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