News and Publications
|K.C. Nicolaou, Ph.D. ||Member and Chairman, Aline W. and L.S. Skaggs Professor of Chemical Biology, Darlene Shiley Chair in Chemistry |
|Dale L. Boger, Ph.D. ||Member/ Richard and Alice Cramer Professor of Chemistry |
|Albert Eschenmoser, Ph.D.* ||Member |
|M. Reza Ghadiri, Ph.D ||Associate Member |
|Hyunsoo Han, Ph.D. ||Assistant Member |
|Donald M. Hilvert, Ph.D. ||Member, Janet and Keith Kellogg Professor of Chemistry |
|Pui Tong Ho, Ph.D. ||Assistant Member |
|Kim D. Janda, Ph.D. ||Member, Ely R. Callaway, Jr., Chair in Chemistry |
|Gerald F. Joyce, M.D., Ph.D.** ||Member |
|Peter A. Kast, Ph.D. ||Assistant Member |
|Jeffery W. Kelly, Ph.D.* ||Member, Lita Annenberg Hazen Professorship in Chemistry |
|Richard A. Lerner, M.D. ||President, TSRI/ Lita Annenberg Hazen Professor of Immunochemistry, Cecil H. and Ida M. Green Chair in Chemistry |
|Tianhu Li, Ph.D. ||Assistant Member |
|Julius Rebek, Jr., Ph.D.* ||Member, Director, The Skaggs Institute for Chemical Biology |
|Pamela Sears, Ph.D. ||Assistant Member |
|K. Barry Sharpless, Ph.D. ||Member, W.M. Keck Professor of Chemistry |
|Erik Sorensen, Ph.D.* ||Assistant Member |
|Paul Wentworth, Ph.D. ||Assistant Member |
|Peter Wirsching, Ph.D.** ||Associate Member |
|Chi-Huey Wong, Ph.D. ||Member, Ernest W. Hahn Professor and Chair in Chemistry |
|Zhen Yang, Ph.D. ||Assistant Member |
INSTRUMENTATION/ SERVICE FACILITIES
|Raj K. Chadha, Ph.D. ||Director, X-Ray Crystallography Facility |
|Dee H. Huang, Ph.D. ||Director, Nuclear Magnetic Resonance Facility |
|Gwo-Jenn Shen, Ph.D. ||Director, Fermentation Facility |
|Gary E. Siuzdak, Ph.D. ||Director, Mass Spectrometry Facility |
|Hans Adolfsson, Ph.D. |
|Costas Agrios, Ph.D. || |
|Brian M. Aquila, Ph.D. || |
|Mufti Asif-Ulah, Ph.D.*** ||University of Karachi, Karachi, Pakistan |
|Richard T. Beresis, Ph.D. || |
|Thorsten Berg, Ph.D. || |
|Lee Bouton, Ph.D.*** ||Parke-Davis Neuroscience Research Centre, Cambridge, England |
|Robert M. Borzilleri, Ph.D.*** ||Bristol-Myers Squibb Pharmaceutical Institute, Princeton, NJ |
|Stefan Braese, Ph.D. |
|Oliver Bruemmer, Ph.D. |
|Klas Broo. Ph.D. |
|Milan Bruncko, Ph.D.*** ||Abbott Laboratories, Chicago, IL |
|Jillian M. Buriak, Ph.D.*** ||Purdue University, West Lafayette, IN |
|René A. Castro, Ph.D. |
|Wenying Chai, Ph.D. |
|Han-Ting Chang, Ph.D.*** ||University of California, Berkeley, CA |
|Shaoqing Chen, Ph.D. |
|Xin-Jie Chu, Ph.D.*** ||Hoffmann-La Roche, Nutley, NJ |
|Christopher Coperet, Ph.D. |
|Anita Datta, Ph.D. |
|Arun Datta, Ph.D. |
|Ruprecht K. Diess, Ph.D. |
|Pierre Ducray, Ph.D. |
|Hicham Fenniri, Ph.D.*** ||Purdue University, West Lafayette, IN |
|Ray Finlay, Ph.D. |
|Alexander Flohr, Ph.D. |
|Peter F. Gaertner, Ph.D.*** ||Vienna University of Technology, Vienna, Austria |
|Changshou Gao, Ph.D. |
|Dennis Gravert, Ph.D. |
|Corinna Grisostomi, Ph.D. |
|Darin Gustin, Ph.D. |
|Andreas Gypser, Ph.D.*** ||BASF AG, Ludwigshafen, Germany |
|Michael Haerter, Ph.D.*** ||Bayer AG, Wuppertal, Germany |
|Renate Hannak, Ph.D. |
|Curtis Harwig, Ph.D. |
|Jens Hasserodt, Ph.D. |
|David Hepworth, Ph.D. |
|Seijiro Hosokawa, Ph.D. |
|Robert Huber, Ph.D. |
|Shang-Cheng Hung, Ph.D. |
|Christoph Huwe, Ph.D. |
|Jill Jablonowski, Ph.D. |
|Bernd Jandeleit, Ph.D.*** ||AgrEVO GmBh, Frankfurt, Germany |
|Andreas Janshoff, Ph.D. |
|Jae U. Jeong, Ph.D. |
|Weiqin Jiang, Ph.D. |
|Qing Jin, Ph.D. |
|Zhendong Jin, Ph.D.*** ||University of Iowa, Iowa City, IA |
|Young-Sik Jung, Ph.D. |
|Alan Kennan, Ph.D. |
|Mbiya Kapiamba, Ph.D.*** ||Eastman-Kodak, Rochester, NY |
|Haripada Khatuya, Ph.D.*** ||The R.W. Johnson Pharmaceutical Research Institute, Raritan, NJ |
|Holger Keim, Ph.D. |
|Kazuya Kikuchi, Ph.D.*** ||University of Tokyo, Tokyo, Japan |
|Sanghee Kim, Ph.D. |
|Nigel Paul King, Ph.D. |
|Laxma R. Kolla, Ph.D. |
|Karin Kraehenbuehl, Ph.D. |
|Krishna Kumar, Ph.D. |
|Thomas Lampe, Ph.D. |
|Van-Duc Le, Ph.D. |
|Richard J. Lee, Ph.D. |
|Taekyu Lee, Ph.D. |
|Guigen Li, Ph.D.*** ||Texas Tech University, Lubbock, TX |
|Chao-Hsiung Lin, Ph.D. |
|Chun-Cheng Lin, Ph.D. |
|Shang-Yi Lin, Ph.D. |
|Olivier Loiseleur, Ph.D. |
|Georgina V. Long, Ph.D.**** |
|Timothy Machajewski, Ph.D. |
|David Manning, Ph.D. |
|Shenlan Mao, Ph.D. |
|Thomas G. Marron, Ph.D.*** ||Abbott Laboratories, Abbott Park, IL |
|Richard Martin, Ph.D.*** ||Tanabe Research Laboratories, San Diego, CA |
|Jose Martinez Perez, Ph.D.*** ||Institut für Organische Chemie, Basel, Switzerland |
|Patrizio Mattei, Ph.D. |
|Dominique Michel, Ph.D.*** ||Lonza AG, Visp, Switzerland |
|Neil Derek Miller, Ph.D.*** ||Glaxo Wellcome Research and Development, Hertfordshire, United Kingdom |
|Francisco Moris-Varas, Ph.D.*** ||Thermogen, Chicago, IL |
|Kianoush Motesharei, Ph.D. |
|Swaminathan Natajaran, Ph.D. |
|Sacha Ninkovic, Ph.D. |
|Joel Osuna, Ph.D. |
|Keun-Chan William Park, Ph.D.*** ||The Paik-Inje Memorial Institute for Biomedical Science, San Diego, CA |
|Joaquin Pastor, Ph.D. |
|Maarten Postema, Ph.D.*** ||Wayne State University, Detroit, MI |
|Scott Priestley, Ph.D. |
|Wallace C. Pringle, Ph.D. |
|Xinhua Qian, Ph.D.*** ||Bristol-Myers Pharmaceutical, New Brunswick, NJ |
|Joshi Ramanjulu, Ph.D. |
|Neal Reed, Ph.D. |
|Frank Roschanger, Ph.D. |
|Frank Rübsam, Ph.D. |
|Joachim Rudolph, Ph.D.*** ||Bayer AG, Leverkusen, Germany |
|Kurt W. Saionz, Ph.D.*** ||Pharmacopia, Princeton, NJ |
|Jorge Sanchez, Ph.D. |
|Francisco Sarabia, Ph.D. |
|Rosa Maria Rodriguez Sarmiento, Ph.D. |
|Axel Schleyer, Ph.D. |
|Gunter Schüle, Ph.D. |
|Gunther Schlingloff, Ph.D. |
|Mark Searcey, Ph.D. |
|Clark A. Sehon, Ph.D. |
|Oliver Seitz, Ph.D.*** ||Universitat Mainz, Mainz, Germany |
|Kay Severin, Ph.D.*** ||University of Munich, Munich, Germany |
|Jo Shaw, Ph.D. |
|Cathryn J. Shelton, Ph.D. |
|Michael Shelton, Ph.D. |
|Gou-qiang Shi, Ph.D. |
|Eric Simanek, Ph.D. |
|Mark Smith, Ph.D. |
|David Spivak, Ph.D. |
|Claudia Steinem, Ph.D. |
|Erland Stevens, Ph.D. |
|Ying Tang, Ph.D.*** ||XYSIS, La Jolla, CA |
|Matthew Taylor, Ph.D. |
|Chung-Ying Tsai, Ph.D. |
|Phillip S. Turnbull, Ph.D. |
|Hans Vallberg, Ph.D.*** ||Medivir AB, Huddinge, Sweden |
|Floris VanDelft, Ph.D. |
|Vassil Vassilev, Ph.D. |
|Andrea Vaupel, Ph.D. |
