1.Application of combinatorial chemistry
Applications in combinatorial chemistry are very wide. It is widely use in pharmaceutical companies. For illustrate this I chose a practical example:
Transition-state analog HIV protease inhbitors
Extensive efforts toward the rational design of aspartyl protease inhibitors such as renin and HIV have led to the discovery of several transition-states analog mimics. These templates can serve as the central unit around which molecular diversity can be generated by application of appropriate chemistries. Recently, solid phase synthesis of hydroxyethylamine and 1,2-diol transition-state pharmacophore units and their utility for synthesis of HIV protease inhibitors have been reported by two different groups.(40, 41)
The first instance, bifunctional linker are used by Wang to serve the dual purpose of protecting the hydroxyl group of these BBs and providing point for attachment on solid support. (Figure 26)
Thus, one linker possesses a vinyl ether group at one end and a free carboxylate group at the other. The vinyl ether moiety is reacted with diamino alcohol BB 1 under acid-catalysed conditions to form an acetal protecting group and the carboxylic acid group is used for ester-type linkage to the solid support. The other linker possesses a methyl ketone and carboxylic groups at the two ends, with the ketone group forming a ketal with diol 3. Resulting intermediates 2 and 4 are now well suited for a bi-directional solid phase synthesis strategy for preparing C2 symmetric HIV protease inhibitors. The two terminal amino groups of 2 and 4 are deprotected and reacted with a variety of carboxylic acid, sulfonyl chlorides, isocyanates, and chloroformates to extend the core unit in both directions and generate a wide variety of aspartyl protease inhibitors. The authors claim that a library of 300 discrete analogs was prepared and screened against HIV protease to identify several potent inhibitors.
In the method reported by Kick and Ellmann, a masked aminodiol pharmacophoric unit is attached through its hydroxyl group onto a dihydropyran functionalised polystyrene support. (Figure 27)
The tosyl and diazo groups of this unit provide convenient handles for bi-directional derivatisation. The tosyl group can be converted to ureas or cylised to give amides. The azo group of the pharmacophore can then be reduce to an amine, which is now available for further functionalisation. The versatility of this approach was demonstrated by synthesis of various known HIV protease inhibitors in good yields.
40 Wang, G.T., Li, S., Wideburg, N., Krafft, G.A., Kempf, D.J. 1995. Synthetic chemical diversity: solid phase synthesis of libraries of C2 symmetric inhibitors of HIV protease containing diamino diol and diamino alcohol cores. J. Med. Chem. 38. 2995 - 3002.
41 Kick, E.K., Ellman, J.A. 1995. Expedient method for the solid phase synthesis of aspartic acid protease inhibitors directed toward the generation of libraries. J.Med.Chem. 38. 1427 - 1430.