Chemistry
Published by TSRI Press®. © Copyright 2005, The Scripps Research Institute. All rights reserved.
M. Reza Ghadiri, Ph.D., Professor, Department of Chemistry
Published by TSRI Press®. © Copyright 2005, The Scripps Research Institute. All rights reserved.
CHEMISTRY 2005 DEPAR TMENT OF CHEMISTRY
Hartmuth Kolb, Ph.D.** University of California Los Angeles, California
Chi-Huey Wong, Ph.D.* Ernest W. Hahn Professor and Chair in Chemistry
Jung-Mo Ahn, Ph.D.** University of Texas Dallas, Texas
Ramanarayanan Krishnamurthy, Ph.D. Associate Professor
Andrew Bin Zhou, Ph.D. Assistant Professor
Dariush Ajami, Ph.D.
Richard A. Lerner, M.D.**** President, Scripps Research Lita Annenberg Hazen Professor of Immunochemistry Cecil H. and Ida M. Green Chair in Chemistry
S TA F F S C I E N T I S T S
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S TA F F
K.C. Nicolaou, Ph.D.* Chairman Aline W. and L.S. Skaggs Professor of Chemical Biology Darlene Shiley Chair in Chemistry Phil Baran, Ph.D. Assistant Professor Dale L. Boger, Ph.D.* Richard and Alice Cramer Professor of Chemistry Bruce Clapham, Ph.D.** Abbott Laboratories Abbott Park, Illinois Tobin Dickerson, Ph.D. Assistant Professor Albert Eschenmoser, Ph.D.* Professor Sheng Ding, Ph.D. Assistant Professor M.G. Finn, Ph.D.* Associate Professor Valery Fokin, Ph.D. Assistant Professor
Lital Alfonta, Ph.D.
Byeong D. Song, Ph.D.
Toru Amaya, Ph.D.** Osaka University Osaka, Japan
Lubica Supekova, Ph.D.
Rajesh Ambasudhan, Ph.D.
I N S T R U M E N TAT I O N /
Masayuki Matsushita, Ph.D. Assistant Professor Evan Powers, Ph.D. Assistant Professor Julius Rebek, Jr., Ph.D.* Professor Director, The Skaggs Institute for Chemical Biology Ed Roberts, Ph.D. Professor
SERVICE FACILITIES
Stellios Arseniyadis, Ph.D.
Raj K. Chadha, Ph.D. Director, X-Ray Crystallography Facility
Gonen Ashkenasy, Ph.D.
Dee H. Huang, Ph.D. Director, Nuclear Magnetic Resonance Facility
Masato Atsumi, Ph.D.
Gary E. Siuzdak, Ph.D. Director, Mass Spectrometry Facility
Christoph Behrens, Ph.D.
Floyd E. Romesberg, Ph.D. Assistant Professor SENIOR RESEARCH
Peter G. Schultz, Ph.D.* Professor Scripps Family Chair
M. Reza Ghadiri, Ph.D.* Professor
K. Barry Sharpless, Ph.D.* W.M. Keck Professor of Chemistry
Inkyu Hwang, Ph.D. Assistant Professor
Anita Wentworth, Ph.D. Assistant Professor
Kim D. Janda, Ph.D.*** Professor Ely R. Callaway, Jr., Chair in Chemistry
Paul Wentworth, Jr., Ph.D. Professor
Narendra B. Ambhaikar, Ph.D.
A S S O C I AT E S
Ashraf Brik, Ph.D. Yanping Chen, Ph.D. Tobin Dickerson, Ph.D. Michael Meijler, Ph.D.
Nurit Ashkenasy, Ph.D.
Elizabeth Barrett, Ph.D.
Clay Bennett, Ph.D. Michael Best, Ph.D.** University of Tennessee Knoxville, Tennessee Jan Bieschke, Ph.D. Babu Boga, Ph.D. Anthony Boitano, Ph.D. Brant Boren, Ph.D. Daryl Bosco, Ph.D.
Jeffery W. Kelly, Ph.D.* Vice President, Academic Affairs Dean, Kellogg School of Science and Technology Lita Annenberg Hazen Professor of Chemistry
Published by TSRI Press®. © Copyright 2005, The Scripps Research Institute. All rights reserved.
Peter Wirsching, Ph.D.*****
R E S E A R C H A S S O C I AT E S
Ramzey Abujarour, Ph.D.
Mohua Bose, Ph.D.** Stanford University Stanford, California
S E C T I O N C O V E R F O R T H E D E P A R T M E N T O F C H E M I S T R Y : A single rotaxane struc-
ture created by threading and capturing a DNA-poly(ethylene glycol) strand inside an α-hemolysin transmembrane pore protein. This supramolecular system constitutes the basis of a research program to design a rapid pore-mediated single-molecule DNA-sequencing technology. Work done in the laboratory of M. Reza Ghadiri, Ph.D.
64 CHEMISTRY 2005
Patrick Braun, Ph.D.** University of Minnesota Minneapolis, Minnesota
Antonella Converso, Ph.D.
