1. An Introduction to Medicinal Chemistry 3/e COMBINATORIAL CHEMISTRY
Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 14
COMBINATORIAL CHEMISTRY
Part 3: Section 14.10

2. Contents
Part 3: Section 14.10
7. Combinatorial synthesis (3 slides)
8. Planning a Combinatorial Synthesis
8.1. Aims (2 slides)
8.2. Scaffolds (4 slides)
8.3. Computer modelling (2 slides)
9. Dynamic combinatorial chemistry (5 slides)

3. 7. Combinatorial synthesis
Heterocyclic synthesis - 1,4-benzodiazepines
Drawback:
Final product must contain X= OH or CO2H

4. 7. Combinatorial synthesis
Heterocyclic synthesis - improved synthesis of benzodiazepines
Functional group released from the resin takes part in the final cyclisation
Does not remain as an extra, possibly redundant group

5. 7. Combinatorial synthesis
Heterocyclic synthesis - synthesis of hydantoins
Functional group released from the resin takes part in the final cyclisation
Does not remain as an extra, possibly redundant group

6. 8. Planning a Combinatorial Synthesis
8.1 Aims
To generate a large number of compounds
To generate a diverse range of compounds
Increase chances of finding a lead compound to fit a binding site
Synthesis based on producing a molecular core or scaffold with functionality attached

7. 8. Planning a Combinatorial Syntheses 8.1 Aims
Target molecules should obey Lipinski’s ‘Rule of Five’ for oral
activity
a molecular weight less than 500
a calculated log P value less than +5
no more than 5 H-bond donating groups
no more than 10 H-bond accepting groups

8. 8. Planning a Combinatorial Syntheses
8.2 Scaffolds
‘Spider’ scaffolds preferable for exploring conformational space
Allows variation of functional groups around whole molecule to increase chances of finding suitable binding interactions
Molecular weight of scaffold should be low to allow variation of
functionality, without getting products with a MWt > 500

9. 8.2 Scaffolds
Tadpole scaffolds
- variation restricted to a specific region round the molecule
- less chance of favourable interactions with a binding site
8. Planning a Combinatorial Syntheses
Privileged scaffolds
- scaffolds which are common in medicinal chemistry and which are associated with a diverse range of activities
- benzodiazepines, hydantoins, benzenesulphonamide etc

10. 8.2 Scaffolds - examples
8. Planning a Combinatorial Syntheses
Benzodiazepines
Pyridines
Hydantoins
b-Lactams
Dipeptides
Good scaffolds
Spider like
Low molecular weight
Variety of synthetic routes available

11. 8.2 Scaffolds - poor examples 8. Planning a Combinatorial Syntheses
Spider like and small molecular weight - good points
But multiple OH groups
Difficult to vary R1-R5 independently
Glucose
Steroid
M.Wt. relatively high
Restricts no. of functional groups to keep MWt.< 500
Relatively few positions where substituents easily added
Indole
Tadpole like scaffold
Restricted region of variability

12. 8.3 Computer modelling
8. Planning a Combinatorial Syntheses
Aims
To maximise the number of possible pharmacophores from the minimum number of compounds
Maximises diversity of structures produced
Method
Identify all possible target structures
Rank in order of rigidity by identifying no. of rotatable bonds
Identify the most rigid structure
Identify all the pharmacophore triangles for all the possible conformations of the most rigid structure
Repeat for the next most rigid structure
Compare the pharmacophores for both structures
Retain the second structure if it contains more than 10% new pharmacophores
Add together both sets of pharmacophores and compare with the next most rigid structure and so on.

13. 8.3 Computer modelling
8. Planning a Combinatorial Syntheses
Results
Eliminates structures which do not contribute significant numbers of new pharmacophores
Can reduce the number of target structures by 80-90%, whilst retaining 90% of possible pharmacophores
Increases efficiency in finding lead compounds
Note
Start with rigid structures since these contain less possible conformations and a smaller number of possible pharmacophores
Pharmacophores are more likely to be fairly represented in rigid structures than in flexible ones.

14. 9. Dynamic combinatorial chemistry
Used in the search for new lead compounds
An alternative to mix and split combinatorial syntheses
Mixtures are screened in situ as the compounds are formed
The desired target is present in the reaction flask along with the building blocks for the synthesis
The reactions involved are reversible
The products formed are in equilibrium with their building blocks
Allows amplification of active compounds
Necessary to ‘freeze’ the equilibrium reaction to identify active compounds
Carried out by doing a further reaction to convert equilibrium products to stable compounds

15. Amplification
9. Dynamic combinatorial chemistry
Active compounds bind to the target as they are formed
Essentially removed from the equilibrium mixture
Equilibrium is disturbed and more active compound is formed
Target serves to screen active compounds and to amplify them

16. 9. Dynamic combinatorial chemistry
Example - Ligands for carbonic anhydrase
Reaction - reversible formation of imines
Reaction carried out in presence of carbonic anhydrase
Three aldehydes and four amines present as building blocks
Sodium cyanoborohydride added to ‘freeze’ the mixture
Products quantified and identified
Experiment repeated in absence of target to identify amplified product(s)
Amplified product is not necessarily present in greatest amounts

17. Example - Ligands for carbonic anhydrase
9. Dynamic combinatorial chemistry
Building blocks
Amplified product

18. Limitations
9. Dynamic combinatorial chemistry
Target must not react with the building blocks
Target must be stable under the reaction conditions
Target normally exists in aqueous surroundings
Reaction must be done in aqueous solution
Reactions must undergo fast equilibration rates to allow amplification
Choose reactants such that one product is not significantly more favoured than any other product - otherwise it confuses the identification of the amplification product