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Comninatural Chemistry basic chemistry .pptx
Combinatorial synthesis is a method in the pharmaceutical industry designed to rapidly produce a vast number of compounds using defined reactions and various reagents, allowing for high-throughput testing of bioactive compounds. This technique, which involves solid-phase and parallel synthesis, enhances efficiency in medicine development by reducing time and cost while increasing diversity in compounds. Additionally, methods such as deconvolution, tagging, and photolithography are employed to isolate active compounds and synthesize complex molecules, including peptides and inhibitors, effectively advancing research in medicinal chemistry.
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Comninatural Chemistry basic chemistry .pptx
- 1. Combinatorial Synthesis Most RapidlyDeveloping Field in the Pharmaceutical industry
- 2. Definition Combinatorial synthesisis 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 combinatorialsynthesis A + B AB (orthodox synthesis) Traditional strategy A1 A2 An B1 B2 B3 Bn A1 A1 A1 A1 B1 B2 B3 Bn An An An An B1 B2 B3 Bn combinatorial strategy ............. ............. ............. ............. A3
- 4. 20 A.A.= 2010 =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 Medicinalchemistry Find a lead compound Isolate active structure Identify the structure Optimise the lead Find a Target SAR combinatorian synthesis
- 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 Polystyrenebeads 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 ? Characteristicsof 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.
- 12. Peptide synthesis OH + NH(Fmoc) R CO2H H pipridine O NH2 R H o O NH (Fmoc) R H o PEPTIDE SYNTHESIS O o aa1aa2aa3 aan NH2 TFA cleavage aa1aa2aa3 aan NH2 HO2 C OH + Fmoc =9-flourinyl methoxy carbonyl
- 15. METHODS IN MIXED COMBINATORIALSYNTHESIS 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 !!!!
- 16. Glycine Gly-Gly Ala-GlyPhe-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
- 17. Synthesis of differentdipeptides Gly Ala Phe val Ser Gly Ala Phe val Ser Gly Ala Phe val Ser Gly Gly Gly Gly Gly Gly
- 18. The Mix andSplit Method Minimize the efforts involved Synthesis of all possible tripeptides of three different amino acids is completed in five stages
- 19.
- 20. Gly Ala Val Gly Val Ala Ala GlyVal Ala Gly Val Stage 2
- 21. Ala Gly Val Ala Gly Val Ala GlyVal ---Gly---Val ---Val---Val ---Ala---Val ---Gly---Ala ---Ala---Ala ---Val---Ala ---Gly---Gly ---Ala---Gly ---Val---Gly Gly Ala Val Stage 3
- 22.
- 23. ---Gly---Val ---Val---Val ---Ala---Val ---Gly---Ala ---Ala---Ala ---Val---Ala ---Gly---Gly ---Ala---Gly ---Val---Gly ---Gly---Val ---Val---Val ---Ala---Val ---Gly---Ala ---Ala---Ala ---Val---Ala ---Gly---Gly ---Ala---Gly ---Val---Gly ---Gly---Val ---Val---Val ---Ala---Val ---Gly---Ala ---Ala---Ala ---Val---Ala ---Gly---Gly ---Ala---Gly ---Val---Gly Stage 5 Gly AlaVal ---Gly---Val---Gly ---Val---Val---Gly ---Ala---Val---Gly ---Gly---Ala---Gly ---Ala---Ala---Gly ---Val---Ala---Gly ---Gly---Gly---Gly ---Ala---Gly---Gly ---Val---Gly---Gly ---Gly---Val---Ala ---Val---Val---Ala ---Ala---Val---Ala ---Gly---Ala---Ala ---Ala---Ala---Ala ---Val---Ala---Ala ---Gly---Gly---Ala ---Ala---Gly---Ala ---Val---Gly---Ala ---Gly---Val---Val ---Val---Val---Val ---Ala---Val---Val ---Gly---Ala---Val ---Val---Ala---Val ---Gly---Gly---Val ---Ala---Gly---Val ---Val---Gly---Val ---Ala---Ala---Val
- 24. DECONVOLUTION “ISOLATION &IDENTIFICATION OF THE MOST ACTIVE COMPOUND IN THE MIXTURE” METHODS OF DECONVOLUTION ARE; 1-MICROMANIPULATION 2-RECURSIVE DECONVOLUTION 3-SEQUENTIAL RELEASE
- 25. Strucure Determination ofActive 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)
- 27. Drawbacks To Tagging Time consuming Require elaborate instrumentation Possibility of an unexpected reaction
- 28. Encoded Sheets Process: Resinbeads 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
- 29. Finally sheetsare 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
- 30. Strips arerestacked 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
- 31. Photolithography “A technique whichpermits 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)
- 32.
- 34. 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
- 35. Testing For Activity High Throughput Screening 96 small wells with capacity of 0.1ml Test volume is reduced to 1-10ųl Fluorescence and chemiluminescence allow simultaneous identification of active wells Major advancement involves the manipulation of Microfluid circuits Separation of analytical sample using capillary electrophoresis
- 36. 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
- 39. Vitamin C (AscorbicAcid) History Physical properties Sources Fresh fruits and vegetable like Guava, Citrus fruits, Tomatoes, Onions, Spinach, Cabbage, Turnips, Melons, Potatoes etc Half Life Excretion
- 40. 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
- 41.
- 42.
- 43. Biochemical Roles ReducingSteroid genesis In oxidation-Reduction Reactions Metabolism of Tyrosine Folic Acid Tetrahydrofolic Acid Proline Hydroxyproline Processing of Polypeptide hormones e.g. ADH Microsomal Drug Metabolism
- 44.
- 45. Deficiency of VitaminC (Scurvy) Disruption of Blood Vessels, Hemorrhages Anemia, Weakness, Motionlessness Impaired wound healing Edema and Fever Convulsions, Hypotension, and death may occur abruptly
- 46.
- 47. Diagnosis of Scurvy Plasma Ascorbic acid level Ranges 0.7-1.2mg/dl In white cells and platelets Ranges 25-30mg/dl
- 48. Overdose of ascorbicacid Nausea and diarrhea Aggravates gout Iron overload