Development and Applications of Click Chemistry

Reported by Gregory C. Patton November 8, 2004 INTRODUCTION Secondary metabolites produced in Nature contain diverse architectures with extensive carboncarbon bond networks. These compounds often possess important biological activities that make them potential therapeutic agents. However, drug discovery based on these natural products is generally slow, costly, and hindered by complex syntheses. The recent development of combinatorial chemistry and high-throughput screening has aided in the rapid generation of compounds in search of biological function but relies heavily on the success of the individual reactions to construct molecular frameworks. Therefore, a set of criteria defining reliable reactions known as “click” chemistry was proposed by Sharpless and coworkers in order to accelerate the synthesis of drug-like molecules. Click chemistry enables a modular approach to generate novel pharmacophores utilizing a collection of reliable chemical reactions. Those reactions thus give products stereoselectively in high yields, produce inoffensive byproducts, are insensitive to oxygen and water, utilize readily available starting materials, and have a thermodynamic driving force of at least 20 kcal mol. Preferably, the reactions should be conducted in benign solvents and chromatography is not used for purification of reaction products. Two types of click reactions that have influenced drug discovery are the nucleophilic opening of strained ring systems and 1,3-dipolar cycloadditions. Of particular interest is the Huisgen [3 + 2] cycloaddition between a terminal alkyne and an azide to generate substituted 1,2,3-triazoles, 1 (Figure 1). This reaction has been termed the “cream of the crop” of click reactions and has found application in various facets of drug discovery. This review focuses on these two types of click reactions, as well as the use of click chemistry in generating natural product derivatives, target-guided synthesis, and activity-based protein profiling. N N N