Rebecca Fraser, Ph.D.
Zhangyong Hong, Ph.D.
Jeromy Cottell, Ph.D.
Graeme Freestone, Ph.D.
Richard Hookey, Ph.D.
Andy Brogan, Ph.D.
James Crawford, Ph.D.
Yanwen Fu, Ph.D.
Daniel Horne, Ph.D.
Adrian Brunkhorst, Ph.D.
Matthew Cremeens, Ph.D.
Jim Fuchs, Ph.D.
Paul Bulger, Ph.D.
Ashton Cropp, Ph.D.** University of Maryland College Park, Maryland
Carmen Galan, Ph.D.** Massachusetts Institute of Technology Cambridge, Massachusetts
Che-Chang (Jeff) Hsu, Ph.D.** EMD Biosciences, Inc. San Diego, California
Kevin Bunker, Ph.D. Mark Bushey, Ph.D. Sara Butterfield, Ph.D. Edelmira Cabezas, Ph.D.** Intel Corp. Santa Clara, California
Francesco De Riccardis, Ph.D.** Università di Salerno Baronissi (SA), Italy
Jianmin Gao, Ph.D.
Tsui-Ling Hsu, Ph.D. Qihong Huang, Ph.D.** Wistar Institute Philadelphia, Pennsylvania
Mu-yun Gao, Ph.D. Zheng-Zheng Huang, Ph.D.
Konstantinos Dellios, Ph.D.** Chemistry Laboratory of the Government Larisa, Greece
Nathan Gianneschi, Ph.D. Amy Hurshman, Ph.D.
David Diaz-Diaz, Ph.D.
Arnaud Gissot, Ph.D.** Université Victor Segalen Bordeaux II Bordeaux, France
Christine Dierks, Ph.D.
Rajesh Grover, Ph.D.
Hayato Ishikawa, Ph.D.
Ross Denton, Ph.D.
Shen Gu, Ph.D.*****
Tetsuo Iwasawa, Ph.D.
Romyr Dominque, Ph.D.** Hoffmann-La Roche, Inc. Nutley, New Jersey
Sayam Sen Gupta, Ph.D.
Michael Jahnz, Ph.D.
Clemens Haas, Ph.D.
Wei Jin, Ph.D.
Song Byeong Doo, Ph.D.
Young Wan Ham, Ph.D.** Molecular Therapeutics, Inc. Ann Arbor, Michigan
Florian Kaiser*****
Akiyuki Hamasaki, Ph.D.
Gyungyoun Kim, Ph.D.
David Edmonds, Ph.D.
Wooseok Han, Ph.D.
Greg Elliott, Ph.D. Nile Emre, Ph.D.
Christophe Hardouin, Ph.D.** Oril Industry, SA Bolbec, France
Sang Jick Kim, Ph.D.** Korean Research Institute of Bioscience and Biotechnology Taejon, Korea
Simon Eppacher, Ph.D.
Frank Hauke, Ph.D.
Youhoon Chong, Ph.D.** Konkuk University Seoul, Korea
Lisa Eubanks, Ph.D.
Mark Hixon, Ph.D.
Raffaella Faraoni, Ph.D.
Benoit Colasson, Ph.D.** University of Pavia Pavia, Italy
Laura Flatauer, Ph.D.
Rebecca Holmberg, Ph.D.** Ionian Technologies, Inc. Upland, California
Alexandre Carella, Ph.D. Giacomo Carenzi, Ph.D.** Nerviano Medical Sciences Nerviana, Italy Michael Cassidy, Ph.D. Aileen Chang, Ph.D.** Kresge Library Scripps Research Shuo Chen, Ph.D. Heng Cheng, Ph.D.** FibroGen, Inc. South San Francisco, California Jodie Chin, Ph.D. Charles Cho, Ph.D. Younggi Choi, Ph.D.** Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, Connecticut
Kevin Cole, Ph.D.
Published by TSRI Press®. © Copyright 2005, The Scripps Research Institute. All rights reserved.
Wu Du, Ph.D.** Merck Research Laboratories Rahway, New Jersey
Der-Ren Hwang, , Ph.D. Giltae Hwang, Ph.D.
Michael Kelso, Ph.D.
Yoonkyung Kim, Ph.D.*****
James Fletcher, Ph.D.** Creighton University Omaha, Nebraska
Sukwon Hong, Ph.D. Wang Hong, Ph.D.
Theocharis Koftis** Pharmathen Pharmaceuticals Thessaloniki, Greece Ravinder Reddy Kondreddi, Ph.D. Antoni Krasinski, Ph.D.** ChemoCentryx, Inc. Mountain View, California
CHEMISTRY 2005
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Andreas Krebs, Ph.D.** BASF Ludwigshafen, Germany
Tao Tao Ling** Nereus Pharmaceuticals, Inc. San Diego, California
Robert Milburn, Ph.D.
Tülay Polat, Ph.D.
Kyung-Hoon Min, Ph.D.
Sreenivas Punna, Ph.D.
Grover Rajesh Kumar, Ph.D.
