Natural products as sources of drugs

Question 1

Where do drugs come from?

Answer 1

The Natural world
• Plant life (flowers, trees, bushes)
• Micro-organisms (bacteria, fungi)
• Animal life (frogs, snakes, scorpions)
• Biochemicals (Neurotransmitters, hormones)
• Marine chemistry (corals, bacteria, fish etc

The synthetic world
• Chemical synthesis (traditional)
• Combinatorial synthesis

The virtual world
• Computer aided drug design

Question 2

Which drugs are chemically synthesised?

Answer 2

chemotherapeutic agents - do not occur naturally and are produced by the pharmaceutical industry

Question 3

What are organic compounds isolated from natural sources known as?

Answer 3

Natural products or secondary metabolites?

Question 4

What does nature mainly used to build proteins?

Answer 4

Enantiomers - e.g. L-amino acids, thus the enzymes and other receptors that play an important part in cell machinery are chiral (with a number of chiral centres)

Question 5

What does chirality in cell machinery mean for the receptors/proteins that recognize them?

Answer 5

They only recognise one isomer out of a pair on enantiomers and thus have very high stereo-specificity

Question 6

What does this mean for the synthesis of single-enantiomer drugs

Answer 6

it is very difficult to synthesize single-enantiomer drugs economically with more than three chiral centres

Question 7

What are characteristics of nature?

Answer 7

• Chirality, stereoselectivity, and stereospecific production of chemicals are characteristics of nature
• Drugs isolated as products of biological synthesis (i.e. natural products) always have been available as single enantiomers

Question 8

What was isolated from bark (old remedy)

Answer 8

Quinine from Cinchona bark

Question 9

Name some plant extracts

Answer 9

• OPIUM - Morphine
• YEW TREE – Taxol
• 1876 – salicylic acid was isolated from willow bark, then aspirin was synthesised from salicylic acid

Cocaine isolated from coca bush, then synthesised to get procaine

Question 10

What do micro-organisms such as fungi provide?

Answer 10

A rich source of antibacterial agents - they have to compete against bacteria for nutrients

Question 11

What are secondary metabolites produced by?

Answer 11

Certain groups of microorganisms or plants - not required for day-to-day life (do not appear to provide a function that is required for growth and life maintenance

Question 12

What are primary metabolites?

Answer 12

Things such as sugars, peptides, proteins, fatty acids, and sterols, which are essential for growth and survival of the producing organism

Question 13

What are secondary metabolites?

Answer 13

metabolites tend to be rather large, complicated, organic molecules and may require as many as 30 separate enzymatic steps to synthesize
• Therefore, microorganisms devote significant energy and resources to the biogenesis of secondary metabolites that are not involved in essential life processes

Question 14

Why do microorganisms produce secondary metabolites?

Answer 14

• One explanation is that drugs (e.g. antibiotics) give plants and microbes survival (nutritional) advantage by antagonism against the competition
• Alternative explanation could be that the toxicity of secondary metabolites to competing organisms is sufficient to make secondary metabolism valuable

Question 15

What is classification of secondary metabolites based on?

Answer 15

Structural properties - depending on biosynthesis

Question 16

What are the main classes of secondary metabolites?

Answer 16

• Specialised amino acids and peptides
• Polyketides
• Terpenoids and steroids
• Alkaloids
• Specialised carbohydrates

Question 17

Specialised amino acids and peptides:

Answer 17

General structure of penicillins: Beta-lactam antibiotics

Question 18

What is the mechanism of action for beta-lactam antibiotics?

Answer 18

• Penicillins inhibit a bacterial enzyme called the Transpeptidase enzyme which is involved in the synthesis of the bacterial cell wall
• The β-lactam ring is involved in the mechanism of inhibition
• Penicillin becomes covalently linked to the transpeptidase enzyme’s active site leading to irreversible inhibition
• Inhibition of Transpeptidase leads to a weakened cell wall
• Cells swell due to water entering the cell, then burst (lysis)

Question 19

Examples of Beta-lactam antibiotics? (specialised amino acids and peptides)

Answer 19

Penicillin G:Penicillin is clinically important antibiotics, which inhibit the growth of various Staphylococci by blocking the peptidoglycan synthesis of the bacterial wall by preventing the final transpeptidation needed for the cross-links.

Cephalosporin C: Cephalosporium acremonium
•	Important medicinal properties: Cephalosporins belong to  a class of β-lactam antibiotics, which block the peptidoglycan synthesis of the bacterial wall by inhibiting the final transpeptidation needed for the cross-links.

Question 20

What are aromatic polyketides?

Answer 20

Polyketides are formed by the linear combination of acetate units:
Tetracyclines are commercially important broad-spectrum antibiotics that inhibit binding of the aminoacyl tRNA to the 30S ribosomal subunit in bacteria.

Question 21

What are non-aromatic polyketides?

Answer 21

Erythromycin is non-aromatic polyketide known as macrolide (contains large ring lactones)
Biological sources: Saccaropolyspora erythraea
Medicinal properties:
All the macrolides inhibit bacterial protein synthesis by binding to the 50S ribosome subunit. These drugs are active against the majority of aerobic and anaerobic gram-positive cocci and against gram-negative anaerobes.

Question 22

What are terpenoids and steroids?

Answer 22

Terpenoids and steroids are assembled from isoprene units:
• Biological sources: Pacific yew, Taxus Brevifolia
•

Question 23

What are alkaloids?

Answer 23

Alkaloids contain nitrogen in their structure. Nitrogen-containing parts of alkaloids are derivatives of amino acids.
• Alkaloids are most commonly encountered in the plant kingdom, but some representatives have been isolated from other organisms (e.g. fungi)

•

Question 24

What is taxol used for ?

Answer 24

Medicinal properties: Taxol possesses powerful activity against a number of tumors. It is used in the treatment of breast and ovarian cancer.
(Terpenoid)

Question 25

What is ephedrine used for?

Answer 25

Biological sources: Ephedra sinica (Chinese medicinal herb)
• Important medicinal properties: Alleviation of bronchial problems
(alkaloid)

Question 26

What is Papaverine used for?

Answer 26

• Biological sources: Papaveraceae plant families
• Important medicinal properties: Papaverine is used as a muscle relaxant
(alkaloid)

Question 27

What are specialised carbohydrates?

Answer 27

Aminoglycosides
The aminoglycosides are clinically important group of antibiotics that bind to the 30S ribosome and inhibit bacterial protein synthesis by preventing the formation of an initiation complex with messenger RNA. They are active only against aerobic gram-negative bacilli and staphylococci.

Question 28

What is gentamycin?

Answer 28

An aminoglycoside