Combinatorial chemistry

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 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 Take some beads made from a polymer 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 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 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 can now be tested for biological activity

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.

Preparation of Libraries Combinatorial Chemistry Preparation of Libraries Parallel Synthesis Each compund is prepared in a specific vessel (on pins or Tea- bags) 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 combi-chem 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

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