|Cornelis Petrus Vlaar, Ph.D.*** ||Bristol-Myers Squibb, San Juan, Puerto Rico |
|Anthony M. Vandersteen, Ph.D.*** ||Putney Heath, London, England |
|Martin Vollmer, Ph.D. |
|Dionisios Vourloumis, Ph.D. |
|Stephen D. Warren, Ph.D.*** ||CombiChem, Inc., San Diego, CA |
|Nobuhide Watanabe, Ph.D. |
|David Weiner, Ph.D.*** ||Diversa Corporation, San Diego, CA |
|Ralf Wischnat, Ph.D. |
|Valentin Wittmann, Ph.D.*** ||Institut für Organische Chemie, Frankfurt/Main, Germany |
|Thomas J. Woltering, Ph.D.*** ||F. Hoffmann La Roche AG, Basel, Switzerland |
|Jason H. Wu, Ph.D. |
|Yiling Xie, Ph.D. |
|Jinyou Xu, Ph.D. |
|Guang Yang, Ph.D. |
|Xin-Shan Ye, Ph.D. |
|Juyoung Yoon, Ph.D. |
|Andrei Yudin, Ph.D. |
|Tai-Yuen Yue, Ph.D. |
|Joanne Yun, Ph.D. |
|Zhiyuan Zhang, Ph.D. |
|Xu-Yang Zhao, Ph.D. |
|Bin Zhou, Ph.D. |
GUEST SCIENTISTS AND VISITING INVESTIGATORS
|Elias A. Couladouros, Ph.D.*** ||Agricultural University of Athens, Athens, Greece |
|Juan Granja, Ph.D.*** ||University of Santiago, Santiago, Spain |
|Paraskevi Giannakakou, Ph.D.*** ||National Institutes of Health, Bethesda, MD |
|Nizar Haddad, Ph.D. ||Technion-Israel Institute of Technology, Haifa, Israel |
|Alfred Hassner, Ph.D.***` ||Bar-Ilan University, Ramat Gan, Israel |
|Masataka Hikota, Ph.D. ||Tanabe Seiyaku Co., Ltd., Saitama, Japan |
|Christoph Hoenke, Ph.D.*** ||Boehringer Ingelheim KG, Ingelheim, Germany |
|Manabu Hori, Ph.D. ||Kanebo, Ltd., Osaka, Japan |
|Kiyoshi Ikeda, Ph.D. ||University of Shizuoka, Shizuoka, Japan |
|Stefan Immel, Ph.D.***` ||Technische Hochschule Darmstadt, Darmstadt, Germany |
|Michio Ishida, Ph.D.*** ||Central Glass Co., Ltd., Saitama-ken, Japan |
|Mahn Joo Kim, Ph.D.*** ||Pohang University of Science & Technology., Pohang, Korea |
|Teiji Kimura, Ph.D.*** ||Eisai Co., Ltd., Ibaraki, Japan |
|Tomoyoshi Koshiyama, Ph.D. ||Mitsubishi Chemical Corporation, Aoba-ku, Yokoshida-cho, Japan |
|Thuy Phuc Le, Ph.D.*** ||University of California, San Diego, CA |
|Glenn McGarvey, Ph.D.*** ||University of Virginia, Charlottesville, VA |
|Seiji Nukui, Ph.D.*** ||Pfizer Central Research Laboratory, Chitagun Aichiken, Japan |
|Iwao Ojima, Ph.D.*** ||State University of New York at Stony Brook, Stony Brook, NY |
|Paul Pachlatko, Ph.D.*** ||Novartis Crop Protection AG, Basel, Switzerland |
|Haruhiko Sato, Ph.D. ||Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan |
|Wen-guey Wu, Ph.D. ||National Tsing Hua University, Hsinchu, Taiwan |
|John Ashley |
|Maria T. Auditor-Dendle |
|Chong Choi |
|Chih-Hung (Larry) Lo, Ph.D. |
| * Joint appointment in The Skaggs Institute for Chemical Biology |
| ** Joint appointment in the Department of Molecular Biology |
| *** Apointment completed; new location shown |
| **** Appointment completed |
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K.C. Nicolaou, Ph.D.
As the "central science," chemistry stands between biology and medicine and provides the crucial bridge for drug discovery and development. But chemistry has a much more profound role in science and society. It is the discipline that continually creates the myriad new substances from which we all benefit in our everyday lives: pharmaceuticals, high-tech materials, polymers and plastics, insecticides and pesticides, fabrics and cosmetics, fertilizers and vitamins--basically everything you can touch, smell, and feel.
Chemistry at TSRI focuses sharply on synthetic and bioorganic chemistry, the two most relevant areas to biomedical research and materials science. Our faculty are distinguished teacher-scholars who maintain highly visible and independent research programs in areas as diverse as biological and chemical catalysis, natural products synthesis, molecular design, chemical evolution, materials science, and chemical biology. The chemistry graduate program, now in its sixth year and under the auspices of Dean Gilula and Senior Vice President Beers, attracts 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. Finally, we are pleased that the Mabel and Arnold Beckman Center for Chemical Sciences is fully operational, with both chemists and biologists.
Research in the chemistry department goes on unabated, attracting international visibility and attention as evidenced by numerous lecture invitations, visits by outside scholars, and headline news in the media.
The Lerner group continues to make advances in the catalytic antibody area, with new antibodies catalyzing unfavorable reactions such as hydroxy epoxide openings, exo Diels-Alder reactions, syn eliminations, and asymmetric aldol reactions. The Sharpless group proceeds in endeavors to discover and develop better catalysts for the synthesis of medicinal agents.
The Eschenmoser group has started its La Jolla--based experimental studies on the chemical etiology of nucleic acid structure by focusing on the investigation of four pentopyranosyl nucleic acid systems that are isomeric to RNA. The Nicolaou group continues explorations of the chemistry and biology of natural and designed molecules such as the new anticancer agents known as epothilones, the neurotoxins associated with the red tide, and the vancomycin-type antibiotics.
The Rebek research group forges ahead in molecular recognition, self-assembly, and self-replicating molecules. During the past year, they developed "molecules within molecules" capable of encapsulation and transport of medicinal agents. These studies give new insights on intermolecular forces and the structure of the liquid state.
Dr. Wong's group has further advanced the field of chemoenzymatic organic synthesis and has accomplished the synthesis of a glycoprotein. The members of this group have also developed new inhibitors of glycosyltransferases and HIV protease, uncovered the molecular recognition specificity in interactions between aminoglycoside antibiotics and RNA, and developed new aminoglycoside antibiotics.
The Boger group continues work in the area of combinatorial chemistry, heterocycle synthesis, and anticancer agents, including CC-1065, duocarmycin, bleomycin, and sandramycin. The Hilvert group continues research on the mechanism of evolution of enzymes, protein design, and exploration of the structure and function of catalytic antibodies.
