Lec 8- Drugs and synthetic intermediate (2)

Question 1

Top selling drugs

Answer 1

Question 2

Isolation, purification

Answer 2

• Extraction:
  
  • A) Solid
  • B) Solvent extraction
• Chromatography: TLC, Column, Solid extraction
• HPLC reversed phase

Question 3

Structure elucidation

Answer 3

• FT-IR spectroscopy
• Mass spectroscopy: EI, FAB, APCI, ES
• 1H-NMR proton resonance spectroscopy
• 13C-NMR spectroscopy, including advanced techniques: NOSY, COSY, inadequate; Correlated spectra’s
• Use of database

Question 4

Snake venom antidotes

Answer 4

Question 5

structure elucidation

Answer 5

*

Question 6

Partial synthesis: Semi-synthetic steriod

Natural product

Chemical target: progesterone

Answer 6

• Ergosterol is cheap starting marterial
  *

Question 7

Semi-synthetic approach

Answer 7

• Starting molecule from nature, isolated
• Cheap and available on large scale
• Example: progesterone from ergosterol
• Limited small number of chemical steps
• Not all modification can be made for full SAR optimisation

Question 8

Example: total synthesis of Ethynyloestradiol

Answer 8

Question 9

Total synthesis

Answer 9

• Full SAR may be required, Me group only by semi-synthetic
• All homologous can be prepared by total synthesis
• Starting material from industrial, technical synthesis
• Usually, a high number of steps
• May not be commercially viable
• Limited use for natural products, standard for synthetic drugs

Question 10

Synthetic examples- Diazepam, Alprazolam

Answer 10

• Appreciate how drug is made/synthesised
• Optimise the drug by classical drug design

Question 11

Diazepam

Answer 11

• Anxiolytic
• Benzodiazepine
• Small number of steps

1. Acylation (form amide)
2. SN reaction
3. Cyclisation: intramolecular imine formation

Question 12

Alprazolam

Answer 12

1. Activation, thioamide- cyclises into 5 membered ring system-(more Nitrogens than diazepam, more H bond, more interaction with GABA receptor)
2. Hydrazide formation
3. Cyclisation

Question 13

Drug receptor interaction

Answer 13

• Aromatic interactions- change transfer complex flurobenzyl-
• Hydrogen binding: Hydrogen donor, hydrogen acceptor NH,OH
• Lipophillic group, induced dipol, Van der Waals interactions, entropy, displace water- Isobutyl
• Ionic binding, carboxylic acid

Question 14

Aromatic Interactions

Answer 14

• Amino acid as part of the peptide (protein) Receptor = protein
• Electron-rich
  *

Question 15

Hydrogen Binding

Answer 15

• Example- Serine—Amine
• Can be amine or amide
  *

Question 16

Drug receptor interaction

Answer 16

• Van der Waals interactions
  
  • Example Alanine of receptor and isopropyl group or ligand, the drug molecule
  • Entropy-driven
  • Displacement of water
• Ionic Bonding
  
  • Example of Lysine, an amino group and carboxylic acid (Aspirin or Diclofenac)
  • Strong when close