Graduate Study in - Chemistry - Johns Hopkins University

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Organic Chemistry; Photochemistry and Photobiology; Characterization of Reactive Intermediates jtoscano@jhu.edu John P. Toscano Most photochemical reactions take place through very short-lived intermediates such as singlet or triplet excited states, radicals, carbenes, nitrenes, and nitrenium ions. A thorough understanding of these intermediates is not only of basic scientific concern, but also has direct relevance to many critical issues in photochemistry and photobiology. The Toscano group’s main research interests involve the application of time-resolved spectroscopic techniques to the study of these intermediates with particular emphasis on the use of newly developed methods in time-resolved infrared spectroscopy. Nitric oxide (NO), a diatomic radical known previously as a noxious environmental pollutant, is now known to be involved in a wide range of important bioregulatory processes including neurotransmission, blood clotting, and blood pressure control. In addition, macrophages have been shown to kill cancerous tumor cells and intracellular parasites by releasing large amounts of NO. Deficiencies in these processes caused by a poor endogenous supply of NO are often treatable with NO-releasing drugs. Diazeniumdiolates (1) are an interesting class of such drugs presently under development. Recent efforts to make diazeniumdiolates more effective pharmaceuticals have concentrated on using derivatives of such compounds to deliver NO specifically to a targeted site. Given the large number of biological phenomena now known to be mediated by NO, such targeting will be critical to the success of most medical applications. We have begun to develop photochemical precursors to diazeniumdiolates that can be used as effective and potentially selective NO-releasing agents. Since initial experiments in other laboratories with classical photoprotecting groups (P) gave unexpected and disappointing results, we are presently clarifying reaction pathways so that more efficient phototriggered NO-releasing drugs can be rationally designed. In addition, if diazeniumdiolates are to enjoy routine medical use, their basic photochemistry must be understood so that phototoxicity issues may be anticipated and avoided. Recent Publications Include: Toscano, J. P. “Structure and Reactivity of Organic Intermediates as Revealed by Time-Resolved IR Spectroscopy” Adv. Photochem. 2001, 26, 41-91. Srinivasan, A.; Kebede, N.; Saavedra, J. E.; Nikolaitchik, A. V.; Brady, D. A.; Yourd, E.; Davies, K. M.; Keefer, L. K.; Toscano, J. P. “Chemistry of the Diazeniumdiolates. 3. Photoreactivity” J. Am. Chem. Soc. 2001, 123, 5465-5472. Srivastava, S.; Ruane, P. H.; Toscano, J. P.; Sullivan, M. B.; Cramer, C. J.; Chiapperino, D.; Reed, E. C.; Falvey, D. E. “Structures of Reactive Nitrenium Ions: Time-Resolved Infrared Laser Flash Photolysis and Computational Studies of Substituted N-Methyl-N-aryl- Nitrenium Ions” J. Am. Chem. Soc. 2000, 122, 8271-8278. Wang, Y.; Toscano, J. P. “Time-resolved IR Studies of 4-Diazo-3-Isochromanone: Direct Kinetic Evidence for a Non-Carbene Route to Ketene” J. Am. Chem. Soc. 2000, 122, 4512-4513. Ph.D., Yale University NIH Postdoctoral Fellow, Ohio State University Camille and Henry Dreyfus New Faculty Award NSF CAREER Award Camille Dreyfus Teacher- Scholar Award Alfred P. Sloan Research Fellowship “Controlled Photochemical Release of Nitric Oxide from O 2 -Benzyl Substituted Diazeniumdiolates” Ruane, P.H.; Bushan, K.M.; Pavlos, C.M.; D’Sa, R.A.; Toscano, J. P. J. Am. Chem. Soc. 2002, in press. “Solvent Dependence of the 2-Napthyl (carbomethoxy)carbene Singlet-Triplet Energy Gap” Wang, Y.; Hadad, C.M.; Toscano, J. P. J. Am. Chem. Soc. 2002, 124, 1761-1767. O R2N N + h N O P O R2N N + N O + P H 2 O pH 7.4 R 2 NH + 2 NO + OH P Graduate Study in Chemistry at The Johns Hopkins University 21
Craig A. Townsend Bioorganic Chemistry townsend@jhunix.hcf.jhu.edu Research programs in Dr. Townsend’s group are broadly in the area of bioorganic chemistry with specific interests in natural product biosynthesis, the enzymology and molecular biology of secondary metabolism and molecular medicine. Underlying these studies are interests in reaction mechanism and synthesis, notably biomimetic synthesis, mechanistic enzymology, protein structure and protein engineering, exploration of the genetic organization and over-expression of biosynthetic enzymes, and the study of and the design and synthesis of fatty acid synthase inhibitors leading to practical treatments in cancer, tuberculosis and obesity. Recent publications include: Khaleeli, N.; Li, R.-F.; Townsend, C. A. “Origin of the -Lactam Carbons in Clavulanic Acid from an Unusual Thiamine Pyrophosphate- Mediated Reaction,” J. Amer. Chem. Soc. 1999, 121, 9223-9224. [See ‘Perspectives’ article: Science 2000, 287, 818-819.] Challis, G. L.; Ravel, J.; Townsend, C. A. “Predictive, Structure-Based Model of Amino Acid Recognition by Non-Ribosomal Peptide Synthetase Adenylation Domains,” Chemistry & Biology 2000, 7, 211-224. Ph.D., Yale University Postdoctoral, Eidgenössiche Teschnische Hochschule Alfred P. Sloan Research Fellowship Camille Dreyfus - Teacher Scholar Award Loftus, T. M.; Jaworsky D.; Frehywot, G. L.; Townsend, C. A.; Ronnett, G.; Lane, M. D.; Kuhajda, F. J. “Inhibitors of Fatty Acid Synthase Induce Weight Loss: A Link Between Fatty Acid Synthesis and Feeding Behavior,” Science 2000, 288, 2379-2381. Jones, P. B.; Parrish, N. M.; Houston, T. A.; Stapon, A. S.; Bansal, N. P.; Dick, J. D.; Townsend, C. A. “A New Class of Anti- Tuberculosis Agents,” J. Med. Chem. 2000, 43, 3304-3314. Li. R.-F.; Stapon, A.; Blanchfield, J. T.; Townsend, C. A. “Three Unusual Reactions Mediate Carbapenem and Carbapenam Biosynthesis,” J. Amer. Chem. Soc. 2000, 122, 9296-9297. Miller, M. T.; Bachmann, B. O.; Townsend, C. A.; Rosenzweig, A. C. “Stucture of ß-Lactam Synthetase Reveals How to Synthesize Antibiotics Instead of Asparagine,” Nature Struct. Biol. 2001, 8, 684-689. Udwary, D.W.; Casillas, L.K.; Townsend, C.A. “Synthesis of 11-Hydroxyl O-Methylsterigmatocystin and the Role of a Cytochrome P- 450 in the Final Step of Aflatoxin Biosynthesis,” J. Amer. Chem. Soc. 2002, 124, 5294-5303. Maryland Chemist of the Year (1992) ACS Arthur C. Cope Scholar Award 22 Graduate Study in Chemistry at The Johns Hopkins University
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