The Joyce group continues breakthrough research in chemical evolution and biological catalysis. Their work has resulted in the development of a variety of novel RNA and DNA enzymes, including molecules that have potential therapeutic application. The Janda group proceeds in research in the areas of combinatorial chemistry, catalytic antibodies, enzyme inhibition, and immunopharmacotherapy.
The Ghadiri laboratory has made several contributions toward understanding the origin of molecular complexity in living systems. Members of this group showed for the first time the feasibility of peptide self-replication and the formation of complex nonlinear chemical systems with dynamic error correcting and hypercyclic emergent properties. These studies serve as the platform for ongoing research on the construction of chemical networks and molecular ecosystems.
The following internationally renowned scientists visited the department as lecturers during the 1996--1997 academic year: Jean-Marie Lehn, Université Louis Pasteur, Strasbourg, France (Sterling Winthrop Lecturer); Peter Kim, Massachusetts Institute of Technology (Frontiers in Chemistry Lecturer); Peter Wipf, University of Pittsburgh (Frontiers in Chemistry Lecturer); Erick Carreira, California Institute of Technology (Frontiers in Chemistry Lecturer); Ahmed Zewail, California Institute of Technology (Frontiers in Chemistry Lecturer); Bernd Geise, Institut für Organische Chemie, Universität Basel, Switzerland (Gensia Lecturer); Shinji Murai, Osaka University, Japan (Tanabe Research Lecturer); and Salo Gronowitz, University of Lund, Sweden.
We again look forward to another exciting year, and we welcome two new colleagues, Jeff Kelly and Erik Sorensen.
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Synthetic and Bioorganic Chemistry
D.L. Boger, C. Andersson, R. Beresis, R. Borzilleri, C. Boyce, H. Cai, S. Castle, R. Castro, W. Chai, J. Chen, P. Ducray, R. Garbaccio, J. Goldberg, N. Han, N. Haynes, M. Hikota, J. Hong, M. Ishida, T. Jenkins, W. Jiang, Q. Jin, D. Johnson, M. Kapiamba, H. Keim, M. Ledeboer, R. Lee, E. Lerner, B. Lewis, O. Loiseleur, M. Loncar, J. McKie, S. Nukui, R. Ozer, J. Patterson, M. Pattricelli, H. Purkey, T. Ramsey, K. Saionz, H. Sato, G. Schüle, M. Searcey, C. Shelton, K. Takahashi, C. Tarby, S. Teramoto, P. Turnbull, A. Vaupel, J. Wu, J. Zhou
The research interests of our group include the total synthesis of natural products, development of new synthetic methods, heterocyclic chemistry, bioorganic and medicinal chemistry, the study of DNA--agent 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.
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.
TOTAL SYNTHESIS OF NATURAL PRODUCTS
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, tropoloalkaloids, the deoxybouvardin and RA-I--RA-XI class of antitumor agents, vancomycin and related agents, the luzopeptins and sandramycin, bleomycin A2 and functional analogs, CI-920, rhizoxin, the combretastatins, and vinblastine (Figs. 2 and 3).
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. Representative of such efforts, studies to determine structural features of (+)-CC-1065 and the duocarmycins that contribute to the agents' sequence-selective DNA alkylation properties (Fig. 4) have resulted in the identification of the source of catalysis for the DNA alkylation reaction. Efforts are under way to develop DNA 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 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 DNA-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 newly discovered endogenous lipid oleamide; and to control intracellular signal transduction through the discovery of antagonists or agonists that affect protein-protein interactions, including receptor dimerization.
Boger, D.L. Applications of free radicals in organic synthesis. Isr. J. Chem. 37:119, 1997.
Boger, D.L. Azadiene Diels-Alder reactions: Scope and applications. Total synthesis of natural and ent-fredericamycin A. J. Heterocycl. Chem. 33:1510, 1996.
Boger, D.L., Bollinger, B., Hertzog, D.L., Johnson, D.S., Cai, H., Mésini, P., Garbaccio, R.M., Jin, Q., Kitos, P.A. Reversed and sandwiched analogs of duocarmycin SA: Establishment of the origin of the sequence selective alkylation of DNA and new insights into the source of catalysis. J. Am. Chem. Soc. 119:4987, 1997.
Boger, D.L., Borzilleri, R.M., Nukui, S., Beresis, R.T. Synthesis of the vancomycin CD and DE ring systems. J. Org. Chem. 62:4721, 1997.
Boger, D.L., Boyce, C.W., Garbaccio, R.M., Goldberg, J.A. CC-1065 and the duocarmycins: Synthetic studies. Chem. Rev. 97:787, 1997.
Boger, D.L., Boyce, C.W., Johnson, D.S. pH Dependence of the rate of DNA alkylation for (+)-duocarmycin SA and (+)-CCBI-TMI. Bioorg. Med. Chem. Lett. 7:233, 1997.
Boger, D.L., Chai, W., Ozer, R.S., Andersson, C.-M. Solution-phase combinatorial synthesis via the olefin metathesis reaction. Bioorg. Med. Chem. Lett. 7:463, 1997.
Boger, D.L., Chen, J.-H. An exceptionally potent analog of sandramycin. Bioorg. Med. Chem. Lett. 7:919, 1997.
Boger, D.L., Chen, J.-H., Salonz, K.W., Jin, Q. Synthesis of key sandramycin analogs: Systematic examination of the intercalation chromophore. Bioorg. Med. Chem., in press.
Boger, D.L., Garbaccio, R.M. Catalysis of the CC-1065 and duocarmycin DNA alkylation reaction: DNA binding induced conformational change in the agents results in activation. Bioorg. Med. Chem. 5:263, 1997.
Boger, D.L., Han, N. CC-1065/duocarmycin and bleomycin A2 hybrid agents: Lack of enhancement of DNA alkylation by attachment to noncomplementary DNA binding subunit. Bioorg. Med. Chem. 5:233, 1997.
Boger, D.L., Haynes, N.-E., Kitos, P.A., Warren, M.S., Ramcharan, J., Marolewski, A.E., Benkovic, S.J. 10-Formyl-5,8,10-trideazafolic acid (10-formyl-TDAF): A potent inhibitor of glycinamide ribonucleotide transformylase. Bioorg. Med. Chem. 5:1817, 1997.
Boger, D.L., Haynes, N.-E., Warren, M.S., Gooljarsingh, L.T., Ramcharan, J., Kitos, P.A., Benkovic, S.J. Functionalized analogs of 5,8,10-trideazafolate as potential inhibitors of GAR Tfase or AICAR Tfase Bioorg. Med. Chem. 5:1831, 1997.
Boger, D.L., Haynes, N.-E., Warren, M.S., Ramcharan, J., Kitos, P.A., Benkovic, S.J. Functionalized analogs of 5,8,10-trideazafolate: Development of an enzyme-assembled tight binding inhibitor of GAR Tfase and an irreversible inhibitor of AICAR Tfase. Bioorg. Med. Chem. 5:1833, 1997.
Boger, D.L., Haynes, N.-E., Warren, M.S., Ramcharan, J., Kitos, P.A., Benkovic, S.J. A multisubstrate analog based on 5,8,10-trideazafolate. Bioorg. Med. Chem. 5:1853, 1997.
Boger, D.L., Haynes, N.-E., Warren, M.S., Ramcharan, J., Marolewski, A.E., Kitos, P.A., Benkovic, S.J. Abenzyl 10-formyl-trideazafolic acid (abenzyl 10-formyl-TDAF): An effective inhibitor of glycinamide ribonucleotide transformylase. Bioorg. Med. Chem. 5:1847, 1997.
Boger, D.L., Hertzog, D.L., Bollinger, B., Johnson, D.S., Cai, H., Goldberg, J., Turnbull, P. Duocarmycin SA shortened, simplified, and extended agents: A systematic examination of the role of the DNA binding subunit. J. Am. Chem. Soc. 119:4977, 1997.
Boger, D.L., Hikota, M., Lewis, B.M. Determination of the relative and absolute stereochemistry of fostriecin (CI-920). J. Org. Chem. 62:1748, 1997.
Boger, D.L., Jenkins, T.J. Synthesis, x-ray structure, and properties of fluorocyclopropane analogs of the duocarmycins incorporating the 9,9-difluoro-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (F2CBI) alkylation subunit. J. Am. Chem. Soc. 118:8860, 1996.
