Lecture 5.2 (slide 36) Flashcards
Where do compound libraries for drug discovery come from?
- chemical synthesis
- natural sources
What is Combichem (combinatorial chemistry)?
chemistry technique to synthesize compounds through methodical combinations of “building block” components
What is the advantage of combinatorial chemistry over traditional strategy?
combinatorial chemistry:
purification and characterization are not necessary before screening
What kinds of molecules was combinatorial chemistry applied for?
peptide or nucleotide origin
Where is combinatorial synthesis carried out on?
solid support or in solution phase
What are the advantages of using solid support for combinatorial chemistry?
- Reagents can be used in excess to drive the reaction to completion
- Purification is easy
- No tedious purifications of synthetic intermediates during a multistep
synthesis
For combichem using solid support, how are excess reagents and by-products separated from solid-support-bound products?
simply by rinsing the solid supports with solvents
For combichem using solid support, how is the final product obtained?
The final products can be chemically cleaved from the solid supports and subjected to a single purification
What are the 2 different methods for combichem?
1.the parallel synthesis method
2. the split-and-pool method
Describe the parallel synthesis method
- each compound synthesised in separate vessels
- 4 building blocks A-D coupled to solid supports
- coupling rxn with 4 building blocks
- 32 runs required for 16 compounds
Describe the split-and-pool method
- solid supports split into diff rxn vessels, blocks A-D coupled to solid support
- solid support pooled tat, mixed, redistributed for next rd of coupling
- 8 rxns to prepare 16 compounds
State the advantage of parallel synthesis method over split-and-pool method
easier work-up and the composition of each compound is known
How are compounds identified in the split-and-pool method?
through the use of various encoding strategies such as radio-frequency tags
In combichem, apart from solid supports, what else could be used?
- precipitation tags
- fluorous tags
If insoluble solid support is used, how to separate excess reagents and reaction byproducts from the desired products?
rxn substrate is attached to insoluble solid support by a CHEMICAL LINKER –> excess reagents and byproducts rinsed off –> linker cleaved to release the product
If precipitation tags are used, how to separate excess reagents and reaction byproducts from the desired products?
adding a reagent that can precipitate the tag with the attached product
-byproducts and excess reagents washed off
-tag resolubilised for subsequent rxns
If fluorous tags are used, how to separate excess reagents and reaction byproducts from the desired products?
-tag is soluble in fluorocarbon solvent
—> extract rxn mixture with immiscible fluorocarbon solvents
What are fluorosis tags?
polyfluorocarbon chains that are soluble in fluorocarbon solvents
For using combichem to develop ‘lead optimisation libraries’, why is it that the set of compounds have diverse structural elements?
so that structure- activity relationships (SAR) can be developed
What are the limitations of CombiChem?
- Only certain types of substances can be made
-Not all types of compounds can be subjected to solid-phase synthesis - lack of applicable chemistry
- lack of ability to quantitate the reaction outcome
- un-interpretable assay results
