Scientific Report 2007

Chemistry

Click Chemistry and Biological Activity

K.B. Sharpless, M. Ahlquist, A. Feldman, J. Fotsing, N. Grimster, J. Hein, J. Kalisiak, K. Korthals, S.-W. Kwok, K. Nagai, S. Pitram, J. Raushel, A. Salameh, J. Tripp, C. Valdez, X. Wang, T. Weide

The driving forces in our research are the discovery and understanding of new chemical reactivity, the harbingers of all new reactions. Our main goal is to develop chemical transformations that facilitate rapid synthesis of compounds with desired properties. The degree of diversity of the building blocks and the speed with which synthesis, screening for the desired function, and lead optimization can be performed are important factors in the search for the new function. The greater the variety of scaffolds and functional groups that can be used in the rapid construction of candidate compounds, the more likely it is that new and useful function will be discovered. Because of the enormous number of compounds to explore (the number of small duglike compounds may be as high as 10⁶⁴), the size of a given collection becomes much less important than the ability to rapidly probe the collection for a desired activity. However, many chemical methods often have restrictions such as limited scope, inaccessibility of starting materials, requirements for protecting groups, and difficult purifications. In addition, inert atmospheres and anhydrous solvents are usually required, a situation that makes these methods difficult to implement for synthesis and scale-up of chemical libraries.

In the past several years, we have sought to develop and use only the best reactions for the synthesis of functional molecules. Inspired by the natural synthesis of myriad functional molecules (nucleic acids, proteins, and carbohydrates) from just a handful of building blocks, we devised a fast, reliable, and highly modular style of organic synthesis, which we termed click chemistry. Click reactions fulfill the most stringent criteria of usefulness and convenience (Fig. 1), they are highly energetically driven, and the majority of them form carbon- heteroatom bonds. We use click reactions to assemble molecules with diverse properties. The new organic substances are obtained in short reaction sequences that establish stable heteroatom links between building blocks. We contend that a wide variety of interesting and useful molecules can be easily made in this way and that the chances for achieving desirable biological activity with such compounds are at least as good as chances with the traditional target structures now favored by medicinal chemists.

Fig. 1. Click chemistry: molecular diversity from a handful of near-perfect reactions.

Recently, we realized that many of the click reactions work as well as, or better, in water as they do in the organic solvents most commonly used. The second realization, which has shaped our research program in the past several years, was that although olefins, through their selective oxidative functionalization, provide convenient access to reactive modules, the assembly of these energetic blocks into the final structures is best achieved by cycloaddition reactions involving the formation of bonds between carbons and heteroatoms, such as 1,3-dipolar cycloadditions and hetero Diels-Alder reactions.

The 1,3-dipolar cycloaddition of azides and alkynes, most extensively studied by R. Huisgen in the 1960s, and its copper-catalyzed version, recently discovered by V.V. Fokin, Department of Chemistry, take a prominent place in click reactions. These transformations enable reliable assembly of complex molecules by means of the 1,2,3-triazole heterocycle. Experimental simplicity and the unusually broad scope of this process enabled a number of applications in synthesis, medicinal chemistry, molecular biology, and materials science.

Although both alkynes and azides are highly energetic, they are quite unreactive to an unusually broad range of reagents, solvents, and other functional groups. This inertness allows clean sequential transformations of broad scope without the need for protecting groups, even if the reactions are performed in aqueous solvent in the presence of atmospheric oxygen. The 1,2,3-triazoles have the advantageous properties of high chemical stability (in general, being inert to severe hydrolytic, oxidizing, and reducing conditions, even at high temperatures), strong dipole moment, presence of aromatic groups, and the ability to accept hydrogen bonds. Thus, they can interact productively in several ways with biological molecules. For example, 1,2,3-triazoles can replace the amide bond in peptides, preventing proteolytic degradation of the peptides.

In addition to developing new click reactions, we are currently engaged in a number of collaborative projects with scientists at Scripps Research and other institutions. The targets include HIV protease, in studies with J.H. Elder and A.J. Olson, Department of Molecular Biology, and B.E. Torbett, Department of Molecular and Experimental Medicine; acetylcholinesterase, in collaboration with P.W. Taylor and Z. Radic, University of California, San Diego; and development of new antibacterial agents (Fig. 2), in research with S. Omura and T. Sunazuka, Kitasato Institute, Tokyo, Japan.

Fig. 2. Spiramycin analogs for antibacterial profiling.

Publications

Dìaz, D.D., Converso, A., Sharpless, K.B., Finn, M.G. 2,6-Dichloro-9-thiabicyclo[3.3.1]nonane: multigram display of azide and cyanide components on a versatile scaffold. Molecules 11:212, 2006.

Hirose, T., Sunazuka, T., Noguchi, Y., Yamaguchi, Y., Hanaki, H., Sharpless, K.B., Omura, S. Rapid ‘SAR' via click chemistry: an alkyne-bearing spiramycin is fused with diverse azides to yield new triazole-antibacterial candidates. Heterocycles 69:55, 2006.

Narayan, S., Fokin, V.V., Sharpless, K.B. Chemistry ‘on water': organic synthesis in aqueous suspension. In: Organic Synthesis in Water: Principles, Strategies and Applications. Lindström, U.M. (Ed.). Blackwell Publishing, Oxford, England, 2007, p. 350.

Sharpless, K.B., Manetsch, R. In situ click chemistry: a powerful means for lead discovery. Expert Opin. Drug Discov. 1:525, 2006.

Whiting, M., Tripp, J., Lin, Y.-C., Lindstrom, W., Olson, A.J., Elder, J.H., Sharpless, K.B., Fokin, V.V. Rapid discovery and structure-activity profiling of novel inhibitors of human immunodeficiency virus type 1 protease enabled by the copper(I)-catalyzed synthesis of 1,2,3-triazoles and their further functionalization. J. Med. Chem. 49:7697, 2006.

Yoo, E.J., Ahlquist, M., Kim, S.H., Bae, I., Fokin, V.V., Sharpless, K.B., Chang, S. Copper-catalyzed synthesis of N-sulfonyl-1,2,3-triazoles: controlling selectivity. Angew. Chem. Int. Ed. 46:1730, 2007.