Boger, D.L., McKie, J.A., Boyce, C.W. Asymmetric synthesis of the CBI alkylation subunit of the CC-1065 and duocarmycin analogs. Synlett, April 1997, p. 515.
Boger, D.L., McKie, J.A., Nishi, T., Ogiku, T. Total synthesis of (+)-duocarmycin A, epi-(+)-duocarmycin A and their unnatural enantiomers: Assessment of chemical and biological properties. J. Am. Chem. Soc. 119:311, 1997.
Boger, D.L., Ozer, R.S., Andersson, C.-M. Generation of symmetrical compound libraries by solution-phase combinatorial chemistry. Bioorg. Med. Chem. Lett. 7:1903, 1997.
Boger, D.L., Teramoto, S., Cai, H. N-Methyl-l-threonine analogs of deglycobleomycin A2: Synthesis and evaluation. Bioorg. Med. Chem., in press.
Boger, D.L., Turnbull, P., Synthesis and evaluation of CC-1065 and duocarmycin analogs incorporating the 1,2,3,4,11,11a-hexahydrocycloporpa[c]naphtho[2,1-b]azepin-6-one (CNA) alkylation subunit: Structural features that govern reactivity and reaction regioselectivity. J. Org. Chem. 62:5849, 1997.
Boger, D.L., Zhou, J. Key analogs of the tetrapeptide subunit of RA-VII and deoxybouvardin. Bioorg. Med. Chem. 4:1597, 1996.
Boger, D.L., Zhou, J., Borzilleri, R.M., Nukui, S., Castle, S.L. Synthesis of (9R,12S)- and (9S,12S)-cycloisodityrosine and their N-methyl derivatives. J. Org. Chem. 62:2059, 1997.
Cravatt, B.F., Giang, D.K., Mayfield, S.P., Boger, D.L., Lerner, R.A., Gilula, N.B. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384:83, 1996.
Eis, P.G., Smith, J.A., Rydzewski, J.M., Case, D.A., Boger, D.L., Chazin, W.J. High resolution solution structure of a DNA duplex alkylated by the antitumor agent duocarmycin SA. J. Mol. Biol. 272:237, 1997.
Ramsey, T.M., Cai, H., Hoehn, S.T., Kozarich, J.W., Stubbe, J., Boger, D.L. Assessment of the role of the bleomycin A2 pyrimidoblamic acid C4 amino group. J. Am. Chem. Soc., in press.
Sakya, S.M., Groskopf, K.K., Boger, D.L. Preparation and inverse electron demand Diels-Alder reactions of 3-methoxy-6-methylthio-1,2,4,5-tetrazine. Tetrahedron Lett. 38:3805, 1997.
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Chemical Etiology of the Structure of Nucleic Acids
A. Eschenmoser, R. Krishnamurthy, T. Wagner, M. Beier, F. Reck, T. Mueller, P. Waldmeier, G. Ceulemans, M. Bolli
Our research programs are directed toward a chemical etiology of the structure of nucleic acids, a quest for a chemical rationalization of Nature's evolution of the structure of RNA. The research strategy is to study the chemical properties of potential alternatives to nucleic acids, alternatives with molecular structures similar to the structure of RNA that, according to chemical reasoning, could have, but did not, or may have only temporarily, become Nature's genetic system. Such alternatives are made by chemical synthesis, and their properties are systematically compared with those chemical properties of RNA that are fundamental to a genetic system's biological function, such as base pairing, replication, sequence-specific catalysis of peptide synthesis, and potential to evolve. The experimental approach is meant to mimic a hypothetical process of structural variation and functional selection that may have led to RNA. This approach is expected to provide insight into those structural features that are responsible for RNA's conjectured functional superiority to chemically conceivable evolutionary alternatives.
Members of the hexopyranosyl-(6´4´)- and the pentopyranosyl-(4´2´)-oligonucleotide families are conformationally promising potential alternatives to nucleic acids, having structures similar to that of RNA. Earlier work done at the Swiss Federal Institute of Technology showed that the pairing properties of (6´4´)-hexopyranosyl alternatives were far inferior to those of RNA; the reason was steric hindrance in the pairing conformation ("too many atoms"). In sharp contrast, base pairing in the ribopyranosyl-(4´2´)-system of the pentose series is both stronger and more selective (with respect to pairing modes) than in natural (i.e., furanosyl) RNA. Conformational and constellational criteria developed and refined in the course of this work led us to predict a unique position of ribose within the family of pentopyranosyl-(4´2´)-oligonucleotides in the sense that lyxopyranosyl-, arabinopyranosyl-, and xylopyranosyl-(4´2´)-oligonucleotides were expected to be (in the order given) weaker pairing systems than is pyranosyl-RNA (Fig. 1). Our introductory work at the Skaggs Institute focused on the chemical synthesis of these three unknown pentopyranosyl systems.
We recently synthesized lyxopyranosyl oligonucleotides containing adenine and thymine bases, and we expect to achieve chemical synthesis of the xylopyranosyl oligonucleotides soon. First observations on base pairing in the (4´2´)-lyxopyranosyl series indicate that these oligonucleotides are a functional pairing system. The pairing strength of the lyxopyranosyl oligonucleotides is comparable to (or even slightly greater than) that of pyranosyl-RNA; on the other hand, their pairing selectivity (with respect to pairing mode) is less.
Oligomers of the constitutional isomer of pyranosyl-RNA that contains the phosphodiester function between positions 4´ and 3´ (instead of 4´2´) have been synthesized and tested (at the Skaggs Institute) for pairing capabilities. We confirmed that this alternative pyranosyl isomer of RNA is not a functional pairing system, as predicted by conformational criteria.
Properties of pyranosyl-RNA that have been compared (at the Swiss Federal Institute of Technology) with the properties of RNA include the replication of pyranosyl-RNA sequences by template-controlled ligation of oligomer 2´,3´-cyclophosphates and the chiroselective self-assembly of higher oligomers by oligomerization and cooligomerization of hemicomplementary tetramer 2´,3´-cyclophosphates. At the Skaggs Institute, we have initiated studies on the potential of pyranosyl-RNA to mediate and direct the formation of oligopeptides from activated -amino acids. We have established a central element of the proposed mechanistic pathway of such a process, namely, the occurrence of a fast and unidirectional migration of an -aminoacyl function from the 2´ to the 3´ position of a pyranosyl-RNA unit.
Further studies will focus on four areas: (1) continuation of efforts to synthesize xylopyranosyl- and arabinopyranosyl-(4´2´)-oligonucleotides; (2) extension of the synthesis of the lyxopyranosyl-(4´2´)-oligonucleotides to sequences containing guanine and cytosine, establishing the system's pairing behavior in comparison with pyranosyl-(4´2´)-RNA, and rationalization of similarities and differences in the pairing behavior of these two closely related pairing systems in terms of constellational and conformational criteria; (3) systematic determination of duplex stabilities and analysis of those stabilities in terms of the ratio between interstrand and intrastrand base stacking in pyranosyl pairing systems such as homo-DNA, pyranosyl-RNA, and lyxopyranosyl-oligonucleotides, and extending the application of this parameter to the rationalization of differences in the pairing behavior of the natural systems RNA and DNA; (4) continuation of studies directed toward (noncoded) oligopeptide synthesis mediated by a pyranosyl-RNA template.
Bolli, M., Micura, R., Eschenmoser, A. Pyranosyl-RNA: Chiroselective self-assembly of base sequences by ligative oligomerization of tetranucleotide-2´,3´-cyclophosphates (with a commentary concerning the origin of biomolecular homochirality). Chem. Biol. 4:309, 1997.
Bolli, M., Micura, R., Pitsch, S., Eschenmoser, A. Pyranosyl-RNA: Further observations on replication. Helv. Chim. Acta 80:1901, 1997.
Eschenmoser, A. Towards a chemical etiology of nucleic acid structure. Orig. Life Evol. Biosph. 27:535, 1997.
Micura, R., Bolli, M., Windhab, N., Eschenmoser, A. Pyranosyl-RNA also forms hairpin structures. Angew. Chem. Int. Ed. Engl. 36:870, 1997.
