Combinatorial chemistry

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This ppt gives an overview on combinatorial technology and combinatorial synthesis methods

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Combinatorial Chemistry S.Sri Hari teja Siddharth Institute of Pharmacy IV year B Pharmacy Regd No- 08CR1R0043

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What is Combinatorial Chemistry? Brief History of Combi-chemistry Principle of Combinatorial chemistry Synthetic Methods a. Solid-Phase synthesis b. Solution-Phase synthesis Separation & analysis of Combinatorial Libraries Screening Methods Applications Conclusion References Contents :-

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Combinatorial chemistry is a new methodology by which we can simultaneously synthesize a large number of possible compounds that could be formed from a number of building blocks. What is Combinatorial chemistr y?

Brief History of Combi-Chemistry:

Brief Histor y of Combi - Chemistr y Bruce Merrifield won the Nobel prize in chemistry in 1984 for his work on solid-phase synthesis. H. Mario Geysen, research scientist at Glaxo Wellcome Inc., in 1984 he developed a technique for synthesizing peptides on pin-shaped solid supports. Another early pioneer was Arpad Furka who introduced the commonly used split and-pool methods.

Principle of Combinatorial Chemistry:

Princi p le of Combinatorial Chemistr y The basic principle of the combinatorial chemistry is to produce a large number of compounds at same time. The characteristic of combinatorial synthesis is that different compounds are synthesized simultaneously under identical reaction conditions in a systematic manner, so that ideally the products of all possible combinations of the starting materials will be obtained at once. The collection of these finally synthesized compounds is referred to as a “ combinatorial library . ”

How does Combinatorial Synthesis differ from traditional synthesis ? :

A + B A A 1 A 2 A 3 A 4 . . . A n B B 1 B 2 B 3 B 4 . . . B n A 1-n B 1-n Traditional Synthesis Combinatorial Synthesis AB How does Combinatorial Synthesis differ from traditional synthesis ?

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S y nthetic Methodolo g ies for p roduction of Combinatorial libraries Solid-Phase Synthesis The compound library have been synthesized on solid phase such as resin bead, pins, or chips. Solution-Phase Synthesis In this method synthesis of compounds takes place in solution form .

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Take Solid support. React the solid support with a group called linker. 3. Mix the Solid support (bead) with a substrate that we want to use in a chemical reaction. The linker will bind to it and hold it on the Solid (bead). Solid – Phase S y nthesis

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Here we have 6 reaction vessels containing a 6 different reagents. Put a 1/6 of beads into a mesh bag and put into the reaction vessels.

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Substrate reacts with the reagent in which they are placed and forms products on the solid support. 6. The Solid (beads) are removed from the vessel by lifting the mesh bag and they are washed to remove any unreacted reagents.

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7. The product are separated from solid support by the breakdown of linkers. The solid supports can be reused. 9. So that 6 different new compounds are synthesized, which can be now tested for biological activity. like this the products are obtained by the solid phase synthesis.

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Re q uirements of Solid – Phase S y nthesis Solid supports Example:- Polystyrene resins, Tenta Gel resins, Polyacrylamide resins, Glass and ceramic beads etc., Linkers To support the attachment of a synthetic target, the polymer is usually modified by equipping it with a linker. Example:- Wang resins, Rink resins, Dihydropyran derivative resins etc., Protecting Groups Example:- FMOC (Fluro methoxy carbonyl benzyl ester) TBOC (Tertiary butyloxy carbonyl) etc.,

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A pp lications of solid p hase s y nthesis Synthesis of 1,4-benzodiazepines, Synthesis of Benzopyran derivatives, Synthesis of luteinizing hormone releasing hormone analogues etc;

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combinatorial synthesis on solid support is usually carried out by using one of the following method Parallel synthesis Mix and Split method. Parallel s y nthesis

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Reagents Substrates - Substrate - Reagent - Product Parallel s y nthesis

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Mix and s p lit techni q ue B A B A B A B A B B A A Mix Split

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Solution – Phase S y nthesis In this method synthesis of compounds takes place in solution form without the aid of solid support.

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Function of scavengers :- To separate the product from the reagent used in the reaction easily. If the reagent is electrophilic, use a nucleophilic scavenger! If the reagent is nucleophilic, use an electrophilic scavenger!

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Filter Example for solution phase synthesis :-

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Se p aration & Anal y sis of “ Combinatorial Libraries ” Seperation and analysis of combinatorial libraries places high demands on existing analytical techniques because (a) The quantities to be analyzed are very small. (b) The analysis should be non destructive and to allow recovery of the compound possible. (c) The methods must be suitable for rapid parallel analysis.

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Anal y tical e q ui p ments used in Combinatorial chemistr y HPLC – it is used to separate the compounds of Combinatorial libraries. UV Spectrophotometer IR Spectrophotometer Hyphenated technique such as HPLC-MS etc;

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Screening is a process by which the biologically active compound are identified among a mixture of chemical compounds . The Screening methods used in combinatorial chemistry High-throughput screening Virtual screening Screenin g Methods

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Hi g h - throu g h p ut screenin g Microtiter Plate Well High-throughput screening (HTS) involves the process of finding a active compound against a chosen target.

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Virtual Screenin g Virtual screening refers to the use of computers to predict whether a compound will show desired activity or not, on the basis of its two dimensional or three dimensional chemical structure.

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A pp lications Mainly it is applied in the discovery of drugs. Eg:- Raloxifen To synthesize analogues of existing lead structure to elucidate the Structure Activity Relationships (SAR).

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Preparation of hydrazones and discovery of an antibiotic compound using traditional synthesis

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Preparation of hydrazones and discovery of an antibiotic compound using traditional synthesis A1-B1 A2-B1 A3-B1 A1-B2 A2-B2 A3-B2 A1-B3 A2-B3 A3-B3

Combinatorial Chemistry within drug design:

Combinatorial Chemistr y within dru g desi g n Chemical Compounds Lead Drug Therapeutic Target Combinatorial Chemistry can impact here Lead Optimization

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Conclusion Combinatorial chemistry had revolutionized drug research by enabling a dramatic reduction in development time (four to seven years) by speeding and identification of lead compounds. Combinatorial chemistry can reduce the time required for drug discovery from its current average of 4 years to 1 year.

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References Text book of Medicinal Chemistry Volume-II K.Ilango, P.Valentina Pg no :- 443-451 A Text book of Synthetic and Medicinal Chemistry G.Devala Rao Pg no:-306-316 Combinatorial chemistry : A Review Drug Invention Today Vol.2.Issue.1.January 2010 Pg no:-49-52 Combinatorial chemistry and its application – a review AK Mishra, A Gupta, AK Singh, P Bansal, S Kumar, V Gupta International journal of chemical and analytical science 2010, 1(5), Pg no :-100-105