Jun Liu, Ph.D.
Christos A. Mitsos, Ph.D.
Jane Kuzelka, Ph.D.
Junjie Liu, Ph.D.** AMSI San Diego, California
Gopi Kumar Mittapalli, Ph.D.
Longwu Qi, Ph.D.** Prolexys Pharmaceuticals, Inc. Salt Lake City, Utah
Lionel Moisan, Ph.D.
Daniela Radu, Ph.D.
Lei Liu, Ph.D.
Ann Montero, Ph.D.
Nicole Rahe, Ph.D.
Wenshe Liu, Ph.D.
Shai Rahimipour, Ph.D.
Surakattula Murali Mohan Reddy, Ph.D.
Carolina Martinez Lamenca, Ph.D. Eltepu Laxman, Ph.D.** MediVas, LLC San Diego, California
Ying (Cindy) Liu, Ph.D.
Yasutaka Morita, Ph.D.** Kinki University Fukuoka, Japan
Byong Se Lee, Ph.D.** Asian Medical Center Seoul, Korea
Dimitrios Lizos, Ph.D.
Mridul Mukherji, Ph.D.
Hing Ken Lee, Ph.D.*****
Jon Loren, Ph.D.** Ligand Pharmaceuticals, Inc. San Diego, California
Oscar Munoz, Ph.D.** Universidad Veracruzana Veracruz, México
Jinq-Chyi Lee, Ph.D. Jongkook Lee, Ph.D.
Hendrick Luesch, Ph.D.** University of Florida Gainesville, Florida
Ki-Bum Lee, Ph.D. Hongzheng (Eric) Ma, Ph.D. Lac Lee, Ph.D** Novartis Institutes for Biomedical Research Inc. Cambridge, Massachusetts Sang Hyeup Lee, Ph.D.** Korean Research Institute of Bioscience and Biotechnology Taejon, Korea
Sunil Mandal, Ph.D.** Acenta Discovery, Inc. Tucson, Arizona Nello Mainolfi, Ph.D. Roman Manetsch, Ph.D. Enrique Mann, Ph.D.
Sanghyup Lee, Ph.D.
Andrew Myles, Ph.D. Joonwoo Nam, Ph.D. Sridhar Narayan, Ph.D. Daniel Nicoletti, Ph.D. Alain Noncovich, Ph.D. Yasuo Norikane, Ph.D. Mehdi Numa, Ph.D. Barun Okram, Ph.D.
Dalit Rechavi-Robinson, Ph.D.
Yosup Rew, Ph.D.** Amgen, Inc. Thousand Oaks, California Sebastien Richeter, Ph.D.** Université Montpellier II Montpellier, France Stefanie Roeper, Ph.D. F. Anthony Romero, Ph.D. Youngha Ryu, Ph.D. Riccardo Salvio, Ph.D. Pradip Sasmal** Dr. Reddy’s Laboratories, Ltd. Hyderabad, India
Felix Marr, Ph.D. Chunmei Li, Ph.D. ** Stephen F. Austin State University Nacogdoches, Texas Ke Li, Ph.D. Yongkai Li, Ph.D.** Ligand Pharmaceuticals, Inc. San Diego, California Antonietta M. Lillo, Ph.D.** Los Alamos National Laboratory Los Alamos, New Mexico Yeon-Hee Lim, Ph.D.
Published by TSRI Press®. © Copyright 2005, The Scripps Research Institute. All rights reserved.
Hideki Onagi, Ph.D.***** Yazmin Osornio, Ph.D.
Alessandro Scarso, Ph.D.** Università Cà Foscari di Venezia Venice, Italy
Charles Papageorgiou, Ph.D.
Patrick Schanen, Ph.D.
Laxman Pasunoori, Ph.D.
Stefan Schiller, Ph.D.
Andrew McPherson, Ph.D.** TargeGen, Inc. San Diego, California
Goran Petrovic, Ph.D.
Edoardo Menozzi, Ph.D.
Steven Pfeiffer, Ph.D.** Gilead Foster City, California
Daniel Schlawe, Ph.D.** Syncom BV Groningen, the Netherlands
Shigeo Matsuda, Ph.D. Laura McAllister, Ph.D. Kathleen McKenzie, Ph.D.
Sergio Meth, Ph.D.** Federal University of Rio de Janeiro Rio de Janeiro, Brazil
Jared Piper, Ph.D. Suresh Pitram, Ph.D.
Michael Schramm, Ph.D. Akira Shigenaga, Ph.D.** Tokushima University Tokushima, Japan
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Dongwoo Shin, Ph.D.** Samsung Seoul, Korea
Gregory Watt, Ph.D.** Nature Chemical Biology Cambridge, Massachusetts
Junhwa Shin, Ph.D.
Lisa Whalen, Ph.D.
Sebastian Steiniger, Ph.D.
Matthew Whiting, Ph.D.
Xiuwen Zhu, Ph.D. Joerg Zimmermann, Ph.D.
Makoto Yamashita, Ph.D. Takeda Chemical Industries, Ltd. Osaka, Japan
V I S I T I N G I N V E S T I G AT O R S
Shula Stokols, Ph.D.