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Molecular Assemblies, Materials, and Complex Chemical Networks
M.R. Ghadiri, D.T.Y. Bong, C. Choi, M.J. Churchill, T.D. Clark, J.R. Granja, J.D. Hartgerink, M.P. Isler, A. Janshoff, A.J. Kennan, H.S. Kim, K. Kumar, C. Lange, D.H. Lee, V.S.-Y. Lin, G.V. Long, J.A. Martinez, K. Motesharei, J. Quesada-Sanchez, A. Saghatelian, K. Severin, C. Steinem, Y. Yokobayashi
Our group is involved in a multidisciplinary research program that seeks to uncover innovative avenues for the design and construction of functionally predetermined supramolecular assemblies, multicomponent nonlinear chemical networks, and novel materials. The overall philosophy is to bring about deliberate self-organizing, self-assembling, and self-replicating processes by exploiting the molecular information stored in the covalent structure of a given design and the readout and processing of this information through noncovalent chemical reactions. In the past few years, our efforts along these lines have yielded a variety of methods for the construction of predefined peptide-based molecular objects.
NANOTUBES AND TRANSMEMBRANE CHANNELS
Open-ended hollow tubular structures with nanometer dimensions, termed "peptide nanotubes," are a new class of functional tubular biomaterials. These species are constructed through the rational design and stacking of simple cyclic peptide subunits. This general strategy has enabled us to design and synthesize a wide range of tubular assemblies with specified internal diameters and surface characteristics and has provided novel applications in both biological and materials science settings.
For example, cyclic peptides have been designed to self-assemble inside lipid membranes to form cylindrical channels and pore structures that can effectively mimic the transport action of biological counterparts. Such membrane-active tubular assemblies have antimicrobial and cytotoxic activities and are expected to be useful as novel chemotherapeutics and drug-delivery vehicles. Self-assembling peptide nanotubes are also efficacious as novel materials, especially in the fabrication of transition-metal nanocomposites and in the design of solid-state biosensors.
SELF-REPLICATING SYSTEMS AND NONLINEAR CHEMICAL NETWORKS
What are the fundamental properties that distinguish the chemistry of living systems, which have animate characteristics, from inanimate in vitro chemical transformations? Recent advances in the mathematical understanding of complex nonlinear systems, chemistry, molecular biology, and analytical sciences are allowing a new, broad, and unique attack on the fundamental understanding of living processes.
The approach used in our laboratory is founded on the following premises: Living systems are autonomous self-reproducing entities that operate on the basis of "information." Information is originated at the molecular level by covalent chemical reactions, transferred and processed through noncovalent chemical reactions, expanded in complexity at the system level, and ultimately changed through reproduction and natural selection. In a living system, the complex blend of nonlinear transfer of molecular information is thought to bring about a coherent self-organized chemical system--a collective of interacting and interdependent molecular species, a "molecular ecosystem"--that as a whole has emergent properties far greater than the simple sum of its chemical constituents.
Therefore, to understand and ultimately mimic the properties of living systems, we must begin by determining the basic forms of self-organized autocatalytic chemical networks, how the networks can be constructed, and how the interplay of information and nonlinear catalysis can lead to the expression of emergent properties. Recently we showed, within the context of de novo designed catalytic and autocatalytic peptides, that simple self-organized autocatalytic networks can be constructed that begin to display some of the most basic properties of living molecular systems, such as selection, adaptation, and the acquisition of new functions.
Other ongoing activities in our laboratory include design of synthetic enzymes, study of early protein-folding kinetics, research on heterogeneous catalysts, and fabrication of novel and practical solid-state biosensors.
Buriak, J.M., Ghadiri, M.R. Self-assembly of peptide nanotubes. Mater. Sci. Eng. C4:207, 1997.
Case, M.A., Ghadiri, M.R., Mutz, M.W., McLendon, G.L. Stereoselection in designed three-helix bundle metalloproteins. Chirality, in press.
Dawson, P.E., Churchill, M.J., Ghadiri, M.R., Kent, S.B.H. Modulation of reactivity in native chemical ligation through the use of thiol additives. J. Am. Chem. Soc. 119:4325, 1997.
Hartgerink, J.D., Ghadiri, M.R. Self-assembling organic nanotubes. In: New Macromolecular Architecture and Function. Kamachi, M., Nakamura, A. (Eds.). Springer, New York, 1996, p. 181.
Lee, D.H., Ghadiri, M.R. Controlling peptide architecture via self-assembling and self-organizing molecular processes. Compr. Supramol. Chem. 9:541, 1996.
Lin, V.S.-Y., Motesharei, K., Dancil, K., Sailor, M.J., Ghadiri, M.R. A porous silicon-based optical interferometric biosensor. Science 278:840, 1997.
Motesharei, K., Ghadiri, M.R. Diffusion-limited size-selective ion sensing based on SAM-supported peptide nanotubes. J. Am. Chem. Soc. 119:11306, 1997.
Severin, K., Lee, D., Martinez, J.A., Ghadiri, M.R. Peptide self-replication via template-directed fragment condensation. Chem. Eur. J. 3:1017, 1997.
Severin, K., Lee, D.H., Kennan, A.J., Ghadiri, M.R. A synthetic peptide ligase. Nature 389:706, 1997.
Severin, K., Lee, D.H., Martinez, J.A., Vieth, M., Ghadiri, M.R. Dynamic error-correction in autocatalytic peptide networks. Angew. Chem. Int. Ed. Engl., in press.
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D. Hilvert, P. Kast, G. Auditor-Dendle, R. Chavez, A. Flohr, C. Grissostomi, D. Gustin, R. Hannak, K. Hotta, N. Jiang, K. Kikuchi, T. Le, G. Macbeath, P. Mattei, J. Osuna, E. Peterson, Y. Tang, S. Warren, S. Zhou
Our group is developing general strategies for creating protein molecules with tailored catalytic activities. The goal of this work is to understand, at the molecular level, the origins of the enormous catalytic rates and the exacting selectivities that enzymes achieve. Successful enzyme engineering may also provide researchers of the future with novel catalysts for a wide range of applications in research, medicine, and industry.
Although it is not yet practical to design and synthesize new proteins from their constituent amino acids, existing protein molecules can serve as convenient starting points for the construction of new active sites. Such molecules can be redesigned by using either recombinant techniques or site-selective chemical modification. For example, we have changed the serine protease subtilisin into an artificial selenoenzyme by chemically converting the active-site serine residue into a selenocysteine.
The resulting protein, selenosubtilisin, has a number of remarkable properties. The modified enzyme catalyzes both the hydrolysis and the aminolysis of activated esters. Indeed, acyl transfer to amines is four orders of magnitude more efficient than with native subtilisin. This result, and the fact that selenosubtilisin does not hydrolyze peptides, suggests that the modified enzyme could be a practical peptide ligase, useful in the convergent synthesis of proteins. Because selenium has several accessible oxidation states, the redox chemistry of selenosubtilisin is also interesting. The artificial enzyme efficiently catalyzes the oxidation of thiols by alkyl hydroperoxides, mimicking the action of glutathione peroxidase, an important enzyme that protects mammalian cells from oxidative damage.
Site-directed mutagenesis, kinetic analyses, proton and selenium-77 nuclear magnetic resonance spectroscopy, and crystallography are integral to our effort to understand how the microenvironment of the active site influences the intrinsic reactivity of the selenium prosthetic group and to our attempts to optimize the chemical efficiency of selenosubtilisin. Extension of these studies to new protein templates and new prosthetic groups may make a wide range of tailored protein catalysts readily available.
In a complementary approach, we are exploiting the diversity and specificity of the mammalian immune system to produce monoclonal antibodies capable of catalysis. Using suitably designed transition-state analogs as haptens, we have prepared antibody catalysts (abzymes) for concerted reactions in which carbon-carbon bonds are made or broken. We have focused on these processes because of their intrinsic chemical interest and because they can illuminate the elementary mechanisms by which proteins catalyze reactions (e.g., the roles of strain, proximity, and desolvation).
To that end, we have successfully generated antibody catalysts for a Claisen rearrangement, a bimolecular Diels-Alder reaction, and a decarboxylation. To investigate the factors that influence the efficiency of proton transfer, another fundamental process, we have explored approaches for eliciting properly positioned acids and bases within antibody active sites. Like natural enzymes, our catalytic antibodies show substantial rate accelerations, substrate specificity, regioselectivity, and stereoselectivity. Moreover, because the selectivity and mechanism of action of these molecules are defined a priori by the structure of the immunizing hapten, this approach provides a versatile and general route to enzymelike molecules for a myriad of practical problems in chemistry and biology.
