Chemistry

Chairman's Overview

K.C. Nicolaou, Ph.D.

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 which 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.

Chemistry at TSRI focuses on chemical synthesis and chemical biology, the two most relevant areas 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 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 unabated, establishing international visibility and attracting attention as evidenced by numerous lecture invitations, visits by outside scholars, and headline news in the media. The Institute for Scientific Information includes five of our chemistry department professors on their list of highly influential chemistry researchers worldwide.

Dr. Baran's laboratory is deeply interested in how the general challenge of chemoselectivity in organic chemistry can be answered through the auspices of total synthesis. His laboratory has developed extremely concise chemical solutions to the synthetic challenges posed by numerous natural product families, several of which can now be procured on a gram-scale. These syntheses systematically tackle the issue of chemoselectivity and are characterized by striking brevity, new biosynthetic postulates, the invention of new methodology, and a minimum use or complete absence of protecting groups and superfluous oxidation state manipulations.

Members of the Boger group 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.

Dr. 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 the Finn laboratory also develop and investigate new organic and organometallic reactions, and use these processes to synthesize biologically active compounds and functional materials.

The research in Dr. Fokin's group is centered on discovery and understanding of new and useful chemical reactivity. Catalytic reactions discovered in the group, such as click-type cycloadditions and reactions of stabilized carbenes, are used for the development of novel small molecule therapeutics, dendrimer-based diagnostic and drug delivery systems, and for studying complex biological systems both in vitro and in vivo.

Ghadiri's laboratory has made significant contributions in the design and study of a new generation of anticancer agents, based on conformationally restricted molecular scaffolds that potently and selectively inhibit histone deacetylase enzymes. In addition, members of the group continues to make novel contributions in several ongoing basic research endeavors such as biosensor designs, molecular computation, design of self-reproducing systems, understanding the origins of life, and design of emergent chemical systems.

The research efforts of the Janda laboratory are focused on studies at the interface of organic chemistry, molecular biology and medicine. More specifically, the laboratory takes both medicinal chemistry-based and immunopharmacotherapy-based approaches toward the discovery of bioactive agents for a wide variety of diseases. Recent targets include filarial infections such as river blindness, microbial pathogenesis, cancer, obesity, and drug abuse. The Janda laboratory has also made significant contributions to the identification of new and novel inhibitors against biological and chemical warfare agents.

Research in the Kelly group explores the interface between the chemistry, biology and medicine of proteome folding and maintenance. Projects aim to understand the physical and biological basis of protein folding, and the competitive misfolding and aggregation processes that lead to age onset neurodegenerative diseases. Comprehension of the biology of proteome maintenance is utilized to develop new small molecule therapeutic strategies for a variety of diseases, including neurodegenerative diseases.

Dr. Lerner and his group continue their groundbreaking research in chemical biology and its applications to chemistry, biology, and medicine.

The Nicolaou group continues explorations in chemical synthesis and chemical biology, focusing on the total synthesis of new anticancer agents, antibiotics, marine-derived neurotoxins, anti-malarial and anti-tuberculosis compounds, and other bioactive natural and designed molecules.

The members of the Rebek group devise biomimetic receptors for studies in molecular recognition. These include molecules that bind neurotransmitters and membrane components. Larger host receptors are capable of surrounding three or more molecular guests and act as chambers where their chemical reactions are accelerated. The group synthesizes small molecules that act as protein helix mimetics for pharmaceutical applications.

Ed Roberts, working with his group of young but talented medicinal chemists and in collaboration with world renowned Scripps scientists, continues to work to identify novel medicaments for disorders that currently have inadequate or no first line treatments. With an emphasis on childhood illnesses, Roberts is working with excellent progress on new medications to treat neurological disorders known as the Autistic spectrum disorders. He is also active in other disease areas such as epilepsy/seizures, neuropathic and chronic (cancer) pain, and inflammatory diseases such as Crohn's and inflammatory bowel disease (IBD).

Research in the Romesberg lab centers around using diverse techniques ranging from bioorganic and biophysical chemistry to synthesis and genetics to study biological systems and their evolution. Major efforts in the group include the design, synthesis and evaluation of unnatural base pairs and the directed evolution of DNA polymerases in an effort to expand the genetic alphabet; using synthesis, chemical biology, and genetics to identify and develop novel antibiotics; and using spectroscopy to understand protein dynamics and folding, and how they are tailored by evolution.

The Schultz group continues their research in chemistry and biology in multifaceted fronts of fundamental and applied nature.

Members of the Sharpless group continue endeavors to construct, through innovative chemistry and biology, libraries of novel compounds for biological screening and to discover and develop better catalysts for organic synthesis. Their click chemistry has had a major impact in many areas of the molecular sciences and continues to be an important focus of their research.

Members of the Wentworth group investigate the chemical basis of complex disease states and synthesize peptide and small molecule-based therapeutics. Their research is focused in disease states that have a prominent inflammatory and reactive oxygen species chemical component, such as atherosclerosis, Alzheimer's disease and other diseases of ageing.

Dr. Wong and his group further advance the fields of chemoenzymatic organic synthesis, chemical glycobiology and the development of enzyme inhibitors. The lab's efforts toward the synthesis of homogenous glycoproteins have continued, resulting in the extension of sugar-assisted ligation to glycopeptides bearing complex carbohydrates, a new thiol-free glycopeptide ligation method, the synthesis of MUC-1 glycopeptides, and the chemoenzymatic synthesis of defined glycoforms of the adhesion domain of the immune cell receptor CD2. In the latter case, a key trisaccharide motif was revealed that is essential for structure and folding. A quantitative glycan array method was developed, which was used to correlate CD1-glycolipid interactions with cytokine production, to measure antibody response in human sera to cancer-specific carbohydrate epitopes, and to dissect the binding of influenza hemagglutinin. Glycodendrons were prepared to mimic the carbohydrates on HIV in a continued effort to develop an HIV vaccine.

Research in Jin-Quan Yu's laboratory focuses on the development of C–H activation reactions as novel synthetic disconnections for chemical synthesis. In particular, they aim to discover new modes of reactivity that expand the scope of traditional C–H insertion processes to new classes of substrates, including abundant and broadly useful chemicals. To date, major advancements have been made in developing novel ligands and new catalytic oxidation systems to effect position-selective and enantioselective C–H functionalization. These chemical processes are finding applications in a range of different settings, including enabling expedient syntheses of drug-like molecules and biologically active natural products

The following internationally renowned scientists participated in the department as the Frontiers in Chemistry Lecturers (20th Annual Symposium) for the 2008–2009 academic year: Erik J. Sorensen, Princeton University; Huw Davies, Emory University; Carl Decicco, Bristol-Myers Squibb; and Ada Yonath, Weizmann Institute of Science (Israel). In addition, we enjoyed hosting the following professors at Scripps this past year: Eric Jacobsen (Harvard University) as the Aldrich Lecturer, Scott Denmark (University of Illinois, Urbana-Champaign) as the Bristol-Myers Squibb Lecturer, and Guy Bertrand (University of California, Riverside) as the Novartis Lecturer, and Hisashi Yamamoto (University of Chicago) as the Roche Lecturer.