Aarron Willingham, Ph.D.
Ji Young Suk, Ph.D.
R. Luke Wiseman, Ph.D.
Daniel Summerer, Ph.D. Xiowen Sun** Lanzhou University Lanzhou, China Leo Takaoka, Ph.D.
Margarita Wuchrer, Ph.D. Hui Xiong, Ph.D.** University of Pennsylvania Philadelphia, Pennsylvania
Trond Vidar Hansen, Ph.D.** University of Oslo Oslo, Norway
Wen Xiong, Ph.D.
Bumpei Hatano, Ph.D.** Yamagata University Yonezawa, Japan
Chung-Yi Wu, Ph.D.
Masamichi Yamanaka, Ph.D.** Shizuoka University Shizuoka, Japan
Eric Tippmann, Ph.D.
Ryu Yamasaki, Ph.D.
Laurent Trembleau, Ph.D.** University of Aberdeen Aberdeen, Scotland
Shuyuan Yao, Ph.D.
Meng-Lin Tsao, Ph.D.
Yong Sik Yoo, Ph.D.
Craig Turner, Ph.D.
Ninghui Yu, Ph.D.** Serono, Inc. Rockland, Massachusetts
Elke Ullrich, Ph.D.** Syncom BV Groningen, the Netherlands Jan Van Maarseveen,** Universiteit van Amsterdam Amsterdam, the Netherlands Juraj Velcicky, Ph.D. David Vodak, Ph.D.** Bend Research, Inc. Bend, Oregon
Robert M. Yeh, Ph.D.
Tomoyasu Hirose, Ph.D.** The Kitasato Institute Tokyo, Japan
Jiayu Liao, Ph.D. Genomics Institute of the Novartis Research Foundation San Diego, California Jie Li, Ph,D.*****
Dawei Yue, Ph.D.
Huaqiang Zeng, Ph.D. Qing-Hai Zhang, Ph.D.** Department of Molecular Biology Scripps Research
Masayuki Oda, Ph.D. Kyoto Prefectural University Kyoto, Japan Masaaki Sawa, Ph.D. Dainippon Pharmaceuticals Co., Ltd. Osaka, Japan
Alexandro Volonterio, Ph.D.
Yuanxiang Zhao, Ph.D.
Masakazu Sugiyama, Ph.D. Ajinomoto Co., Inc. Kawasaki-shi, Japan
Jiangyun Wang, Ph.D.
LianXing Zheng, Ph.D.** Models of Disease Center Cambridge, Massachusetts
Shin-Ichi Takanashi, Ph.D. Mitsubishi Pharma Corporation Osaka, Japan
Xiaolong Wang, Ph.D.
Published by TSRI Press®. © Copyright 2005, The Scripps Research Institute. All rights reserved.
Qisheng Zhang, Ph.D.
Suresh Mahajan, Ph.D.
* Joint appointment in The Skaggs Institute for Chemical Biology ** Appointment completed; new location shown *** Joint appointments in The Skaggs Institute for Chemical Biology and the Department of Immunology **** Joint appointments in The Skaggs Institute for Chemical Biology and the Department of Molecular Biology ***** Appointment completed
Jiyong Hong, Ph.D. Genomics Institute of the Novartis Research Foundation San Diego, California
Zhanqian Yu, Ph.D.
Felix Zelder, Ph.D.
Jon Ashley Maria-Teresa Dendle
Masakazu Fujio, Ph.D. Mitsubishi Pharma Corporation Yokohama, Japan
Wenjun Tang** Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, Connecticut
Jim Turner, Ph.D.
S C I E N T I F I C A S S O C I AT E S
Luda Bazhenova, M.D. Moores Cancer Center La Jolla, California
CHEMISTRY 2005 67
K.C. Nicolaou, Ph.D.
