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The Skaggs Institute for Chemical Biology
Scientific Report 1999-2000


Studies in Organic Synthesis and Chemical Biology


E.J. Sorensen, G. Adam, E. Anderson, J. Rohde, G. Scheffler, H. Seike, W. Shipe, L. Stark, J. Tamiya, C. Vanderwal, D. Vosburg

We are interested generally in novel organic chemical reactivity, and a broad goal of our research is to approximate the efficiency with which Nature creates architecturally unique, biologically active products. In our work, we develop concise reaction sequences by which abundant and inexpensive building blocks can be transformed into molecules that have great promise as therapeutic agents. Achievements in this area of chemical investigation foster exciting, multidisciplinary research opportunities.

To achieve efficiency in our research in organic synthesis, we often emulate chemistry that Nature uses (or may use) to create bioactive, structurally novel products. A common theme of several investigations is the experimental evaluation of hypotheses about the natural origin of molecular structure. Our recent synthesis of the novel phospholipase C inhibitor (-)-hispidospermidin (4 in Fig. 1) is representative of the way in which we approach a complex objective in organic synthesis.

Our strategy evolved from a perceived homology between the structures of (-)-hispidospermidin and spirocyclic cation (3 in Fig. 1). The cation can be traced, via the well-known compound γ-bisabolene (2 in Fig. 1), to farnesyl pyrophosphate (1 in Fig. 1), the fundamental building block in sesquiterpene biogenesis. We noted that the constitution of spirocyclic cation is quite clearly expressed in the structure of (-)-hispidospermidin and reasoned that (-)-hispidospermidin might be a unique trimethylspermidine-containing sesquiterpene. Gratifyingly and somewhat unexpectedly, when compound 5 (Fig. 2) was dissolved in acetic acid, it underwent an easy bicyclization to compound 6 (Fig. 2), a substance with the novel, cagelike architecture of the natural product.

Our interests in chemical reactivity have also taken us in an exciting new direction. As the focus of biological research shifts from the genome to the proteome, innovative strategies are needed to characterize protein function.

In collaboration with B. Cravatt's group, The Scripps Research Institute, we use chemical synthesis to create novel, biotinylated affinity agents that can effect covalent modification of particular classes of proteolytic enzymes and other biochemically important enzymes. These agents and straightforward avidin chemiluminescence blot assays allow visualization of enzyme activities in complex tissue proteomes, including proteins present in low abundance and proteins that are bonafide markers of diseases such as cancer. The ability to profile classes of proteins on the basis of changes in their activity will accelerate both assignment of protein function and identification of potential pharmaceutical targets.

Publications

Adam, G.C., Cravatt, B.F., Sorensen, E.J. Profiling the specific reactivity of the proteome with nondirected activity-based probes. Chem. Biol., in press.

Cravatt, B.F., Sorensen, E.J. Chemical strategies for the global analysis of protein function. Curr. Opin. Chem. Biol. 4:663, 2000.

Scheffler, G., Seike, H., Sorensen, E.J. An enantiospecific synthesis of the potent immunosuppressant FR901483. Angew. Chem. Int. Ed. 39:4593, 2000.

Sorensen, E.J. Albert Eschenmoser. Helv. Chim. Acta 83:1673, 2000.

Sorensen, E.J. Selected, recent developments in the chemical synthesis of biologically-active natural products. Curr. Opin. Drug Discov. Dev. 2:606, 1999.

Tamiya, J., Sorensen, E.J. A concise synthesis of (-)-hispidospermidin guided by a postulated biogenesis. J. Am. Chem. Soc. 122:9556, 2000.

 

 







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