Introduction of Combinatorial Chemistry 5th Year Pharmacy 2016-2017

Definition A branch of applied chemistry concerned with the rapid synthesis and screening of large numbers of different but related chemical compounds generated from a mixture of known building blocks in order to recover new substances optimally suited for a specific function

Other definition that make it possible to prepare a large number (tens to thousands or even millions) of compounds in a single process. These compound libraries (products ) can be made as mixtures, sets of individual compounds or chemical structures generated in silico

Disadvantages High affected molecular size, solubility, Achiral products

1- Solid Phase Synthesis A common combinatorial technique uses organic synthesis on solid support.  Linker groups are attached to resin beads in the solid phase and the reactants are passed over in solution to make the intermediates and a final detachment-from-resin reaction is run to get the desired product out of the column.   

SUPPORTS AND LINKERS Most solid-state combinatorial chemistry is conducted by using polymer beads 10 to 750 µm in diameter. The polymers are inert, except for the functional groups to which the molecules are attached. In general, the compounds 10 be synthesized are not attached directly to the polymer molecules.

They are usually attached using a "linker"" moiety that : a) enables attachment in a way that can be easily reversed without destroying the molecule that is being synthesized and b ) allows some room for rotational freedom of the molecules attached to the polymer

The types of solid supports that are used include Poly styrene resins, TentaGel resins Polyacyamide resins Glass & Ceramic resins

Mixed Combinatorial Synthesis There 20 amino acids AA1 + AA2 AA1-AA2 ( 20 )n n=2 20 X 20 = 400 DIPEPTIDES AA1 + AA2 + AA3 AA1-AA2-AA3 ( 20 )3 20 X 20 X20 = 8000 TRIPEPTIDES Home work calculate mixed combinatorial synthesis of Tetrapeptides ?

DETECTION, PURIFICATION, AND ANALYSIS Detection, analysis, and purification of combinatorial libraries places high demands on exiciting analytical techniques because {a) the quantities to be analyzed are very small, sometimes pico-moles of materials (b) the analysis should be non destructive, to allow recovery of the compound if possible, and c) the methods must be suitable for rapid parallel analysis Chromatographic methods used ( HPLC – MS). FT-IR ( Fourier transmission Infra-red )spectroscopy NMR ( Nuclear Magnetic Resonance ) Spectroscopy