Chairman’s Overview s 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 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
A
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(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 2004, the Institute for Scientific Information ranked 4 members of the department as highly cited researchers (in the top 100 worldwide); 2 of the 4 are among the top 35. Dr. 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 research of the group recently was expanded to include the fundamental chemistry of polyoxygen species. Members of the Sharpless 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 the La Jolla–based Eschenmoser group advance in experimental studies on the chemical etiology of nucleic acid structure by investigating nucleic acid alternatives that have novel backbone structures unrelated to the canonical phosphodiester-based oligonucleotide systems. Members of my group continue explorations of chemical synthesis and chemical biology, focusing on the total synthesis of new anticancer agents, antibiotics, marine-derived neurotoxins, antimalarial compounds, antifeedant agents, other biologically active natural products, solid-phase synthesis, and combinatorial chemistry. 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 can surround 3 or more molecular guests and act as chambers where the chemical reactions of the guests are accelerated. Scientists in the Schultz laboratory continue to expand the genetic code. Using unique triplet and quadruplet codons, they have genetically encoded more than 30 novel amino acids in bacteria, yeasts, and mammalian cells. Dr. Wong and his group further advance the fields of chemoenzymatic organic synthesis, chemical glycobiology, and the development of enzyme inhibitors. A new
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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 in microtiter plates for study of saccharides and aminoglycosides that bind to proteins and RNA, respectively. This group also developed new inhibitors of glycosyltransferases, sulfotransferases, and the HIV protease. Members of the Boger group continue their work on chemical synthesis; combinatorial chemistry; heterocycle synthesis; anticancer agents, such as fostriecin and yatakemycin; and antibiotics, such as vancomycin, teicoplanin, and ramoplanin. Scientists in the Janda laboratory focus on the impact of organic chemistry in specific biological systems. Their targeted programs span a wide range of interests, from drug addiction to biological and chemical warfare agents to catalytic antibodies to combinatorial chemistry. Their recent achievements include the discovery that a secondary nicotine metabolite can inhibit the formation of the fibrils characteristic of Alzheimer’s disease, the biological validation of a common quorumsensing molecule, and a high-throughput assay based on a blue fluorescent antibody sensor. Dr. Ghadiri and members of his laboratory are making significant contributions in the design and study of a new generation of antimicrobial agents, based on selfassembling peptide nanotube architecture, to combat multidrug-resistant infections. In addition, they continue to make novel contributions in several ongoing basic research endeavors, such as design of biosensors, molecular computation, design of self-reproducing systems, understanding the origins of life, and design of emergent chemical systems. 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. Research by members of the Kelly group emphasizes the role of protein conformational changes in neurodegenerative disease and the alteration of these processes through the design and synthesis of small molecules. These scientists also take advantage of the power of chemistry and biology to study β-sheet folding. An emerging interest is self-assembling biomaterials made from peptides and proteins. Published by TSRI Press®. © Copyright 2005, The Scripps Research Institute. All rights reserved.
Researchers in the Romesberg laboratory are using diverse techniques ranging from bioorganic and biophysical chemistry to bacterial and yeast genetics to understand and manipulate evolution. Major efforts include the design of unnatural base pairs and the 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. Dr. Baran and his group have made extraordinary contributions in synthetic organic chemistry. In only 2 years, they have invented practical chemical solutions to several long-standing synthetic challenges of great interest, such as the biologically active natural products pyrrole-imidazole alkaloids, stephacidins, welwitindolinones, and chartellines. The Frontiers in Chemistry Lecturers (17th Annual Symposium) for the 2004–2005 academic year were Carolyn Bertozzi, University of California, Berkeley; EiEichi Negishi, Purdue University; Thomas Steitz, Yale University; and David Liu, Harvard University. Jean-Marie Lehn, ISIS, Université Louis Pasteur, Strasbourg, and Collège de France, Paris, also visited Scripps this year as the 2004 Merck lecturer.
CHEMISTRY 2005
INVESTIGATORS’ R EPORTS Practical Total Synthesis of Natural Products P.S. Baran, N.B. Ambhaikar, C.A. Mitsos, K. Li, R.A. Shenvi, D.P. O’Malley, N.Z. Burns, M.P. DeMartino, C.A. Guerrero, B.D. Hafensteiner, D.W. Lin, J.M. Richter
rom penicillin to paclitaxel (Taxol), natural products have an unparalleled track record in the betterment of human health. In fact, 9 of the top 20 best-selling drugs were either inspired by or derived from natural products. Even the best-selling drug of all time, atorvastatin (Lipitor), was based on a natural product lead. Total synthesis, the art and science of recreating these entities in the laboratory, invariably leads to fundamental discoveries in chemistry, biology, and medicine. We focus on solving interesting challenges in the total synthesis of natural products and on bridging gaps in synthetic capabilities by inventing new reactions. Through judicious target selection and creative retrosynthetic analyses, total synthesis becomes an engine for discovery that drives organic chemistry to new levels of sophistication and practicality. Synthetic organic chemistry requires tremendous ingenuity, artistic taste, experimental acumen, persistence, and character. Not surprisingly, drug development relies on the expertise of researchers who have these characteristics. Although we focus entirely on educating students in fundamental chemistry, we also collaborate with expert biologists to explore the medicinal potential of newly synthesized natural products and the products’ analogs. Recently completed total syntheses (Fig. 1) include the anticancer agents stephacidins A and B and avrainvillamide, the antibacterial agents sceptrin and ageliferin, and several members of the bioactive fischerindole and hapalindole indole alkaloid family. Current natural product targets (Fig. 2) include chartelline C, welwitindolinone A, haouamine A, strictamine, axinellamine, and sarcodonin.
F
PUBLICATIONS Baran, P.S., Guerrero, C.A., Ambhaikar, N.B., Hafensteiner, B.D. Short, enantioselective total synthesis of stephacidin A. Angew. Chem. Int. Ed. 44:606, 2005. Baran, P.S., Guerrero, C.A., Hafensteiner, B.D., Ambhaikar, N.B. Total synthesis of avrainvillamide (CJ-17,665) and stephacidin B. Angew. Chem. Int. Ed. 44:3892, 2005.
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F i g . 1 . Recently completed total syntheses.
