Revision

Question 1

Name 6 methods by which metabolism can be studied

Answer 1

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)

Question 2

Describe how a prodrug can be used to prolong drug activity

Answer 2

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

Question 3

Describe how a prodrug can be used to target tumours

Answer 3

Cyclophosphamide is an anti-cancer drug/DNA alkylating agent. Metabolised into active form by phosphoamidase, which is found in high levels in tumours

Question 4

Describe how a prodrug can be used to protect the drug from stomach acid

Answer 4

Also addition of a long molecule onto the antibiotic Piyamampicillin gives something for the stomach enzymes to attack, protecting the rest of the molecule

Question 5

How would you test if an amide group was a pharmacophore?

Answer 5

Hydrolysis
Reduce the carbonyl to CH2
Cap the carbonyl with a methyl group
Convert it to an ester

Question 6

How would you test if an aromatic ring was a pharmacophore?

Answer 6

Hydrogenate it so it is saturated with hydrogens

Add on a bulky aryl group

Question 7

How would you test if a nitro group was a pharmacophore?

Answer 7

Swap it with chlorine

Chlorine and nitro groups are interchangeable

Question 8

What are all the isosteres of OH?

Answer 8

SH
NH2
CH3
Cl
F

Question 9

What are all the isosteres of Cl?

Answer 9

F
CF3
CN

Question 10

Name an isostere of Bromine

Answer 10

Isopropyl

Question 11

Name an isostere of Iodine

Answer 11

Tertiary butyl group

Question 12

How could a molecular structure be rigidified to optimise it?

Answer 12

Introduction of double bonds
Introduction of aromatic rings into long alkyl chains
Removal of chiral centres

Question 13

Why do ring fusions improve a compound?

Answer 13

Two fused benzene rings is called Napthalene

Allows for more pi stacking

Question 14

What are the possible ring variations you could introduce into a compound to try and optimise it?

Answer 14

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

Question 15

What is the DNA groove binder “Distamycin” used to treat and how does it work?

Answer 15

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

Question 16

Name an example of a DNA intercalator: What is it used to treat and how does it work?

Answer 16

Amsacrine (Type of Acridine)
Used to treat leukaemia
Polycyclic aromatic molecules
Forms hydrophobic interactions with the heteroaromatic part of DNA bases
Causes DNA unwinding

Question 17

How does the DNA cleavage agent “Bleomycin” work?

Answer 17

Thiazole rings intercalate into the minor groove

Nitrogen atoms bind oxygen and generate superoxide radicals which extracts hydrogen atoms from DNA, cause cleavage

Question 18

What are the 3 general structural modifications that can be made to a lead compound to produce analogues for QSAR?

Answer 18

1. Size and shape of carbon skeleton
2. Nature and degree of substitution
3. Stereochemistry of lead compound (to do with chiral centres)

Question 19

Why are the electronic effects of a drug important for affecting the biological activity?

Answer 19

Influences drug ionisation and polarity, which affects the chemical bonding it can partake in

Question 20

How does an electron withdrawing substituent, or an electron donating substituent affect the equilibrium constant of benzoic acid (k) and the value of sigma?

Answer 20

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

Question 21

How is Tafts steric parameter (Es) for different substituents calculated?

Answer 21

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

Question 22

What is molar refractivity and how is it calculated?

Answer 22

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

Question 23

When calculating molar refractivity, why is the index of refraction important?

Answer 23

Tells you about the polarisability of a compound

Question 24

What is Verloop’s steric parameter and how is it calculated?

Answer 24

A computer calculates a steric value for a substituent using bond angles, van der Waals radii, bond lengths and conformations.

Question 25

Name 2 advantages of QSAR

Answer 25

1. Provides understanding of structure-activity relationships that may not be obvious from the raw data
2. Data sets can be interpolated (NOT extrapolated) to help make informed decisions regarding synthesis, which saves time and money

Question 26

Name 3 disadvantages of QSAR

Answer 26

1. Might assume false correlations as changing a single substituent often has hydrophobic, electronic and steric effects
2. Your data set might not be wide enough to ‘capture’ the best combination - the best answer might lie outside the range you have tested
3. Heavy reliance on biological data which is very error prone

Question 27

Why is the rate of ester hydrolysis constant (sigma i) not very reliable for predicting the electronic effects of a substituent?

Answer 27

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

Question 28

What are the two stages of drug action as proposed by Hansch, and how do these relate to drug activity?

Answer 28

1. Transport of the drug to the target site (depends on hydrophilicity/hydrophobicity)
2. Binding of the drug to the target site (depends on electronic and steric effects)

Question 29

Name an example of an irreversible enzyme inhibitor

Answer 29

Aspirin

Question 30

Name and example of a suicide inhibitor and explain how it works

Answer 30

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

Question 31

Give two examples of drugs that target a structural protein

Answer 31

1. Colchicine. Anti-inflammatory and anti-gout treatment. Binds tubulin, causing microtubules to depolymerise, preventing neutrophils from being active
2. 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

Question 32

Give an example of a reversible non-competitive inhibitor

Answer 32

6-Mercaptopurine
Inhibitor of ATase, which catalyses the first step of purine synthesis
Used to treat leukaemia