Revision Flashcards
Name 6 methods by which metabolism can be studied
Radiolabelled drugs e.g. 3H (measure conc in plasma/urine)
Chromatography e.g. HPLC or MS (Mass Spectrometry) to analyse blood/urine samples
NMR
In vitro liver preparations
Transgenic mice (e.g. that lack certain enzymes)
Describe how a prodrug can be used to prolong drug activity
Azathioprine (immunosuppressant) contains an aromatic ring, which has to be removed via a non-enzymatic reaction which takes a very long time
Or addition of a fatty side chain ensures absorption into fat and slow release into the bloodstream
Describe how a prodrug can be used to target tumours
Cyclophosphamide is an anti-cancer drug/DNA alkylating agent. Metabolised into active form by phosphoamidase, which is found in high levels in tumours
Describe how a prodrug can be used to protect the drug from stomach acid
Also addition of a long molecule onto the antibiotic Piyamampicillin gives something for the stomach enzymes to attack, protecting the rest of the molecule
How would you test if an amide group was a pharmacophore?
Hydrolysis
Reduce the carbonyl to CH2
Cap the carbonyl with a methyl group
Convert it to an ester
How would you test if an aromatic ring was a pharmacophore?
Hydrogenate it so it is saturated with hydrogens
Add on a bulky aryl group
How would you test if a nitro group was a pharmacophore?
Swap it with chlorine
Chlorine and nitro groups are interchangeable
What are all the isosteres of OH?
SH NH2 CH3 Cl F
What are all the isosteres of Cl?
F
CF3
CN
Name an isostere of Bromine
Isopropyl
Name an isostere of Iodine
Tertiary butyl group
How could a molecular structure be rigidified to optimise it?
Introduction of double bonds
Introduction of aromatic rings into long alkyl chains
Removal of chiral centres
Why do ring fusions improve a compound?
Two fused benzene rings is called Napthalene
Allows for more pi stacking
What are the possible ring variations you could introduce into a compound to try and optimise it?
Transform an aromatic ring to a heteroaromatic ring e.g replace a C with an N or O
Add in multiple heteroatoms
Try the heteroatoms in different positions
What is the DNA groove binder “Distamycin” used to treat and how does it work?
Anticancer drugs
Binds AT rich region of DNA using hydrogen bonding and hydrophobic interactions
Slightly curved structure fits in the minor groove
Alters DNA conformation to inhibit transcription
Name an example of a DNA intercalator: What is it used to treat and how does it work?
Amsacrine (Type of Acridine) Used to treat leukaemia Polycyclic aromatic molecules Forms hydrophobic interactions with the heteroaromatic part of DNA bases Causes DNA unwinding
How does the DNA cleavage agent “Bleomycin” work?
Thiazole rings intercalate into the minor groove
Nitrogen atoms bind oxygen and generate superoxide radicals which extracts hydrogen atoms from DNA, cause cleavage
What are the 3 general structural modifications that can be made to a lead compound to produce analogues for QSAR?
- Size and shape of carbon skeleton
- Nature and degree of substitution
- Stereochemistry of lead compound (to do with chiral centres)
Why are the electronic effects of a drug important for affecting the biological activity?
Influences drug ionisation and polarity, which affects the chemical bonding it can partake in
How does an electron withdrawing substituent, or an electron donating substituent affect the equilibrium constant of benzoic acid (k) and the value of sigma?
If X is electron withdrawing, it stabilises the anion (ionised form) and increases k, and sigma is positive
If X is electron donating, k decreases and sigma is negative
How is Tafts steric parameter (Es) for different substituents calculated?
The rate of acid catalysed-hydrolysis of a reference ester (usually just with H attached), and the ester with the substituent attached.
The rate of hydrolysis = k
Es = logkRCOOX - logkRCOOH
The second logk is the log of the rate constant for the reference ester. This is usually RCOOH but can sometimes be RCOOMe. Important to check
What is molar refractivity and how is it calculated?
A measure of the volume of a given substituent MR = (n(sq)-1)/(n(sq)+2) x MW/d Where: n=index of refraction MW = molecular weight d = density MW/d = molar volume
When calculating molar refractivity, why is the index of refraction important?
Tells you about the polarisability of a compound
What is Verloop’s steric parameter and how is it calculated?
A computer calculates a steric value for a substituent using bond angles, van der Waals radii, bond lengths and conformations.
Name 2 advantages of QSAR
- Provides understanding of structure-activity relationships that may not be obvious from the raw data
- Data sets can be interpolated (NOT extrapolated) to help make informed decisions regarding synthesis, which saves time and money
Name 3 disadvantages of QSAR
- Might assume false correlations as changing a single substituent often has hydrophobic, electronic and steric effects
- Your data set might not be wide enough to ‘capture’ the best combination - the best answer might lie outside the range you have tested
- Heavy reliance on biological data which is very error prone
Why is the rate of ester hydrolysis constant (sigma i) not very reliable for predicting the electronic effects of a substituent?
The steric effects of the substituent will also have a big effect on the rate of ester hydrolysis. So cannot be sure the effects are entirely attributable to the electronic effects
What are the two stages of drug action as proposed by Hansch, and how do these relate to drug activity?
- Transport of the drug to the target site (depends on hydrophilicity/hydrophobicity)
- Binding of the drug to the target site (depends on electronic and steric effects)
Name an example of an irreversible enzyme inhibitor
Aspirin
Name and example of a suicide inhibitor and explain how it works
DMFO
Used to treat African sleeping sickness
Binds to ornithine decarboxylase, after which the carboxyl group and fluoride atom are removed to generate an electrophilic species which covalently bonds to cysteine
Inhibition of this enzyme in the parasite leads to build up of urea which kills it
Give two examples of drugs that target a structural protein
- Colchicine. Anti-inflammatory and anti-gout treatment. Binds tubulin, causing microtubules to depolymerise, preventing neutrophils from being active
- Paclitaxel. Anticancer drug. Stabilises microtubules so the mitotic spindle cannot disassemble, therefore halting mitosis. Affects cancer cells more than healthy cells because cancer cells divide more frequently
Give an example of a reversible non-competitive inhibitor
6-Mercaptopurine
Inhibitor of ATase, which catalyses the first step of purine synthesis
Used to treat leukaemia