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bioorganic and medicinal chemistry, the study of DNAagent interactions, and the chemistry of antitumor antibiotics. We place a special emphasis on investigations to define the structure-function relationships of natural or designed organic agents. SYNTHETIC METHODS
Central to much of our work are investigations to develop and apply the hetero Diels-Alder reaction, including the use of heterocyclic and acyclic azadienes (Fig. 1), the thermal reactions of cyclopropenone ketals, intermolecular and intramolecular acyl radical–alkene addition reactions, medium- and large-ring cyclization technology, and solution-phase combinatorial chemistry. In each instance, the development of the methods represents the investigation of chemistry projected as a key element in the synthesis of a natural or designed agent.
F i g . 1 . N-Sulfonyl-1-aza-1,3-butadiene Diels-Alder reaction. F i g . 2 . Ongoing natural product total syntheses. Baran, P.S., Richter, J.M., Lin, D.W. Direct coupling of pyrroles with carbonyl compounds: short, enantioselective synthesis of (S)-ketorolac. Angew. Chem. Int. Ed. 44:609, 2005. Baran, P.S., Shenvi, R.A., Mitsos, C.A. A remarkable ring contraction en route to the chartelline alkaloids. Angew. Chem. Int. Ed. 44:3714, 2005.
Synthetic and Bioorganic Chemistry D.L. Boger, S.B. Boga, K. Bunker, K. Capps, H. Cheng, Y. Choi, Y. Chong, R. Clark, J. Cottell, B. Crowley, J. DeMartino, R. Dominique, W. Du, G. Elliott, J. Fuchs, J. Garfunkle, Y. Ham, A. Hamasaki, W. Han, N. Haq, C. Hardouin, S. Hong, D. Horne, I. Hwang, H. Ishikawa, W. Jin, D. Kastrinsky, M. Kelso, G. Kim, B. Lawhorn, S. Lee, Y. Li, K. MacMillan, J. Nam, S. Pfeiffer, Y. Rew, A. Romero, M. Schnermann, D. Shin, C. Slown, L. Takaoka, H. Tao, M. Tichenor, J. Trzupek, J. Velcicky
T
he research interests of our group include the total synthesis of natural products, development of new synthetic methods, heterocyclic chemistry,
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T O TA L S Y N T H E S I S O F N AT U R A L P R O D U C T S
Efforts are under way on the total synthesis of a number of natural products that constitute agents in which we have a specific interest. Representative agents currently under study include (+)-CC-1065 and functional analogs; the duocarmycin class of antitumor antibiotics, including yatakemycin; tropoloalkaloids; prodigiosin and roseophilin; the deoxybouvardin and RA-I class of antitumor agents; vancomycin, teicoplanin, ristocetin, chloropeptins and related agents; ramoplanin; the luzopeptins, quinoxapeptins, thiocoraline, BE-22179 and sandramycin; bleomycin A2 and functional analogs; HUN-7293; chlorofusin; CI-920 (fostriecin); the combretastatins; storniamide A; phomazarin; ningalins; lamellarin O; lukianol A; piericidins; nothapodytine and mappicine; rubrolone; and vinblastine (Figs. 2 and 3). BIOORGANIC CHEMISTRY
The agents listed in the previous paragraph were selected on the basis of their properties; in many instances, they are agents related by a projected property. For example, (+)-CC-1065 and the duocarmycins are antitumor antibiotics and related sequence-selective DNA minor groove alkylating agents. Representa-
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F i g . 3 . Additional recent total syntheses.
F i g . 2 . Recent total syntheses.
tive of such efforts, studies to determine the structural features of (+)-CC-1065 and the duocarmycins that Published by TSRI Press®. © Copyright 2005, The Scripps Research Institute. All rights reserved.
