Comb Chem

Question 0

How many organic molecules MW <850 are there?
How many have drug like properties?
From commercially avail catalogues how many combos?

Answer 0

10^200
10^4
6000000
Ridiculously big

Question 1

Steps of drug disco

Answer 1

Choose target
Biology validation
Lead discovery
SAR/refinement
Lead optimisation

Question 2

Comb chem

Answer 2

Technique for producing large no of compounds in less time

Using defend reaction routes, large variety of starting materials and reagents

Question 3

Comb synthesis

Answer 3

All possible compounds from a range of stating materials generated together - library

Question 4

3 requirements for comb chem

Answer 4

Highly efficient chemistry
Limited work up, isolation and purification
Rapid through put……. Automation

Question 5

Three main comb strategies

Answer 5

Mixed (spilt and pool)
Parallel
Miniaturisation (eg spot synthesis)

Question 6

Advantages of comb synth 4

Answer 6

Increase productivity
Prevent chemistry bottle necks
Companies can patent sooner
Cost saving and increased time for revenue generation

Question 7

Comb chem was inspired by

Answer 7

SPPS

Solid phase peptide synthesis

Question 8

SPPS

Answer 8

Peptide synthesis in solution
At each step it is isolated, purified and characterised

(A very long process if many amino acids)

Question 9

Merrifield process

Answer 9

Attach starting material (First amino acid) to solid support ( resin bead)

Question 10

Advantages of the resin bead solid support? 2

Answer 10

After each reaction we just wash off by products no sxcess…. We don’t need to isolate and purify
Can be automated

Question 11

How to ensure reaction goes to completion?

Answer 11

Use large excess of reactants.

At the end of reaction we just remove insoluble material

Question 12

Parallel synthesis for four dipeoetides involves how many steps

Answer 12

8
4 individual coupling reactions +
4 cleaving the molecules from the polymers

Question 13

Mix and spilt synthesis requires how many steps for 4 amino acids?

Answer 13

4
Mix the polymers together so you have 2 mixtures.
React one mixture with one amino acid (2)
Remove polymers from both mixtures (2)
2+2=4

Question 14

Mix and split results in

Answer 14

Sub mixtures

Question 15

When calculating the number of steps remember

Answer 15

In practice you always need more, this is a minimum

Question 16

Pro and con of mix and split?

Answer 16

Pro: fewer step so more practical for larger libraries
Con: you end up with a mixture

Question 17

Ways around the issue of it being a mixture?

Answer 17

Test it while it’s still attached to the bead? (Fewer steps)

Test it while in a mixture, maybe only one has activity, you can go back and loot at it by conventional methods

Question 18

Tea bag method

Answer 18

Each batch leads to individual compound that is kept physically separate in porous bag ( parallel synthesis with the efficiency of mix and split)

Question 19

Microkans and nanokans

Answer 19

Polyethylene tea bag fitted with rf tag for automated sorting

Question 20

Advantage of tea bagging

Answer 20

Allows combining the tea bags for common steps

Question 21

Linkers

Answer 21

• a unit attached to the solid support that contains a functional group which the starting material in the synthesis can react with (i.e. provides point of attachment for small molecules)

Question 22

When selecting linker consider

Answer 22

functional group(s) present in the chosen starting materials, and the functional group required in the product (after cleavage from the solid phase)

Question 23

Linkers … How to attach carboxylic acid, amine, alcohol

Answer 23

Ester
Displace a Cl in som strange three benzene ring ting
Ether

Question 24

Traceless linkers and “cyclo-release” 2

Answer 24

On cleavage form resin functional group is replaced with hydrogen
Or
Functional group used to join to starting materials is incorporated into product

Question 25

Multicomponent reactions

Answer 25

Three or more different reactive compounds each with functional group chosen to be compatible. Mid together to get a structures with lots of diversity.

Question 26

In Multicomponent reactions how to we get rid of unchanged starting materials?

Answer 26

Scavenger resins for solution synthesis

Question 27

Scavenger resins

Answer 27

a(excess) + b -> ab + a(excess) (all in solution)
Add solid scavenger for A
Filter and evaporate, leaving just ab

Question 28

Supported reagents

Answer 28

Reagent (enzyme) on a solid support used with reaction in solution

Question 29

Comb chem was made becuase

Answer 29

Traditional techniques could not keep up the pace for demand of early small molecule lead discovery