Lecture 15 - Natural product inspired drug discovery

Question 1

Advantages and disadvantages of natural products

Answer 1

• Most biologically active natural products are secondary metabolites from plants, microorganisms, marine and animal sources
• High biological activity
• Complex structures e.g. beta lactams

Question 2

What is transpeptidase? What is penicillin structure similar to? Mechanism of penicillin inhibition of transpeptidase

Answer 2

• Transpeptidase is a serine protease
• conformation of penicillin similar to D-Ala-D-Ala
• serine OH of transpeptidase attacks carbonyl of penicillin, cleaves amide bond of penicillin which attacks H+
• peptide chain containing Gly cannot attack resulting carbonyl due to steric hindrance
• strained beta lactam is essential
• penicillin = suicide inhibitor; irreversible inhibition

Question 3

Why is penicillin G acid sensitive?

Answer 3

• large ring strain on beta lactam
• increases reactivity of amide as there is no resonance for the lone pair on N

Question 4

Semi-synthesis of penicillin analogues

Answer 4

Fermentation
- can only produce limited variations

Chemical synthesis
- 6-APA (penicillin without acyl chain) is challenging to synthesise

Semi-synthesis
- combined biochemical transformations

Question 5

Other naturally occurring beta-lactam antibiotics

Answer 5

• Cephalosporin C
• Clavulanic acid (no antibiotic properties, mimics penicillin)
• Carbapenems

Question 6

Artemisinin

Answer 6

• commonly used anti-malarial
• quinolines used to be first line treatments until wide spread of resistance
• contains necessary endoperoxide bridge

Question 7

Artemisinin mode of action (6)

Answer 7

• still under debate
• activation by ferrous (ii) ions
• totally different from quinine based anti-malarials
• endoperoxide bridge is essential
• highly reactive radicals generated
• suicide inhibitor or prodrug

Question 8

Artemisinin properties wrt function

Answer 8

• poorly soluble in water or organic solvents
• carbonyl group is not essential for activity
• fully synthetic endoperoxides have the longest half-lives and lowest cost (important as malaria is prominent in impoverished regions)