News and Publications

Synthetic and Bioorganic Chemistry

D.L. Boger, C. Andersson, B. Aquila, B. Austin, R. Beresis, C. Boyce, H. Cai, S. Castle, R. Castro, W. Chai, P. Ducray, B. Fink, R. Garbaccio, J. Goldberg, J. Hong, W. Jiang, Q. Jin, Y.-S. Jung, H. Keim, M. Kume, M. Labroli, M. Ledeboer, J.K. Lee, R. Lee, E. Lerner, B. Lewis, O. Loiseleur, T. Matsuzaki, S. Miyazaki, J. Patterson, M. Pattricelli, H. Purkey, L. Resnick, K. Saionz, A. Santillán, H. Sato, S. Satoh, R. Schaum, G. Schüle, M. Searcey, C. Sehon, P. Turnbull, A. Vaupel, G. Wilke, J. Wu

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.

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 radical­alkene 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 class of antitumor agents; vancomycin, chloropeptins, and related agents; ramoplanin; the luzopeptins and sandramycin; bleomycin A₂ and functional analogs; HUN-7293; CI-920; rhizoxin; the combretastatins; stornamide A; phomazarin; ningalin A; lamellarin O; lukianol A; polycitone A; 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. Representative of such efforts, studies to determine structural features of (+)-CC-1065 and the duocarmycins that contribute to sequence-selective DNA alkylation properties of these agents (Fig. 4) have resulted in the identification of a unique 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.

PUBLICATIONS

Boger, D.L., Garbaccio, R.M., Jin, Q. Synthesis and evaluation of CC-1065 and duocarmycin analogs incorporating the iso-CI and iso-CBI alkylation subunits: Impact of relocation of the C-4 carbonyl. J. Org. Chem. 62:8875, 1997.

Boger, D.L., Loiseleur, O., Castle, S.L., Beresis, R.T., Wu, J.H. Thermal atropisomerism of fully functionalized vancomycin CD, DE, and CDE ring systems. Bioorg. Med. Chem. Lett. 7:3199, 1997.

Boger, D.L., Teramoto, S., Cai, H. N-Methyl-l-threonine analogs of deglycobleomycin A₂: Synthesis and evaluation. Bioorg. Med. Chem. 5:1573, 1997.

Guan, X., Cravatt, B.F., Ehring, G.R., Hall, J.E., Boger, D.L., Lerner, R.A., Gilula, N.B. The sleep-inducing lipid oleamide deconvolutes gap junction communication and calcium wave transmission in glial cells. J. Cell Biol. 139:1785, 1997.