Transcript simple - hcopgnt

1
contents
•
•
•
•
•
•
•
•
combinatorial chemistry
History of combi-chem
Principle of combi-chem
Synthetic methods
a)solid phase synthesis,
b) solution phase synthesis,
Screening methods
Application
Conclusion
Bibliography
COMBINATORIAL CHEMISTRY
 Combinatorial chemistry (or CombiChem) is an innovative method of
synthesizing many different substances quickly and at the same
time. Combinatorial chemistry contrasts with the time-consuming
and labor intensive methods of traditional chemistry where
compounds are synthesized individually, one at a time.

CombiChem is used to synthesize large number of chemical
compounds by combining sets of building blocks. Each newly
synthesized compound's composition is slightly different from the
previous one.
History of combi-chem
-> Although combinatorial chemistry
has only really been taken up by
industry since the 1990s, its roots can
be seen as far back as the 1960s when
are searcher at Rockefeller University,
Bruce Merrifield, started investigating
the solid-state synthesis of peptides
-> Bruce Merrifield won the Nobel prize
in chemistry in 1984 for his work on
solid-phase synthesis.
Principle:
• Used extensively in relation with drug
discovery
• Principle of Combinatorial Chemistry:
• -> Generation of Compound Libraries from
Molecular Building blocks which are
usually used in high-throughput
screening.
HTS
Library
How does combinatorial chemistry
differ from traditional methods
In contrast to this approach, combinatorial chemistry
offers the potential to make every combination of
compound A1 to An with compound B1 to Bn.
Synthetic methodologies for production of
combinatorial libraries
a) Solid phase synthesis
the compound library have been synthesized
on solid phase such as resin bead , pins or
chips.
b) solution phase synthesis
In this method synthesis of compounds takes
place in solution phase.
A simple model
1.
Take some beads made from a polymer
2. React the beads with a group called a linker
3. Mix the bead in with an alcohol that you want
to use in a chemical reaction. The linker will
bind to it and hold it on the bead.
A simple model
4. Have 6 reaction vessels each containing a
different acyl chloride. Put a 1/6 of your beads
into a mesh bag and put into a container.
A simple model
5. Esterification occurs forming 6 different
esters.
6. The beads are removed from the vessel by
lifting up the mesh bag. They are washed to
remove any unreacted acyl chloride
A simple model
7. A reaction is used to break the linker
group down.
8. The polymer beads are reused
9. You have made 6 different esters which
now be tested for biological activity
can
A simple model
10. How many esters would you have made if
you had attached 6 different alcohols to the
beads?
Solid phase synthesis. Introduction
Organic reaction that carried out on solid
support / substrate that are covalently attached
to a polymeric resin
RECENT EXAMPLES
- Epothilone A
- Radiolabeled biotinylated peptide
substrate
- Human big gastrin2 and cholecystokin
- Dipeptide mimetic
- Phosphopeptide thioesters
Advantages of solid phase synthesis
over traditional synthesis.
1. Over all process is quick.
2. Purification of each product can be achieved in
one step.Only purification technique is filtration.
3. Purification in each step is possible.
4. Synthetic intermediates don’t have to be
isolated.
5. Can be automated with robots.
Disadvantages of solid
phase synthesis
1.High chemical consume.
2.Expensive.
3.Low reaction rates.
4.Special substrates needed.
5.Extra labor required to develop solid phase
route.
6.Yields can be low and produces very few
molecule at a time for testing.
Combinatorial Chemistry
Preparation of Libraries
• Parallel Synthesis
▫ Each compund is prepared in a specific vessel (on pins or Teabags)
▫ Array of reaction vessels (96 well plates -> each well other
compound)
▫ Automated control of reactions -> easy to keep track of each
compound
▫ High yields
▫ Useful for epitope mapping
▫ Just applicable when small number of positions are being
varied -> small libraries
Analytical equipments used in combichem
• HPLC – it is used to separate the
compounds of combinatorial
libraries
• UV-spectrophotometry
• IR- spectrophotometry
• Hypenated techniques such as
HPLC-MS etc
Screening methods
• Screening is a process by which the
biologically active compounds are identified
among a mixture of chemical compounds
• The screening methods are
 High-throuhput screening,
 Virtual screening.
CADD methods (COMPUTER AIDED DRUG
DESIGN)
• To examine, evaluate and compare complex molecular
structure
• To modify structure and assess geometric and
energetic consequences of such modifications
• To perform conformational analysis
• To build macromolecules
Applications
 Mainly it is applied in the discovery of drugs
Eg: RALOXIFN
 To synthesis analogues of existing lead
molecules to elucidate the SAR.
 Preparation of hydrazones and discovery of
anti biotic compounds synthesis.
CONCLUSION:
• Combi-chem had revolutinized drug research by
enabling a dramatic reduction in development time
(4-7 years) by speeding abd identification of lead
compound.
• Combi-chem can reduce the required for drug
discovery from its current average of 4 to 1 year.
Bibliography
Donald.J.Abraham, Burgers medicinal chemistry and
drugs discovery, vol-2, sixth edition, pg.no-1-69.
Thomas.L.Lemke, David.A.Williams, Foyes principles
of medicinal chemistry, sixth edition,pg no-186-187.
K.Ilango, P.Valentina, Text book of medicinal
chemistry , sixth edition, pg. no-443-445.
Ramarao nadendla, Medicinal chemistry, Revised
edition, pg no- 56-61.
www.google.com