In addition to extending this technology to other chemical transformations (Fig. 1), we are carrying out detailed investigations of our existing catalysts. In this regard, recent nuclear magnetic resonance and crystallographic studies on an immunoglobulin with chorismate mutase activity have provided the first insights into the structural basis of antibody catalysis.
GENETIC SELECTION OF ENZYMES
Although it is now possible to create new enzyme active sites by using immunologic methods or by redesigning existing proteins, the chemical efficiency of these catalysts is typically much lower than that of naturally occurring enzymes. Genetic selection is a potentially general method for reengineering the properties of these first-generation molecules. To test this notion, we have expressed the genes that encode abzymes with modest chorismate mutase activity in a strain of the yeast Saccharomyces cerevisiae that lacks the corresponding natural enzyme. The natural enzyme is required for the biosynthesis of the aromatic amino acids phenylalanine and tyrosine. Through random mutagenesis, we have identified a permissive host strain deficient in chorismate mutase that requires the activity of our antibody for efficient growth. This work not only establishes the feasibility of using catalytic antibodies in vivo to effect vital biochemical reactions but also provides the growth-selection assay needed to improve the properties of these primitive catalysts through selection.
We have similarly used strains of Escherichia coli deficient in chorismate mutase to investigate structure-function relationships in natural chorismate mutases. For example, combinatorial random mutagenesis and selection in vivo have contributed to our understanding of electrostatic effects in Bacillus subtilis chorismate mutase. More recently, we used this approach to elucidate sequence constraints on an interhelical turn in E. coli chorismate mutase (Fig. 2) and to engineer small, monomeric chorismate mutases from much larger proteins. We anticipate that analogous selection strategies will be broadly applicable in mechanistic studies of many enzymes and as a valuable tool in protein design.
Haynes, M.R., Lenz, M., Taussig, M.J., Wilson, I.A., Hilvert, D. Sequence similarity and cross-reactivity of a Diels-Alder catalyst and an anti-progesterone antibody. Isr. J. Chem. 36:151, 1996.
Hilvert, D., MacBeath, G., Shin, J.A. The structural basis of antibody catalysis. In: Peptides and Proteins. Hecht, S.M. (Ed.), Oxford University Press, New York, in press.
Kast, P., Hilvert, D. Genetic selection strategies for generating and characterizing catalysts. Pure Appl. Chem. 68:2017, 1996.
Kast, P., Hilvert, D. Three-dimensional structural information as a guide to protein engineering by genetic selection. Curr. Opin. Struct. Biol. 7:470, 1997.
Kast, P., Tewari, Y.B., Wiest, O., Hilvert, D., Houk, K.N., Goldberg, R.N. Thermodynamics of the conversion of chorismate to prephenate: Experimental results and theoretical predictions. J. Phys. Chem., in press.
MacBeath, G., Kast, P., Hilvert, D. Exploring sequence constraints on an interhelical turn using in vivo selection for catalytic activity. Protein Sci., in press.
Na, J., Houk, K.N., Hilvert, D. Transition state of the base-promoted ring-opening of isoxazoles: Theoretical prediction of catalytic functionalities and design of haptens for antibody production. J. Am. Chem. Soc. 118:6462, 1996.
Peterson, E.B., Hilvert, D. Selenosubtilisin's peroxidase activity does not require an intact oxyanion hole. Tetrahedron 53:12311, 1997.
Zhou, Z.S., Jiang, N., Hilvert, D. An antibody-catalyzed selenoxide elimination. J. Am. Chem. Soc. 119:3623, 1997.
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Biological Chemistry and Biotechnology
K.D. Janda, J.A. Ashley, T. Berg, O. Bruemmer, R. Carrera, S. Chen, A. Datta, C. Gao, D. Gravert, H. Han, C. Harwig, J. Hasserodt, T. Hoffman, M. Hori,* D.M. Kubitz, M. Kubitz, C.-H. Lin, C.-H. Lo, S. Mao, G.P. McElhaney, J. Shaw, D. Spivak, M. Taylor, D. Weiner, P. Wentworth, Jr., P. Wirsching, Y. Xie, J. Yoon, X. Zhao, B. Zhou
* Kanebo, Ltd., Osaka, Japan
Our group is involved in four major areas of research: catalytic antibodies, combinatorial chemistry, enzyme inhibition, and immunopharmacotherapy. The foundation of these four areas of research is organic synthesis. However, we place special emphasis on such fields as molecular biology, immunology, enzymology, and neuropharmacology to enable us to tackle scientific problems at the interface of chemistry and biology.
We have isolated antibody catalysts that have chemoselectivity, enantioselectivity, large rate accelerations, and even an ability to reroute chemical reactions. However, the full power of this combinatorial system can only be exploited if a system is available that allows the direct selection of a particular function. We have devised a method that allows direct chemical selection for catalysis from antibody-phage libraries (Fig. 1).
Combinatorial chemistry is one of the most popular tools in drug discovery. Founded on peptide and oligonucleotide libraries, combinatorial chemistry has funneled most synthetic efforts down the path of solid-phase synthesis, because this method allows use of excess reagents and does not require tedious purification of products. However, with these advantages also come limitations: in most instances, solid-phase chemistry cannot be used to synthesize complex molecules that classic solution-phase synthesis permits. We have advocated using soluble polymer supports (liquid-phase synthesis), because this method has the advantages of both solid- and solution-phase synthesis. We have developed a novel non--cross-linked soluble copolymer that supports the synthesis of prostanoid libraries of a general structure (Fig. 2). The approach is wholly convergent technology that fosters synthetic economy and the opportunity for diversification through the permutation of three building blocks.
Our efforts in enzyme inhibition have focused on three classes of enzymes: proteases, phosphodiesterases, and phosphotriesterases. Recently, we designed, synthesized, and investigated effective inhibitors of RNase A. One of these is a novel, pentavalent, distorted, square pyramidal rhenium chelate of adenosine (Fig. 3). We think this compound is a close transition-state mimic in the specific hydrolysis of phosphodiester bonds of RNA because it is a potent inhibitor of the reaction.
Cocaine is a powerful reinforcer that has become a popular drug of abuse. It has a variety of pharmacologic effects on the CNS, the cardiovascular system, body temperature, the sympathetic nervous system, and nerve conduction. We are involved in a multifaceted immunochemical and molecular biological approach to the treatment of the pharmacologic effects of cocaine. Our plan focuses on antibody technology (Fig. 4). In this regard, we are developing aspects of the chemistry, immunology, and molecular biology required to generate and use antibodies to alleviate the toxic effects of cocaine use and addiction.
Chaiken, I.M., Janda, K.D., Eds. Molecular Diversity and Combinatorial Chemistry: Libraries and Drug Discovery. American Chemical Society, Washington, DC, p. 328, 1996.
Gravert, D.J., Janda, K.D. Organic reactions on soluble polymer supports as an alternative methodology for combinatorial solid-phase synthesis. In: Biotechnology International. Connor, T.H., Hairi, R.J. (Eds.). Universal Medical Press, San Francisco, in press.
Gravert, D., Janda, K.D. Organic synthesis on soluble polymer supports: Liquid-phase methodologies. Chem. Rev. 97:489, 1997.
Han, H., Janda, K.D. Multipolymer Sharpless asymmetric dihydroxylation reaction. Angew. Chem. Int. Ed. Engl., in press.
Han, H., Janda, K.D. A soluble polymer-bound approach to the Sharpless catalytic asymmetric dihydroxylation (AD) reaction: Preparation and application of a [(DHQD)2 PHAL-PEG-OMe] ligand. Tetrahedron Lett. 38:1527, 1997.
Han, H., Janda, K.D. Soluble polymer-bound ligand-accelerated catalysis: Asymmetric dihydroxylation. J. Am. Chem. Soc. 118:7632, 1996.
Hasserodt, J., Janda, K.D., Lerner, R.A. Antibody catalyzed terpenoid cyclization. J. Am. Chem. Soc. 118:11654, 1996.