contribute to the sequence-selective DNA alkylation properties of these agents have resulted in the identification of a unique source of catalysis for the DNA alkylation reaction. Efforts are under way to develop DNA
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cross-linking agents of a predefined cross-link, to further understand the nature of the noncovalent and covalent interactions between agents and DNA, and to apply this understanding to the de novo design of DNA-binding and DNA-effector agents. Techniques for the evaluation of the agent-DNA binding and alkylation properties, collaborative efforts in securing biological data, nuclear magnetic resonance structures of DNA-agent complexes, molecular modeling, and studies of DNA-agent interactions are integral parts of the program. Additional ongoing studies include efforts to define the fundamental basis of the DNA-binding or cleavage properties of bleomycin A2, sandramycin, and the luzopeptins; to design inhibitors of the folate-dependent enzymes glycinamide ribonucleotide transformylase and aminoimidazole carboxamide ribonucleotide transformylase as potential antineoplastic agents; to establish the chemical and biological characteristics responsible for the sleep-inducing properties of the endogenous lipid oleamide; to inhibit tumor growth through inhibition of angiogenesis; to inhibit aberrant gene transcription associated with cancer; and to control intracellular signal transduction through the discovery of antagonists or agonists that affect protein-protein interactions, including receptor dimerization. PUBLICATIONS Chen, L., Yuan, Y., Helm, J.S., Hu, Y., Rew, Y., Shin, D., Boger, D.L., Walker, S. Dissecting ramoplanin: mechanistic analysis of synthetic ramoplanin analogues as a guide to the design of improved antibiotics. J. Am. Chem. Soc. 126:7462, 2004. Crowley, B.M., Mori, Y., McComas, C.C., Tang, D., Boger, D.L. Total synthesis of the ristocetin aglycon. J. Am. Chem. Soc. 126:4310, 2004. Ham, Y.W., Boger, D.L. A powerful selection assay for mixture libraries of DNA alkylating agents. J. Am. Chem. Soc. 126:9194, 2004. Kastrinsky, D.B., Boger, D.L. Effective asymmetric synthesis of 1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]indol-4-one (CBI). J. Org. Chem. 69:2284, 2004. Lee, P.S., Du, W., Boger, D.L., Jorgensen, W.L. Energetic preferences for α,β versus β,γ unsaturation. J. Org. Chem. 69:5448, 2004. Lichtman, A.H., Leung, D., Shelton, C.C., Saghatelian, A., Hardouin, C., Boger, D.L., Cravatt, B.F. Reversible inhibitors of fatty acid amide hydrolase that promote analgesia: evidence for an unprecedented combination of potency and selectivity. J. Pharmacol. Exp. Ther. 311:441, 2004. Lillo, A.M., Sun, C., Gao, C., Ditzel, H., Parrish, J., Gauss, C.-M., Moss, J., Felding-Habermann, B., Wirsching, P., Boger, D.L., Janda, K.D. A human single-chain antibody specific for integrin α3β1 capable of cell internalization and delivery of antitumor agents. Chem. Biol. 11:897, 2004. Parrish, J.P, Hughes, T.V., Hwang, I., Boger, D.L. Establishing the parabolic relationship between reactivity and activity for derivatives and analogues of the duocarmycin and CC-1065 alkylation subunits. J. Am. Chem. Soc. 126:80, 2004. Parrish, J.P., Trzupek, J.D., Hughes, T.V., Hwang, I., Boger, D.L. Synthesis and evaluation of N-aryl and N-alkenyl CBI derivatives. Bioorg. Med. Chem. 12:5845, 2004. Rew, Y., Shin, D., Hwang, I., Boger, D.L. Total synthesis and examination of three key analogues of ramoplanin: a lipoglycodepsipeptide with potent antibiotic activity. J. Am. Chem. Soc. 126:1041, 2004.
Published by TSRI Press®. © Copyright 2005, The Scripps Research Institute. All rights reserved.
Shin, D., Rew, Y., Boger, D.L. Total synthesis and structure of the ramoplanin A1 and A3 aglycons: two minor components of the ramoplanin complex. Proc. Natl. Acad. Sci. U. S. A. 101:11977, 2004. Tao, H., Hwang, I., Boger, D.L. Multidrug resistance reversal activity of permethyl ningalin B amide derivatives. Bioorg. Med. Chem. Lett. 14:5979, 2004. Tichenor, M.S., Kastrinsky, D.B., Boger, D.L. Total synthesis, structure revision, and absolute configuration of (+)-yatakemycin. J. Am. Chem. Soc. 126:8396, 2004. Tse, W.C., Boger, D.L. A fluorescent intercalator displacement assay for establishing DNA binding selectivity and affinity. Acc. Chem. Res. 37:61, 2004. Tse, W.C., Boger, D.L. Sequence-selective DNA recognition: natural products and nature’s lessons. Chem. Biol. 11:1607, 2004.
Chemical and Functional Genomic Approaches to Regenerative Medicine S. Ding, R. Abu-Jarour, R. Ambasudhan, A. Brunkhorst, P. Descargues, C. Despon, N. Emre, H.S. Hahm, S. Hilcove, J. Hsu, S. Takanashi, W. Xiong, S. Yao, D. Yue, Y. Zhao, X. Zhu
ecent advances in stem cell biology may make possible new approaches for the treatment of a number of diseases, including cardiovascular disease, neurodegenerative disease, musculoskeletal disease, diabetes, and cancer. These approaches could involve cell replacement therapy and/or drug treatment to stimulate the body’s own regenerative capabilities by promoting survival, migration/homing, proliferation, and differentiation of endogenous stem/progenitor cells. However, such approaches will require identification of renewable cell sources of engraftable functional cells, an improved ability to manipulate proliferation and differentiation of stem cells, and a better understanding of the signaling pathways that control the fate of stem cells. Equipped with large arrayed molecular libraries— combinatorial chemical libraries (>100,000 discrete and diverse small molecules), cDNA overexpression libraries (>30,000 human and mouse genes), and small interfering RNA libraries (targeting >20,000 human and mouse genes)—and a high-throughput screening platform, we are developing and integrating chemical and functional genomic tools to study stem cell biology and regeneration. We screen these libraries to identify small molecules and genes that can control the fate of stem cells in various systems, including (1) self-renewal, as well as directed neuronal, cardiac and
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CHEMISTRY 2005
pancreatic differentiations of pluripotent mouse and human embryonic stem cells; (2) directed neuronal differentiation and subtype neuron specification of human and rodent neural stem cells; (3) directed differentiation of mesenchymal stem cells to osteogenic, adipogenic, chondrogenic, and myogenic lineages; (4) functional proliferation of adult cardiomyocytes and islets/beta cells; (5) cellular plasticity and dedifferentiation of lineage-restricted somatic cells; and (6) developmental signaling pathways. In addition, we are doing systemic biochemical and cellular studies, including detailed investigations of the structure-activity relationship, affinity chromatography for target identification, genome-wide expression analysis, and cDNA and/or RNA interference complementation screens to map signaling pathways, to characterize the molecular mechanism of these identified small molecules and genes. The results may ultimately facilitate the therapeutic application of stem cells and the development of small-molecule drugs to stimulate tissue and organ regeneration in vivo.
