Scientific Report 2007

Chemistry

Chairman’s Overview

As the 'central science,' chemistry stands between biology and medicine and between physics and materials science and provides the crucial bridge for drug discovery and development. But chemistry has a much more profound and useful role in science and society. It is the discipline that continually creates the myriad of new materials that we all encounter in our everyday lives: pharmaceuticals, high-tech materials, polymers and plastics, insecticides and pesticides, fabrics and cosmetics, fertilizers, and vitamins—basically everything we can touch, feel, and smell.

Chemists at Scripps Research focus on chemical synthesis and chemical biology, the areas most relevant to biomedical research and materials science. The members of our faculty are distinguished teacher-scholars who maintain highly visible and independent research programs in areas as diverse as biological and chemical catalysis, synthesis of natural products, combinatorial chemistry, molecular design, supramolecular chemistry, chemical evolution, materials science, and chemical biology. The chemistry graduate program attracts some of the best-qualified candidates from both the United States and abroad. Our major research facilities, under the direction of Dee H. Huang (nuclear magnetic resonance), Gary Siuzdak (mass spectrometry), and Raj Chadha (x-ray crystallography), are second to none and continue to provide crucial support to our research programs. In addition, the Mabel and Arnold Beckman Center for the Chemical Sciences constantly receives high praise from visitors from around the world for its architectural design and operational aspects, both highly conducive to research.

Research in the Department of Chemistry goes on unabated, establishing international visibility and attracting attention, as evidenced by numerous lecture invitations, visits by outside scholars, and headline news in the media. As of 2006, the Institute for Scientific Information ranked 3 members of our department as highly cited researchers (in the top 100 worldwide).

Richard Lerner and his group continue to make advances in catalytic antibodies, with new antibodies that catalyze important synthetic and biological reactions and novel applications in chemical synthesis. The group's research has recently expanded to include the fundamental chemistry of the polyoxygen species.

Barry Sharpless and his group continue endeavors to discover and develop better catalysts for organic synthesis and to construct, through innovative chemistry and biology, libraries of novel compounds for biological screening.

Scientists in Albert Eschenmoser's California-based group advance their experimental studies on the chemical etiology of nucleic acid structure by investigating nucleic acid alternatives that have novel backbones and recognition elements unrelated to the canonical phophodiester-based oligonucleotide systems.

Members of my own group continue to explore chemical synthesis and chemical biology, with a focus on the total synthesis of new anticancer agents, antibiotics, marine-derived neurotoxins, antimalarial compounds, antifeedant agents, and other biologically active natural and designed molecules.

Julius Rebek and his group devise biomimetic receptors, including molecules that bind neurotransmitters and membrane components, for studies in molecular recognition. Larger host receptors surround 3 or more molecular guests and act as chambers where the chemical reactions of the guests are accelerated. Members of the group also synthesize small molecules that act as protein helix mimetics for pharmaceutical applications.

Peter Schultz and researchers in his laboratory continue to expand the number of genetically encoded amino acids to include fluorescent, photocaged, metal-binding, chemically reactive, and posttranslationally modified amino acids. These scientists have also adapted this technology to mammalian cells and are using these tools in a number of basic and applied problems in cell biology. In addition, members of the group have used cell-based screens to identify small molecules that selectively differentiate and expand embryonic and adult stem cells and reprogram lineage-committed cells, as well as novel genes and small molecules that affect a number of physiologic and disease processes.

Chi-Huey Wong and his group further advance the fields of chemoenzymatic organic synthesis, chemical glycobiology, and the development of enzyme inhibitors. A new strategy for the synthesis of glycoproteins has been developed. The programmable 1-pot synthesis of oligosaccharides developed by this group has been further used in the assembly of glycoarrays for study of saccharides that bind to proteins. Members of this group also developed new probes to study glycosyltransferases and the roles of these enzymes in cancer.

Researchers in Dale Boger's laboratory continue their work on chemical synthesis; combinatorial chemistry; heterocycle synthesis; anticancer agents, such as vinblastine, cytostatin, chlorofusion, and yatakemycin; and antibiotics, such as vancomycin, teicoplanin, and ramoplanin.

Scientists in Kim Janda's laboratory focus on the impact of organic chemistry in specific biological systems. The targeted programs span a wide range of interests from immunopharmacotherapy to biological and chemical warfare to filarial infections such as 'river blindness' to quorum sensing in bacteria. Recent achievements include in vivo detection of antagonists of botulinum neurotoxins, the development of a cyclic peptide that homes to cancer cells as a drug delivery module, and the discovery of antibodies that can degrade the active component of marijuana.

M. Reza Ghadiri and his group are making important contributions in the design and study of a new generation of antimicrobial agents, based on self-assembling peptide nanotube architecture, to combat multidrug-resistant infections. In addition, members of the group continue to make novel contributions in several ongoing basic research endeavors, such as designing biosensors, developing molecular computation, designing self-reproducing systems, understanding the origins of life, and creating emergent chemical systems.

M.G. Finn and his group have pioneered the use of virus particles as chemical reagents and building blocks for nanochemical structures. This effort is directed toward the development of new diagnostics for disease and catalysts for organic reactions. Members of Dr. Finn's laboratory also develop and investigate new organic and organometallic reactions and use these reactions to synthesize biologically active compounds.

Jeff Kelly and his group are exploring the interface between chemistry, biology, and medicine. The aim of their projects is to understand the physical and biological basis of protein folding and the misfolding and aggregation processes that lead to age-associated neurodegenerative diseases. This information is used to develop new small-molecule therapeutic strategies for a variety of neurodegenerative diseases.

Anita Wentworth and the researchers in her laboratory are investigating the chemical basis of complex disease states and are synthesizing peptide- and small molecule–based therapeutic agents. These scientists focus on disease states in which inflammation and reactive oxygen species are prominent, such as atherosclerosis, Alzheimer's disease, and other diseases of aging.

Researchers in Floyd Romesberg's laboratory are using diverse techniques ranging from bioorganic and biophysical chemistry to bacterial and yeast genetics to understand and manipulate the process of evolution. Major efforts include designing unnatural base pairs and using directed evolution of DNA polymerases to efficiently synthesize unnatural DNA containing the base pairs, using spectroscopy to understand biological function and how it evolves, and understanding how induced and adaptive mutations contribute to evolution in eukaryotic and prokaryotic cells.

Phil Baran and his group recently developed extremely concise chemical solutions to the synthetic challenges posed by numerous families of marine natural products, including sceptrin, ageliferin, chartelline, haouamine, welwitindolinone, and the stephacidins. These syntheses are characterized by striking brevity, new biosynthetic postulates, the invention of new methods, and a minimum use or complete absence of protecting groups and superfluous oxidation-state manipulations.

The Frontiers in Chemistry Lecturers (18th Annual Symposium) for the 2006–2007 academic year were Brian M. Stoltz, California Institute of Technology; Dean Toste, University of California, Berkeley; Colin Nuckolls, Columbia University; and Eric T. Kool, Staford University. John Montgomery, University of Michigan, also visited Scripps as the 2006 Bristol-Myers Squibb Lecturer.