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Scientific Report 2008


Chemistry




Synthetic and Bioorganic Chemistry


D.L. Boger, E. Anderson, S. Baraldi, K. Boyle, C. Burke, R. Clark, D. Colby, C. Crane, J. DeMartino, J. Elsner, C. Ezzili, J. Garfunkle, H. Ge, D. Hochstatter, I. Hwang, R. Jones, H. Kakei, D. Kato, F.S. Kimball, J. Lajiness, S. Lee, C. Liu, K. MacMillan, J. Nam, K. Otrubova, P. Patel, W. Robertson, Y. Sasaki, M. Schnermann, S. Seto, C. Slown, S. Stamm, J. Stover, S. Takizawa, A. Tam, P. Va, L. Whitby, J. Xie, A. Zuhl

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 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.

Fig. 1. N-Sulfonyl-1-aza-1,3-butadiene Diels-Alder reaction.

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, 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) and cytostatin; the combretastatins; storniamide A; phomazarin; ningalins; lamellarin O; lukianol A; piericidins; nothapodytine and mappicine; rubrolone; vindoline; 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, the duocarmycins, and yatakemycin are antitumor antibiotics and related sequence-selective DNA minor groove alkylating agents. Representative of such efforts, studies to determine the structural features of yatakemycin and the duocarmycins that 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 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.



Fig. 2. Recent total syntheses.

Fig. 3. Additional recent total syntheses.


Publications

Eubanks, L.M., Hixon, M.S., Jin, W., Hong, S., Clancy, C.M., Tepp, W.H., Baldwin, M.R., Malizio, C.J., Goodnough, M.C., Barbieri, J.T., Johnson, E.A., Boger, D.L., Dickerson, T.J., Janda, K.D. An in vitro and in vivo disconnect uncovered through high-throughput identification of botulinum neurotoxin A antagonists [published correction appears in Proc. Natl. Acad. Sci. U. S. A. 104:6490, 2008]. Proc. Natl. Acad. Sci. U. S. A. 104:2602, 2007.

Hardouin, C., Kelso, M.J., Romero, F.A., Rayl, T.J., Leung, D., Hwang, I., Cravatt, B.F., Boger, D.L. Structure-activity relationships of the α-ketooxazole inhibitors of fatty acid amide hydrolase. J. Med. Chem. 50:3359, 2007.

Ishikawa, H., Boger, D.L. Total synthesis of (—)- and ent-(+)-4-desacetoxy-5-desethylvindoline. Heterocycles 72:95, 2007.

Jin, W., Trzupek, J.D., Rayl, T.J., Broward, M.A., Vielhauer, G.A., Weir, S.J., Hwang, I., Boger, D.L. A unique class of duocarmycin and CC-1065 analogues subject to reductive activation. J. Am. Chem. Soc. 129:15391, 2007.

Lee, S.Y., Clark, R.C., Boger, D.L. Total synthesis, stereochemical reassignment, and absolute configuration of chlorofusin. J. Am. Chem. Soc. 129:9860, 2007.

Nam, J., Shin, D., Rew, Y., Boger, D.L. Alanine scan of [L-Dap2]ramoplanin A2 aglycon: assessment of the importance of each residue. J. Am. Chem. Soc. 129:8747, 2007.

Romero, F.A., Du, W., Hwang, I., Rayl, T.J., Kimball, F.S., Leung, D., Hoover, H.S., Apodaca, R.L., Breitenbucher, J.G., Cravatt, B.F., Boger, D.L. Potent and selective α-ketoheterocycle-based inhibitors of the anandamide and oleamide catabolizing enzyme, fatty acid amide hydrolase. J. Med. Chem. 50:1058, 2007.

Tichenor, M.S., MacMillan, K.S., Stover, J.S., Wolkenberg, S.E., Pavani, M.G., Zanella, L., Zaid, A.N., Spalluto, G., Rayl, T.J., Hwang, I., Baraldi, P.G., Boger, D.L. Rational design, synthesis, and evaluation, of key analogues of CC-1065 and the duocarmycins. J. Am. Chem. Soc. 129:14092, 2007.

Tichenor, M.S., MacMillan, K.S., Trzupek, J.D., Rayl, T.J., Hwang, I., Boger, D.L. Systematic exploration of the structural features of yatakemycin impacting DNA alkylation and biological activity. J. Am. Chem. Soc. 129:10858, 2007.

Xu, L., Chong, Y., Hwang, I., D'Onofrio, A., Amore, K., Beardsley, G.P., Li, C., Olson, A.J., Boger, D.L., Wilson, I.A. Structure-based design, synthesis, evaluation, and crystal structures of transition state analogue inhibitors of inosine monophosphate cyclohydrolase. J. Biol. Chem. 282:13033, 2007.

 


Dale L. Boger, Ph.D.
Professor



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