W11 Protecting Groups in Pharm Chem

Question 1

What are Protecting Groups?

Answer 1

A chemical modification of a functional group which allows for chemoselectivity in a reaction / synthesis
* The reaction will be guided to only take place at the desired part of the molecule
* Prevents unwanted by-products
* Protect parts of the molecule being destroyed in a reaction

Question 2

Example: Reduction of an Ester

Answer 2

• If you want to convert the ester in the molecule below to an alcohol, LiAlH4 could be used – but it will also reduce the ketone.
• Therefore the ketone must be protected to prevent the formation of a diol
  Protecting group (PG)= ethylene glycol

Question 3

PGs: What to Consider? (5)

Answer 3

• Inexpensive
• Commercially available
• Easy and efficient to introduce
• Stable (reaction and purification)
• Efficient removal

Question 4

PGs: What they must do?(5)

Answer 4

• React Selectively
• Provide a good yield
• Selectively removed
• Have no additional functionality (side reactions)
• No additional stereocentres (uncontrolled stereocentres are a major concern in pharmaceutical chemistry)

Question 5

Which Functional Groups are commonly Protected? (3)

Answer 5

1. Alcohols
2. Carbonyls- Aldehydes, Ketones, Carboxylic acids
3. Amines

Question 6

Methods of protecting the common functional groups?

Answer 6

Alcohols- PG= Ethers, benzyl ethers, acetals
Carbonyls- Acetals, ketals
Amines- Amides/Carbamates

Question 7

What are prodrugs?
What are the properties of prodrugs? (7)

Answer 7

Inactive compounds that yield an active compound in the body- usually converted by enzymes.

➢Increase solubility (lipid or water)
➢Improve taste
➢Increase stability (biological and chemical)
➢Reduce toxicity
➢Modify the time of duration of action
➢Deliver drugs to specific site in the body
➢Alleviate pain when administered by injection

Question 8

What are the classes of prodrugs? (2)

Answer 8

Bioprecursor prodrugs & Carrier prodrugs

Bioprecursor Prodrugs:
* Already contain the active component
* Rely on metabolism or chemical modification to release the active component
* Can involve one step, or a series of steps (oxidation or reduction)

Carrier Prodrugs:
* Combination of active drug and carrier species
* Example: lipophilic carrier transport drug across membranes
* The link between the carrier and active species must be a group that is easily metabolised e.g. ester or amide

Question 9

What are some specific uses of Carrier Prodrugs? (6)

Answer 9

➢ Improving absorption and transport through membranes
➢ Slow release e.g. slow hydrolysis of ester- and amide-linked fatty acid carriers
➢ Site-specificity e.g. hydrophilic drugs with lipophilic carriers to cross the blood-brain barrier (dihydropyridine is a particularly useful carrier)
➢ Minimising side effects e.g. aspirin is a prodrug for salicylic acid to minimise bleeding in the GI tract
➢ Improving drug stability e.g. adding metabolically labile groups so stable to undergo first-pass metabolism
➢ Antibody-directed enzyme prodrug therapy (ADEPT) – used to target cancer cells

Question 10

Drug Alliances

Some drugs affect the activity/ pharmacokinetics of other drugs. This can be manipulated and put to good use:

Examples? (3)

Answer 10

➢ Sentry Drugs:
▪ Second drug administered with the principal drug, usually to inhibit the enzyme metabolising it
▪ Example: clavulanic acid inhibits β-lactamase, protecting penicillins (antibiotics)
▪ Example: ritonavir inhibits CYP3A4 enzyme from metabolising lopinavir (HIV treatment)

➢ Localizing the Area of Activity:
▪ Adrenaline is often administered with procaine. Adrenaline constricts the blood vessels in the vicinity of the injection an d so prevents the procaine being removed from the area too quickly by the blood supply

➢ Increasing Absorption:
▪ Metoclopramide is administered alongside analgesics to treat migraine. It increases gastric motility and so helps with faster absorption of the analgesic.