Janda, K.D., Lo, L.-C., Lo, C.-H.L., Sim, M.-M., Wang, R., Wong, C.H., Lerner, R.A. Chemical selection for catalysis in combinatorial antibody libraries. Science 275:945, 1997.
Jung, K.S., Zhao, X.Y., Janda, K.D. Development of new linkers for the formation of aliphatic C-H bonds on polymeric supports. Tetrahedron 53:6645, 1997.
Jung, K.W., Janda, K.D., Sanfilippo, P.J., Wachter, M. Syntheses and biological evaluation of two new naproxen analogs. Bioorg. Med. Chem. Lett. 6: 2281, 1996.
Jung, K.W., Zhao, X.Y., Janda, K.D. A linker that allows efficient formation of aliphatic C-H bonds on polymeric supports. Tetrahedron Lett. 37:6491, 1996.
Lavey, B.J., Janda, K.D. Antibody catalyzed hydrolysis of a phosphotriester. Bioorg. Med. Chem. Lett. 6:1523, 1996.
Lavey, B.J., Janda, K.D. Catalytic antibody mediated hydrolysis of paraoxon. J. Org. Chem. 61:7633, 1996.
Li, T., Lerner, R.A., Janda, K.D. Antibody catalyzed cationic reactions: The rerouting of chemical reactions via antibody catalysis. Accounts Chem. Res. 30:115, 1997.
Lo, C.-H.L., Gao, C., Mao, S., Matsui, K., Janda, K.D. Chain shuffling: Investigations into the specificity and selectivity of antibody catalysis. Isr. J. Chem. 36:195, 1996.
Lo, L.C., Lo, C.-H.L., Kassel, D.B., Raushel, F.M., Janda, K.D. versatile mechanism based reaction probe for the direct selection of biocatalysis. Bioorg. Med. Chem. Lett. 6:2117, 1996.
Sakurai, M., Wirsching, P., Janda, K.D. Design and synthesis of a cocaine-diamide hapten for vaccine development. Tetrahedron Lett. 37:5479, 1996.
Vandersteen, A.M., Han. H., Janda, K.D. Liquid phase combinatorial synthesis: In search of catalysis. Mol. Divers. 2:89, 1996.
Vandersteen, A.M., Janda, K.D. A re-examination of two linear pentapeptides claimed to be serine protease mimics. J. Am. Chem. Soc. 118:8787, 1996.
Weiner, D.P., Wiemann, T., Wolfe, M.M., Wentworth, P., Jr., Janda, K.D. A pentacoordinate oxorhenium (V) metallochelate elicits antibody catalysts for phosphodiester cleavage. J. Am. Chem. Soc. 119:4088, 1997.
Wentworth, P., Janda, K.D. A facile and efficient route to 3´,5´-diamino- 3´,5´-dideoxynucleosides. J. Chem. Soc. Chem. Commun. 1996, p. 2097.
Wentworth, P., Vandersteen, A.M., Janda, K.D. Poly(ethylene) glycol (PEG) as a reagent support: The preparation and utility of PEG-triphenylphosphine in liquid-phase organic synthesis (LPOS). J. Chem. Soc. Chem. Commun. 1997, p. 759.
Wentworth, P., Wiemann, T., Janda, K.D. A new class of potent ribonuclease inhibitors: Synthesis, characterization and inhibition studies of pentacoordinate ribonucleoside oxorhenium (V) complexes as inhibitors of ribonuclease U2. J. Am. Chem. Soc. 118:12521, 1996.
Yli-Kauhaluoma, J., Janda, K.D. Catalytic antibodies: The rerouting of chemical reactions towards electrophilic aromatic substitution by carbon dioxide. Ann. N.Y. Acad. Sci. 799:26, 1996.
Zhao, X.-Y., Jung, K.W., Janda, K.D. Soluble polymer synthesis: An improved traceless linker methodology for aliphatic C-H bond formation. Tetrahedron Lett. 38:977, 1997.
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Synthetic Organic and Bioorganic Chemistry
K.C. Nicolaou, C. Agrios, C. Boddy, L. Boulton, S. Bräse, X.-J. Chu, S. Conley, E. Couladouros, M. Finlay, P. Gärtner, J. Gross, J. Gunzner, M. Härter, Y. He, D. Hepworth, S. Hosokawa, R. Huber, M. Izraelewicz, B. Jandeleit, Z. Jin, H. Khatuya, S. Kim, N. King, K. Koide, H. Li, J. Li, T. Li, S. McComb, N. Miller, H. Mitchell, S. Natarajan, S. Ninkovic, J. Pastor, M. Postema, J. Ramanjulu, R. Rodriguez, F. Roschangar, F. Rubsam, F. Sarabia, G. Shi, B. Smith, J. Trujillo, H. Vallberg, F. van Delft, D. Vourloumis, N. Wanatabe, D. Weinstein, N. Winssinger, J. Xu, G. Yang, Z. Yang, W.-H. Yoon, E. Yue, T.-Y. Yue
Our group is currently involved in the development of new synthetic technologies and strategies and in the total synthesis of natural products and designed molecules (Fig. 1). Major programs under way include the synthesis of target molecules such as brevetoxins, oligosaccharides, enediyne anticancer agents, DNA-interacting molecules, cholesterol-lowering compounds, taxoids, antibiotics, and other bioactive molecules. Other areas of investigation include the chemical, biological, and medical profiles of such compounds, solid-phase synthesis, and combinatorial chemistry.
Overall, our programs are based on sophisticated synthetic organic chemistry and are directed toward the construction of novel molecular architectures of natural or designed origins. Emphasis is placed on both biomedical relevance and the advancement of organic synthesis as a science for its own sake.
The marine neurotoxins brevetoxin A, ciguatoxin, and maitotoxin are active principles of the catastrophic "red tide" blooms, whose increasing frequency poses a major menace to marine life, the environment, and humans. Substantial efforts are under way in our laboratories for the chemical synthesis and elucidation of the mechanism of action of these compounds as a first step toward understanding and controlling these phenomena.
Cancer continues to be a major killer, second only to heart disease. New chemotherapeutic agents are in demand, particularly to combat drug-resistant types of cancer. Our efforts in this area include programs for the total synthesis of taxoids, enediynes, and epothilones A and B. Particularly exciting is the last group of compounds, because of their effectiveness against cell lines resistant to Taxol (paclitaxel).
Heart disease in humans has been convincingly linked to serum levels of cholesterol, and cholesterol-lowering drugs are therefore of great value for maintaining normal health. Substantial progress has been made in our group toward the synthesis of cholesterol-lowering agents, including the naturally occurring zaragozic acid A, CP-225,917, and CP-263,114.
Antibiotic resistance is emerging as a serious threat to human health and new antibiotics are urgently needed. Vancomycin and everninomicin 13,384-1 are two such compounds for which chemical synthesis is progressing in our laboratories.
In addition to these target-oriented programs, we are also pursuing the discovery and development of new synthetic methods, including new reactions, solid-phase synthesis, and combinatorial chemistry.
Bunnage, M.E., Nicolaou, K.C. The oxide anion accelerated retro-Diels-Alder reaction. Chem. Eur. J. 3:187, 1997.
Nicolaou, K.C., Boddy, C.N., Natarajan, S., Yue, T.-Y., Li, H., Bräse, S. New synthetic technology for the synthesis of aryl ethers: Construction of C-O-D and D-O-E ring model systems of vancomycin. J. Am. Chem. Soc. 119:3421, 1997.
Nicolaou, K.C., Bräse, S., Pastor, J., Sarabia, F.R., Rodriguez, R.M. Total synthesis of naturally occurring substances. In: Proceedings of the 26 Reunión Bienal de la real Sociedad Española de Química. Servicio de Publicaciones de la Universidad de Cadiz, Seville, Spain, in press.
Nicolaou, K.C., Chu, X.-J., Ramanjulu, J.M., Natarajan, S., Bräse, S., Rübsam, F., Boddy, C.N.C. New synthetic technology for the construction of vancomycin-type biaryl ring systems. Angew. Chem. Int. Ed. Engl., in press.
Nicolaou, K.C., Claiborne, C.F., Paulvannan, K., Postema, M.H.D., Guy, R.K. The chemical synthesis of C-ring aryl taxoids. Chem. Eur. J. 3:339, 1997.
Nicolaou, K.C., Guy, R.K., Gunzner, J.L. Intelligent drug discovery from nature. MedChem News 7:12, 1997.
