → Mn²⁺+O₂
| Mn²⁺+O₂⁻+2H⁺→Mn³⁺+H₂O₂
57
3 considerations in M and L addition, elimination, oxi/red addition
reactions.
changes in oxi state
changes in geometry
charge of ligands
58
Superoxide dismutase catalysis to hydrogen peroxide mechanism
- Mn centre begins as +3, then goes to +2
- Intermediate then can be oxidised back to +3 to complete catalytic circle
- Mn at first has 5 ligands bound
- Coordination number changes to 6, 6 ligands, octahedral shape
- Then after loss of O₂, becomes pentacoordinated (to only 5 atoms)
59
Mechanism of carbonic acid formation from carbonic anhydrase as catalytic enzyme
- Tetrahedral to start with - what ligand is in top of zinc?
- Water in first, OH- in second, then O- in final
- Metal centre although doesn't change its oxidation state, does change ligand in position at top
60
What are 4 analytical techniques we can use to characterise metalloproteins?
UV-Vis
MS
EPR (instead of NMR)
RAMAN (instead of IR)
61
Why can we use UV-Vis to characterise metalloproteins?
electrons can jump between different energy levels/orbitals
62
What are the 3 types of electron jumps that can occur in metalloproteins?
1) intra-ligand where electrons start and end in ligand
2) metal-ligand/ligand-metal where electrons start in ligand, jump to higher energy state in metal orbital or vice versa
3) metal d-d bands where electrons can jump between occupied and unoccupied d-orbitals
63
e- moving up or down orbital in M-L and L-M charge transfer in UV-Vis?
M-L: down
| L-M: up
64
what do metal d-d bands depend on? in UV-Vis
orbital e.g. d d-d jump orbs
| characteristic of each metal
65
How does the absorbance and wavelength of different electron jumps look like on a UV-vis spectra?
absorbance/wavelength nm
IL then ML and LM then d-d
66
UV-Vis can only be done if you have....
chromophore
| BUT metals most often solution coloured by d-d transition bands
67
What type of electron jumps generate coloured spectra on a UV-vis spectrum?
d-d bands
68
What about metals gives them a distinctive MS pattern?
the metal's isotopes: the height of the signals of intensity of peaks next to them gives an indication of the number of isotopes
69
What does EPR stand for?
electronic paramagnetic resonance
70
What analytical technique does EPR correspond with?
NMR
71
How do EPR and NMR compare?
NMR:
- nuclei w spin can align in favour of magnetic field, reducing/inc its energy
- this difference in energy is measured in relation to time
EPR:
- instead of nuclei, unpaired e- can align with/against field
- this difference in energy corresponding to time creates an EPR spectra
72
Why are EPRs easier to read for metalloproteins than NMRs?
- NMR has too many overlapping signals (hard read)
| - EPR only has 2 signals generated by Fe atom, allowing differentiation between alpha and beta subunit
73
Which analytical technique does RAMAN correspond with?
IR
74
How do RAMAN and IR compare?
IR:
- stretching/bending/ movement of bonds/atoms generates polar changes
- generates stretched signals seen in red spectra
RAMAN:
- no changes in dipolar moments but atoms still making same usual movements as in IR
- lower number of signals
75
In NMR, what part of a molecule with a metal centre will produce the signals?
the ligands (¹H-NMR and ¹³C-NMR)
76
What is required in a molecule with a metal centre for EPR to be used on it?
unpaired electrons !!! odd num
77
What can the data obtained from an EPR allow for determination of?
oxidation state,
| nature of ligands directly bound to metal centre
78
Is fragmentation in MS for molecules with metal centres any different?
molecule will fragment as usual, the fragments that still contain the metal will show the isotope pattern characteristic of that metal
79
How do RAMAN spectra normally compare to IR spectra in terms of signals?
normally have less than IR
80
What are the 3 indications of lithium carbonate?
- acute treatment of mania
- prophylaxis in bipolar disorder
- antidepressant augmentation in treatment of refractory recurrent depression
81
How does lithium carbonate work?
selectively interferes with the inositol lipid cycle and relies on its similarities to Na/K/Ca/Mg, occupying their sites in several critical neuronal enz and NT receptors...
82
What is therapeutic range of lithium carbonate?
narrow: 0.8-1.2mmol/L
| therefore monitor levels
83
How do we monitor lithium plasma levels?
atomic spectroscopy (as this a salt, not a metal centre surrounded by ligands)
- signals are thin and don't overlap with other signals
- intensity relates to concentration
- can use either absorption (find how much there is) or emission spectra (specific to each metal)
2 signals/sticks: absorption, emission
84
What roles do metals place in CT and MRI scanning? Name examples for eacg
they act as contrast agents:
- CT scan: tomographic images, X-ray based; iodine, barium, gallium based
- MRI: NMR based technique mapping mostly water and fat; usually gallium based
85
Describe the structure of gadolinium and its medical role
- contrast agent for CT and MRI: allows for better diagnosis due to better image quality
- 3 N ligand bands
- 5 Os bound + additional O from addition of water molecule
- can accept many ligands and has a high coordination sphere
86
What arthritis treatment are gold based?
- oral
- IM
- auranofin: has 2 ligands in linear shape: one is S, other is P
- IM injection is myocrisin
87
What is the Lipinski rule of 5?
- no more than 5 HBDs
- no more than 10 HBAs
- molecular mass <500 Da
- LogP not greater than 5
88
Does auranofin and myocrisin comply with Lipinski's rule of 5? What does this say about metal medicines' compliance with the rule?
- only myocrisin complies
- metal centres ar every heavy meaning the MW tends to be high, breaking Lipinski's rule
- the logP changes as well due to the metal
89
Auranofin: use and, hows it taken?
