Philip R. DeShong, Ph.D. - US grants

The specific aim of the research outlined in this proposal is to synthesize the antitumor antibiotic menogarol (A). The strategy is divided into three parts: (1) the preparation of benzoxocin B which comprises the DEF-rings of menogarol, (2) the annulation of the anthracycline rings onto B, and (3) the manipulation of the functionality in the A ring to give menogarol. The proposal also includes a section concerning the use of 4- and 5-silyl-substituted isoxazolidines for the synthesis of allylic amines and the pyrrolidine neurotoxins kainic acid (C) and allo-kainic acid (D). Silylisoxazolidines are prepared by the [3+2] dipolar cycloaddition of nitrones and vinylsilanes.

This research proposal outlines strategies for the completion of the total synthesis of tirandamycin B and streptolydigin which is patterned after the approach developed for the synthesis of tirandamycin A. The tirandamycins and streptolydigin are members of the dienoyl tetramic acid family of antibiotics isolated from various strains of Streptomyces. Streptolydigin has been shown to selectively inhibit terminal deoxynucleotidyl transferase (TDT), an enzyme present in large quantities in leukemic lymphoblasts, but not in normal leucocytes. TDT is believed to play a crucial role in the cellular metabolism of these cancer cells. It is possible that streptolydigin/tirandamycin or an analog of these natural products will prove effective in the treatment of various leukemias. The proposal also contains sections concerning the development of methodology for the synthesis of spiroketals and piperidones. Using this methodology, we propose to synthesize the spiroketal moieties of the anthelmintic compounds avermectin B1b and B2b, and glycosidase inhibitors 1-deoxynojirimycin, N-methyl-1-deoxynojirimycin, and 1-deoxymannojirimycin. Glycosidase inhibitors are used to characterize lysosomal enzymes involved in the biosynthesis and processing of glycoproteins and to determine the relationship between normal lysomal metabolism and lysosomal disease states. A human lysosomal storage disease is known for each of the glycosidases which are inhibited by these substances and study of their inhibitory activity will aid in understanding the aberrant metabolism associated with these human disorders.

health science research support; university;

This research proposal describes a series of experiments designed to probe the ability of organomanganese pentacarbonyl complexes to serve as reagents for the synthesis of structurally complex organic substances. The proposal is comprised of three sections. In the first, methodological studies are outlined. These include determination of the scope and limitation of the sequential insertion reaction, novel methodology for the preparation of highly functionalized manganese complexes, in particular glycosylmanganese complexes, and intramolecular variants of the sequential insertion reaction. The second section of the proposal describes the application of organomanganese reagents to the total synthesis of C-glycosyl substances tiazofurin (NSC-286193), selenazofurin, and pyrazofurin in optically active form. Tiazofurin and selenazofurin are synthetic C-nucleosides which possess potent antiviral and antitumor activity. For instance, both substances exhibit activity against Lewis lung carcinoma and L1210 and P388 leukemias in vivo. Pyrazofurin is a C-nucleoside isolated from Streptomyces candidus which has antitumor and broad spectrum antiviral activity. Pyrazofurin suppresses the replication of vaccinia, herpes simplex, measles, rhino and influenza viruses, and Friend and Rauscher leukemia virus in mice. Cultured Novikoff rat hepatome cells, HeLa cells and mouse L cells are also sensitive to pyrazofurin. The final section of the proposal describes preliminary studies of the utilization of organomanganese pentacarbonyl complexes for the synthesis of systems found in natural products such as C-arylated glycosyl compounds and polyether systems. The compounds synthesized during this investigation will serve as model compounds for the total synthesis of vineomycin B, pluramycin, chrysomycin B, lasolocid and monensin.

biomedical equipment resource; biomedical equipment purchase;

Dr. Philip DeShong and other members of the Chemistry Department of University of Maryland are being supported for a Research Experiences for Undergraduates (REU) site in Chemistry. For the period 1993-5, eight undergraduate students will spend ten weeks each summer actively engaged in a variety of research projects. Projects cover the traditional areas of chemistry-analytical, inorganic, organic, physical and biochemistry. A unique feature of this program is targeting of schools within a 200 hundred mile radius with special emphasis on women and minorities.

DESCRIPTION: (Applicant's Abstract) The long term goal of this research is to determine the scope and limitations of the palladium-catalyzed cross-coupling of hypervalent siloxanes with allylic ester and aryl derivatives. This methodology could serve as an alternative to Stille and Suzuki coupling protocols that have several limitations in the field of natural product synthesis. In this study, the reactions of aryl, vinyl, and allyl siloxanes with a variety of substrates will be investigated. In addition, evaluation of new palladium catalysts for cross-couplings with aryl chlorides and the use of chiral ligands for an asymmetric version of the cross-coupling reaction will be undertaken. Once the scope of the coupling methodology has been determined, the siloxane methodology will be employed for the total synthesis of the antitumor antibiotic (+)-pancratastatin and the antimitotic agent (-)-colchicine.