Nicolaou, K.C., Härter, M.W., Boulton, L., Jandeleit, B. Synthesis of the bicyclic core of CP-225,917 and CP-263,114 by an intramolecular Diels-Alder strategy. Angew. Chem. Int. Ed. Engl. 36:1194, 1997.
Nicolaou, K.C., Härter, W.M., Gunzner, J.L., Nadin, A. The Wittig and related reactions in natural product synthesis. Liebigs Ann., July 1997, p. 1283.
Nicolaou, K.C., He, Y., Vourloumis, D., Vallberg, H., Roschangar, F., Sarabia, F., Ninkovic, S., Yang, Z. The olefin metathesis approach to epothilone A and Its analogs. J. Am. Chem. Soc. 119:7960, 1997.
Nicolaou, K.C., He, Y., Vourloumis, D., Vallberg, H., Yang, Z. An approach to epothilones based on olefin metathesis. Angew. Chem. Int. Ed. Engl. 35:2399, 1996.
Nicolaou, K.C., He, Y., Vourloumis, D., Vallberg, H., Yang, Z. Total synthesis of epothilone A: The olefin metathesis approach. Angew. Chem. Int. Ed. Engl. 36:166, 1997.
Nicolaou, K.C., Koide, K. Synthetic studies on maduropeptin chromophore, 1: Construction of the aryl ether and attempted synthesis of the [7.3.0] bicyclic system. Tetrahedron Lett. 38:3667, 1997.
Nicolaou, K.C., Koide, K., Xu, J., Izraelewicz, M.H. Synthetic studies on maduropeptin chromophore, 2: Synthesis of the madurosamine aryl amide and the C1´-C9´ fragments. Tetrahedron Lett. 38:3671, 1997.
Nicolaou, K.C., Ninkovic, S., Sarabia, F., Vourloumis, D., He, Y., Vallberg, H., Yang, Z. Total syntheses of epothilones A and B via a macrolactonization based strategy. J. Am. Chem. Soc. 119:7974, 1997.
Nicolaou, K.C., Sarabia, F., Finlay, M.R.V., Ninkovic, S., King, N.P., Vourloumis, D., He, Y. Total synthesis of oxazole- and cyclopropane-containing epothilone B analogs by the macrolactonization approach. Chem. Eur. J., in press.
Nicolaou, K.C., Sarabia, F., Ninkovic, S., Yang, Z. Total synthesis of epothilone A: The macrolactonization approach. Angew. Chem. Int. Ed. Engl. 36:525, 1997.
Nicolaou, K.C., Shi, G.-Q., Gunzner, J.L., Gärtner, P., Yang, Z. Palladium-catalyzed functionalization of lactones via their cyclic ketene acetal phosphates: Efficient new synthetic technology for the construction of medium and large cyclic ethers. J. Am. Chem. Soc. 119:5467, 1997.
Nicolaou, K.C., Smith, B.M., Pastor, J., Watanabe, Y., Weinstein, D.S. Synthesis of DNA-binding oligosaccharides. Synlett, May 1997, p. 401.
Nicolaou, K.C., Theodorakis, E.A. Total synthesis of natural products and designed molecules: Brevetoxin B. In: Pure Applied Chemistry, Medicinal Chemistry: Today and Tomorrow. Yamazaki, M. (Ed.). Blackwell Science, Cambridge, England, 1997, p. 49.
Nicolaou, K.C., Trujillo, J.I., Chibale, K. Design, synthesis and biological evaluation of carbohydrate-based mimetics of RGDFV. Tetrahedron 53:8751, 1997.
Nicolaou, K.C., Vallberg, H., King, N.P., Roschangar, F., He, Y., Vourloumis, D. Total synthesis of oxazole- and cyclopropane-containing epothilone A analogs by the olefin metathesis approach. Chem. Eur. J., in press.
Nicolaou, K.C., Winssinger, N., Pastor, J., DeRoose, F. A general and highly efficient solid phase synthesis of oligosaccharides: Total synthesis of heptasaccharide phytoalexin elicitor (HPE). J. Am. Chem. Soc. 119:449, 1997.
Nicolaou, K.C., Winssinger, N., Pastor, J., Ninkovic, S., Sarabia, F., He, Y., Vourloumis, D., Yang, Z., Li, T., Giannakakou, P., Hamel, E. Synthesis of epothilones A and B in solid and solution phase. Nature 387:268, 1997.
Nicolaou, K.C., Yang, Z., Ouellette, M., Shi, G.-Q., Gärtner, P., Gunzner, J. L., Agrios, C., Huber, R., Huang, D.H. New synthetic technology for the construction of 9-membered ring cyclic ethers: Construction of the EFGH ring skeleton of brevetoxin A. J. Am. Chem. Soc. 119:8105, 1997.
Nicolaou, K.C., Yue, E.W. New roads to molecular complexity. In: The New Chemistry. Cambridge University Press, New York, in press.
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Selective Catalysis and Organic Synthesis
K.B. Sharpless, H. Adolfsson, M. Bruncko, J. Chiang, H.-T. Chang, C. Copéret, R. Dress, A. Gypser, P.T. Ho, S. Immel, J. Jeong, L. Kolla, G. Li, D. Michel, D. Nirschl, W. Pringle, J. Rudolph, E. Rubin, G. Schlingloff, E. Stevens, B. Tao, A. Thomas, C. Vlaar, A. Yudin
The central theme of our research is the use of inorganic catalysts to uncover new and useful transformations for organic synthesis (Fig. 1).
The primary goal is to discover unprecedented reactivity, the harbinger of all important new reactions. This discovery can be accomplished by design or, as often happens, serendipitously; in either case, a new type of transformation often reveals itself for the first time as a minor or trace product in a reaction mixture. When useful new reactivity is recognized in a minor product, shaping this embryonic reaction and nurturing its potential becomes the goal. Thus, our research is characterized by two distinct phases: the prospecting phase that leads to the discovery of new reactivity and the development phase that determines if the reactivity will become an useful new reaction or simply remain a curiosity.
Current research interests include development of new homogeneous catalysts for the oxidation of organic compounds, use of inorganic reagents to effect new transformations in organic chemistry, and studies of asymmetric catalysis involving both early and late transition metal--mediated processes.
Three discoveries from our laboratory, titanium-catalyzed asymmetric epoxidation, osmium-catalyzed asymmetric dihydroxylation and osmium-catalyzed asymmetric aminohydroxylation, depend crucially on ligand-accelerated catalysis for their effectiveness. Part of our current effort is exploring this newly uncovered phenomenon and seeking to discover other systems driven by it.
We also have a large commitment to developing synthetic applications of our new catalytic asymmetric aminohydroxylation process. The main synthetic targets are drugs and other biologically active molecules.
Bruncko, M., Schlingloff, G., Sharpless, K.B. N-Bromoacetamide: A new nitrogen source for the catalytic asymmetric aminohydroxylation. Angew. Chem. Int. Ed. Engl. 36:1483, 1997.
Chang, H.T., Sharpless, K.B. Molar scale synthesis of enantiopure stilbene oxide. J. Org. Chem. 61:6456, 1996.
Copéret, C., Adolfsson, H., Sharpless, K.B. A simple and efficient method for epoxidation of terminal alkenes. Chem. Commun. 16:1565, 1997.
Li, G., Angert, H.H., Sharpless, K.B. N-Halocarbamate salts provide a more useful catalytic-asymmetric-aminohydroxylation process. Angew. Chem. Int. Ed. Engl. 35:2813, 1996.
Nelson, D.W., Gypser, A., Ho, P.T., Kolb, H.C., Kondo, T., Kwong, H.-L., McGrath, D.V., Rubin, A.E., Norrby, P.-O., Gable, K.P., Sharpless, K.B. Toward an understanding of the high enantioselectivity in the osmium-catalyzed asymmetric dihydroxylation, 4: Electronic effects in amine-accelerated osmylations. J. Am. Chem. Soc. 119:1840, 1997.
Rudolph, J., Reddy, K.L., Chiang, J.P., Sharpless, K.B. Highly efficient epoxidation of olefins using aqueous H2O2 and catalytic methyltrioxorhenium/pyridine: Pyridine-mediated ligand acceleration. J. Am. Chem. Soc. 119:6189, 1997.