RA treatment. doesnt reduce pain but reduces inflamm
| orally
90
pharmacokinetics of auranofin?
```
peak plasma time: 2 hrs
peak plasma conc: 0.025mcg/ml
onset of effects= 3-6mon
plasma half life=21-31 days
protein bound: 60% (mostly albumin)
excretion: urine. feces (after 55-80 days)
```
91
how is auranofin metabolised?
phase 1: de-acetylation
92
auranofin mechanism of action
inhib of red/oxi (redox) enzymes such as TrxR.
| also appears to induce heme oxygenase 1(HO-1) mRNA- an inducible heme-degrading enz w anti-inflamm properties
93
What are the 3 types of treatment available for cancer?
- surgery
- radiotherapy
- chemotherapy
94
In the selection of drugs used for cancer chemotherapy, what is the feature of the 1 common drug used?
- it's metal based (platinum - Pt)
| - tends to be cisplatin
95
50% of all chemotherapeutic regimes use what-based drugs?
platinum-based drugs
96
What are 4 platinum-based drug examples?
- cisplatin (original)
- carboplatin
- oxaliplatin
- nedaplatin
97
When developing an anticancer agent, two drug properties need to be measured. What are these?
- the cytotoxicity of a drug
- the drug uptake (important to know how much is getting into patient cells, can be determined using atomic spectroscopy)
98
size of cisplatin and what 2 different ligands surround it?
small
| NH₃ and Cl
99
How is cisplatin synthesised from PtCl₄?
- Cl atoms substituted by iodine atoms using excess KI
- then 2 of the I atoms substituted by NH₃ atoms... intermediate
- I-Pt bonds are hydrolysed and Cl atoms are added in place
100
Which of cisplatin's ligands have the key role in its mechanism of action? What does it do? Why is stereochemistry also important?
- Cl binds to the N residues on a specific side
- stereochemistry is important to ensure that it can bind both N residues, hence why transplatin is not cytotoxic
--------------------
Cisplatin binds to DNA- platin both at same time
can have Cl- Pt- Cl
101
Why is cisplatin normally prepared in saline (NaCl) and administered by IV?
- ensure we have enough Cl conc to keep eqm from being shifted + keeps molecule intact
- once in blood, there's enough Cl to prevent hydrolysis
- if wasn't admin with enough NaCl and was given hydrolysed, the non-DNA-proteins in the cell cytosol would bind it and deactivate it
102
How does cisplatin enter cancer cells?
via a CTR1 transporter
| responsible for 2/3 of total uptake
103
After entering a cancer cell through the respective transporter, what happens to cisplatin?
- begins to hydrolyse, losing both Cl atoms
- this is due to the Cl conc dropping between the plasma and cytoplasm
- this leaves the Pt in the nuclei
104
Describe the mechanism of action of cisplatin (how it enters the cancer cell, how and what atoms are lost, what's substituted for what from DNA)
- enters cell via CTR1 transporter
- hydrolysed due to Cl conc dropping from plasma to cytoplasm, leading to only Pt remaining and going on to nuclei
- Cl atoms replace H₂O in hydrolysis, being substituted with N from DNA (hence why the stereochemistry is important)
where Cl lost, binds to DNA w 2 hands
105
After being hydrolysed, what else could happen to cisplatin preventing it from carrying out its mechanism of action? (2)
could be:
- kicked out via ATP channels: ATP7A/7B
- conjugated with glutathione, where MRP2 will recognise its tag
106
What are the two types of mechanisms of resistance that cancer cells have towards cisplatin?
- inherent
| - acquired
107
What is meant by a tumour having inherent resistance?
- it lacked sensitivity to a given drug from the start
| - therefore doesn't respond to treatment
108
What is meant by a tumour having acquired resistance?
tumour originally responded to treatment, but effect lessens or stops entirely after time
- due to development of cellular detoxification mechanisms such as an increased efflux, decreased influx and enhanced DNA repair
109
How do cancer cells develop increased efflux?
generates higher glutathione levels that can bind cisplatin and export it through transporters
110
How do cancer cells develop decreased influx?
downregulates things like CTR1 which transports cisplatin back in = less available to bind to DNA
111
What do we do in terms of treatment when a cancer cell has all 3 forms of acquired resistance?
give a different drug
112
How are carboplatin, oxaliplatin and nedaplatin better than cisplatin?
- instead of 2 Cl ligands, 2 O ligands are used meaning hydrolysis is slower giving the drug a longer time to reach the nuclei and exert its anticancer effect
- these all however also have a different side-effect, PK and hence administration profile
113
How is oxaliplatin better than cisplatin?
- instead of 2 NH₃ ligands, 2 NH₂ groups are linked to a ring
- this causes a different type of DNA damage
- as a result those cells with acquired resistance (that can only repair damages caused by cisplatin) are unable to repair DNA
114
What are the 3 unwanted side-effects of platinum anti-cancer drugs?
- nephrotoxicity
- hepatic malfunction
- ototoxicity
115
A new drug called FM190 is being trialled for cancer. How does it work?
- when shined on with light in a given wavelength, it is activated
- Pt centre ends up adding directly to DNA, causing direct damage unlike cisplatin
- due to its light activation, it can be non-toxic and have less side-effects
116
A new drug called BBR3464 is being trialled for cancer. How does it work?
- 3 Pt containing complexes are grouped together
- this is so that the cell would intake 3 units
- therefore if some hydrolysed, at least 1 unit will be able to make lesions on DNA
117
cisplatin doses usually based on?
body surface area range of 20-140mg/m2
118
hows cisplatin administered?
single dose, bolus injection/ blood infusion
infusions: reduces saline soln, dextrose and mannitol in IV drip
119
pH of cisplatin?
3.5-4.5