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us to consider the triazines (2,4-diamino-triazines and their oxygen analogs) as alternative nucleobases that may be able to function as informational base pairs through a type of hydrogen-bond arrangement that differs from the canonical Watson-Crick type with its pairing axis parallel to the nucleosidic bond. Because carboxyl groups can easily be converted to suitably functionalized triazine rings, a large variety of oligomer backbones tagged with informational triazines (instead of conventional nucleobases) could be envisioned (Fig. 1). In collaboration with B. Han, Swiss Federal Institute of Technology, Zürich, Switzerland, we developed the triazination of the carboxyl group of a variety of α-amino acids such as glycine, serine, cysteine, aspartic acid, glutamic acid, β-amino-alanine, and α-carboxy-glycine to produce correspondingly triazine-tagged building blocks of potentially informational oligomers.
PUBLICATIONS Chen, S., Zhang, Q., Wu, X., Schultz, P.G., Ding, S. Dedifferentiation of lineagecommitted cells by a small molecule. J. Am. Chem. Soc. 126:410, 2004. Ding, S., Schultz, P.G. A role for chemistry in stem cell biology. Nat. Biotechnol. 22:833, 2004. Liu, J., Wu, X., Mitchell, B., Kintner, C., Ding, S., Schultz, P.G. A small-molecule agonist of the Wnt signaling pathway. Angew. Chem. Int. Ed. 44:1987, 2005. Wu, X., Ding, S., Ding, Q., Gray, N.S., Schultz P.G. Small molecules that induce cardiomyogenesis in embryonic stem cells. J. Am. Chem. Soc. 126:1590, 2004. Wu, X., Walker, J., Zhang, J., Ding, S., Schultz, P.G. Purmorphamine induces osteogenesis by activation of the hedgehog signaling pathway. Chem. Biol. 11:1229, 2004. Zheng, L., Liu, J., Batalov, S., Zhou, D., Orth, A., Ding, S., Schultz, P.G. An approach to genomewide screens of expressed small interfering RNAs in mammalian cells, Proc. Natl. Acad. Sci. U. S. A. 101:135, 2004.
F i g . 1 . 2,4-Diamino-triazine–tagged oligomeric systems.
O L I G O M E R S B A S E D O N T R I A Z I N E - TA G G E D BACKBONES
Chemical Etiology of the Structure of Nucleic Acids A. Eschenmoser, R. Krishnamurthy, O. Munoz, H. Xiong, G. Kumar, F. De Riccardis, R. Kondreddi, S. Eppacher, J. Nandy
D
uring the past year, we worked on the following projects.
T R I A Z I N E - TA G G E D A M I N O A C I D D E R I VAT I V E S
Our earlier work on the synthesis of C-nucleosides with a family of allopurines (formerly isopurines) led Published by TSRI Press®. © Copyright 2005, The Scripps Research Institute. All rights reserved.
Of the 2 planned variants (compounds 1 and 2 in Fig. 1) of ethylenediamine-based oligomer systems containing triazine as recognition elements, we were able to synthesize and study oligomers (up to dodecamer) of 1 of them (2 in Fig. 1). As expected, oligomers of this chemical structure underwent efficient cross-pairing with polyuracil (RNA) and polythymine (DNA) (Table 1). However, to our surprise, the backbones of oligomers of this type were unstable because of a triazine-assisted eliminative fragmentation. A comparative conformational analysis relative to RNA (tagged with the conventional nucleobases) of oligomer backbones tagged with triazines predicted that oligodipeptides of type 2 and 4 (Fig. 1) might be
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T a b l e 1 . T m values of duplexes formed by the triazine-tagged oligomers 2–5 with RNA and DNA*
System Tm (°°C) 2 12-mer 3 6-mer 12-mer 4 6-mer 12-mer 5 8-mer 12-mer
DNA poly(T)
RNA poly(U)
DNA d(T 12)
RNA r(T 12)
Organic, Materials, and Analytical Chemistry M.G. Finn, W.G. Lewis, D. Díaz, S. Punna, V. Rodionov, S. Sen Gupta
44.1†
29.2†
30.3†
28.5†