DESCRIPTION (provided by applicant): Funding is requested for a high performance LC-TOF instrument with electrospray, nanospray and atmospheric pressure chemical ionization. An HPLC will be interfaced for use with electrospray and APCI. The orthogonal acceleration TOF analyzer provides accurate mass determinations (5ppm at m/z 609) with an externally calibrated mass range up to m/z 10,000 da. Resolution is specified as 6000. The detector, and ADC continuous digital averager, provides improved peak shapes and wider dynamic range, compared to TDC detectors. These features of the ADC allow analysis of true isotope distributions, including HID exchange product correlation of signal to sample size, e.g. through four orders of magnitude with an R=0.998. Major users propose to use the instrument to; . Identify key nucleophiles involved in self-adduct formation and target alkylation of oligonucleotides, to determine the kinetics of these processes; Characterize non-natural self assemblies constructed by hydrophobic effects, e.g. self complementary amphiphiles and self sorted molecular clips; . Analyze and localize hydrogen/deuterium exchange to characterize a key intermediate in the assembly transcriptional regulatory complex of the biotin repressor; . Characterize polyubiquitin chains, synthetic and isotope labeled analogs for subsequent NMR studies and dynamics; . Characterize intermediates in the synthesis of un-natural analogs of pancratistatin, streptonigrin and nephritogenoside. The instrument will be housed in the existing Departmental Central Instrumentation Facility, where it will be managed by the staff mass spectroscopist Mr. Noel Whittaker, and operated by him and trained users. It is anticipated that the use of the instrument by scientists working across a broad range of chemistry, biochemistry and cell biology will help stimulate cross-disciplinary discussions and collaboration.

With support from the Chemistry Research Instrumentation and Facilities (CRIF) Program, the Department of Chemistry at the University of Maryland in College Park will acquire instrumentation for time correlated single photon counting. This equipment will enhance research in a number of areas including the following: a) single-molecule studies of protein-induced DNA conformational populations; b) measurement of fluorescence lifetimes from short-lived low quantum yield species; c) studies of complex fluorescence kinetics and reorientation of new molecular surfactants adsorbed to liquid/liquid interfaces; and d) investigations of radical chemistry in environmental systems.
Measuring time resolved fluorescence affords researchers direct insight into the local environment and dynamics around a probe. Techniques developed to monitor time resolved fluorescence have been broadly applied to established fields such as photobiology as well as newly emerging areas in materials chemistry.

This award is made through the Ethics Education in Science and Engineering solicitation (NSF 06-524). The project will develop a set of ethics courses and workshops that focus on graduate-student education, but also provide training on research integrity for postdoctoral associates and for new assistant professors that will enable these individuals to be better "role models" in research ethics for their graduate students. These courses will be developed first within the colleges of the Principal Investigators at the University of Maryland, College Park, using the extensive experience of the Principal Investigators in such courses. In the second year of the grant, the courses will be extended to the other science and engineering colleges and departments on the College Park campus. In the third year, the courses will be made available across the State of Maryland in the University System of Maryland. The courses will engage graduate students in actively solving real-world research-integrity problems, and the influence of the courses will be extended by training postdoctoral associates as ethics teachers. These trained teachers will later disperse across this country and abroad. The course for graduate students, Research Ethics, will include an introduction to the philosophy of ethics and value systems, and an introduction to the philosophy of science and how science is structured. Then it will discuss the issues that arise in trying to do "good Science" and to avoid bias in research, and the cross-checks against error and bias. Other topics will include animal subjects, human subjects, attribution and authorship, mentoring, intellectual property, and under-represented groups. A second course, Advanced Research Ethics, will be developed for postdoctoral associates and for graduate students who wish to obtain the Graduate Certificate in Research Ethics that will also be developed. This course will develop the course topics more deeply and will cover the pedagogy of ethics training. A new Research Ethics Workshop will be developed as a 4- to 6-hour one-day workshop for untenured faculty members in science and engineering, to introduce them to ethical concerns and to prepare them to mentor their own students on research integrity.
Intellectual merit: The project will engage graduate students and postdoctoral research associates in the analysis of the serious and complex ethical issues that face all scientists and engineers in the course of their careers.
Broader impacts: The project will produce (1) graduate students who know how to address ethical issues; (2) postdoctoral research associates who not only understand these issues, but know how to teach on these issues and can expand the impact of the project across Maryland, the United States, and beyond; (3) new faculty members who appreciate the importance of research integrity and can apply it in the training of their own students; and (4) extension of the courses developed at College Park to other campuses in Maryland.