Advanced Techniques in Medicinal Chemistry (DONE) Flashcards
What are the advantages of multicomponent reactions?
Complexity easily generated Many compounds easily accessible by changing basic components Great atom economy No protecting groups needed Solid phase
What is combinatorial chemistry?
Method to speed up synthesis of compounds for testing
Various methods to produce libraries of compounds for screening
Usually automated
Often involves solid phase synthesis
What are the steps for combinatorial chemistry?
Compounds are built up by a combination of building blocks
Compounds are prepared by adding building blocks to the template
There is more than one type of each building block
Therefore we can rapidly build a library
What is solid phase synthesis?
Combinatorial chemistry is often on solid phase
Allows automation and simplifies purification
Growing chemical is attached to resin bead
The resin is usually made of polystyrene
What are the advantages of solid phase synthesis?
Beads can be filtered and washed to remove excess reagents and by-products
Large excesses of reagents can push reactions to completion
Whole process can be automated
Much faster than conventional chemistry
What are the requirements for solid phase synthesis?
The compound must be joined to the resin by a bond that will survive all the reagents used during the synthesis
It should be possible to cleave the product from the resin without damaging it
Reagents must be compatible with the resin
Each step must be high yielding to avoid contamination
What are the disadvantages of solid phase synthesis?
Limited amount of product made
Difficult/impossible to monitor reactions, so you do not know when the reaction has gone to completion
Many traditional reagents are incompatible with solid phase chemistry
If a particular coupling does not go to completion it can be difficult/impossible to purify the products
What are the different ways of carrying out combinatorial chemistry?
Parallel synthesis
Synthesis of mixtures
Split and mix
Encoded libraries
What is fragment based drug design?
Drug like molecules can be regarded as the combination of two or more fragments
These fragments would still have some affinity for the biological target
Fragments have a low molecular weight (120-250)
What are the steps of fragment based drug design?
Screening of a fragment library for biological activity
Generation of the fragment or target structure (NMR or x-ray)
Combination of the active fragments and design of a high affinity compound
What are the advantages and disadvantages of fragment based drug design?
Novel and very powerful technique
Higher hit rate than HTS
Target structure needs to be easily determined
Modelling can be used, but it is less accurate
Traditional chemical synthesis
Slow
A good chemist could make two compounds per week on a straight forward project
Often several synthetic steps are required to prepare a single compound
Only 1 out of 10000-100000 compounds prepared in the lab will become a drug
Multi-component reactions
Reactions where three or more simple molecules react to form a complex compound
The reagents do not react all at the same time in a single step, but they follow a specific sequence
