Comninatural Chemistry basic chemistry .pptx

Comninatural Chemistry basic

1. Combinatorial Synthesis Most Rapidly Developing Field in the Pharmaceutical industry

2. Definition Combinatorial synthesis is a means of producing large number of compounds in a short time using a defined reaction route and large variety of starting material and reagents.

3. Principal of combinatorial synthesis

4. 20 A.A. = 20 10 =10 240 000 000 000 Collection of compounds intended for bioassay that typically share a common pharmacophore or activity towards a given class of target. More than 10,000 compounds per week

5. Application Pharmaceuticals Medicinal chemistry

6. Advantages Less time More economical More diversity w.r.t. Time

7. Techniques of Combinatorial-synthesis Solid phase synthesis (SPS) Parallel synthesis SPS 1 . solid support 2 . The anchor/linker 3 . Reagent

8. Solid support Polystyrene beads cross linked with 1-2% divinely benzene Tanta Gel- 80% poly( ethylene glycol) grafted to cross linked polystyrene Sheppard's polyamide resin Beads, Pins, Functionalized glass surface

9. The Anchor/Linker Linker ? Characteristics of linker ? Cleavage acid labile, base labile, photo labile, cyclative cleavage, bio labile

10. Resins Wang resin, + & - of RCOOH Rink resin, + RCOOH & - of carboxamide Dihydropyran derivitized, + & - alcohols

11. Peptide synthesis

12. METHODS IN MIXED COMBINATORIAL SYNTHESIS DESIGNED TO PRODUCE A MIXTURE OF PRODUCTS IN EACH REACTION VESSEL STARTING WITH A WIDE RANGE OF STARTING MATERIALS & REAGENTS SYNTHESIS OF ALL POSSIBLE DIPEPTIDES OF 5 DIFFERENT A.A REQUIRES 25 EXPERIMENTS USING ORTHODOX CHEMISTRY COMBINATORIAL SYNTHESIS REQUIRES ONLY 5 EXPERIMENTS !!!!

13. Glycine Gly-Gly Ala-Gly Phe-Gly Val-Gly Ser-Gly Alanine Gly -Ala Ala-Ala Phe-Ala Val-Ala Ser-Ala Phenyl Alanine Gly-Phe Ala-Phe Phe-Phe Val-Phe Ser-Phe Valine Gly -Val Ala-Val Phe-Val Val-Val Ser-Val Serine Gly -Se Ala-Ser Phe-Ser Val-Ser Ser-Ser

14. Synthesis of different dipeptides

15. The Mix and Split Method Minimize the efforts involved Synthesis of all possible tripeptides of three different amino acids is completed in five stages

16. DECONVOLUTION “ISOLATION & IDENTIFICATION OF THE MOST ACTIVE COMPOUND IN THE MIXTURE” METHODS OF DECONVOLUTION ARE; 1-MICROMANIPULATION 2-RECURSIVE DECONVOLUTION 3-SEQUENTIAL RELEASE

17. Strucure Determination of Active Compounds Tagging Building up of two molecules on same bead One molecule is new structure to be tested Other is a molecular tag (usually a peptide or oligonucleotide) Tag will act as code for each step of synthesis Bead must have multiple linker Reagent is added to one part of linker and an encoding amino acid is added to another part of the linker Example of multiple linker “Safety catch linker” (SCAL)

18. Drawbacks To Tagging Time consuming Require elaborate instrumentation Possibility of an unexpected reaction

19. Encoded Sheets Process: Resin beads are sandwiched between two woven sheets of inert polypropylene Sheets are marked into squares Each square Each square Is given a three letter code Sheets are separated and are treated with an amino acid

20. Finally sheets are treated with piperdine to remove F-moc protecting group Sheets are restacked and cut into three sets of columns Each column with another activated F- moc amino acid

21. Strips are restacked and cut into rows Each set is treated with third amino acid to form all possible 27 Tripeptides Each square containing a unique Tripeptide sequence

22. Photolithography “A technique which permits miniaturization and spatial resolution such that specific products are synthesized on a plate of immobilized solid support” Amino acids are protected by photo labile protecting groups Nitroveratryl oxycarbonyl (NVOC)

23. Photolithography

24. Examples of Combinatorial Chemistry HIV Protease inhibitors Antimicrobials agents Opiates receptors ligands Aspartic acid Protease inhibitors Earliest example was 1,4-benzodiazepines Piperazinediones 2,5-disubsituted tetrahydrofurans and thiazolidines have also been synthesized

25. Testing For Activity High Throughput Screening 96 small wells with capacity of 0.1ml Test volume is reduced to 1-10 ųl Fluorescence and chemiluminescence allow simultaneous identification of active wells Major advancement involves the manipulation of Microfluid circuits Separation of analytical sample using capillary electrophoresis

26. Screening “ON Bead” or “OFF Bead ” ON bead involves interaction with targets tagged with an enzyme , fluorescent probe, radionuclide or a chromosphere Positive interaction results in fluorescence or a color change Active beads picked out by micromanipulation and structure of active compound determined False negative might obtained if solid phase sterically interferes with assay

27. Vitamin C (Ascorbic Acid) History Physical properties Sources Fresh fruits and vegetable like Guava, Citrus fruits, Tomatoes, Onions, Spinach, Cabbage, Turnips, Melons, Potatoes etc Half Life Excretion

28. Physical properties Molar mass: 176.1256 g/mol Density (in natural state): 1.7 g/mL Boiling Point: not applicable Melting Point: 190 to 192 oC

29. Sources

30. Intake requirements

31. Biochemical Roles Reducing Steroid genesis In oxidation-Reduction Reactions Metabolism of Tyrosine Folic Acid Tetrahydrofolic Acid Proline Hydroxyproline Processing of Polypeptide hormones e.g. ADH Microsomal Drug Metabolism

32. Synthesis of Ascorbic Acid

33. Deficiency of Vitamin C (Scurvy) Disruption of Blood Vessels, Hemorrhages Anemia, Weakness, Motionlessness Impaired wound healing Edema and Fever Convulsions, Hypotension, and death may occur abruptly

34. Synthesis

35. Diagnosis of Scurvy Plasma Ascorbic acid level Ranges 0.7-1.2mg/dl In white cells and platelets Ranges 25-30mg/dl

36. Overdose of ascorbic acid Nausea and diarrhea Aggravates gout Iron overload