Scientific Report 2007

Chemistry

Synthetic and Bioorganic Chemistry

D.L. Boger, R. Clark, D. Colby, J. Cottell, C. Crane, J. DeMartino, J. Elsner, C. Ezzili, J. Fuchs, J. Garfunkle, H. Ge, N. Haq, I. Hwang, H. Ishikawa, W. Jin, R. Jones, H. Kakei, D. Kato, F.S. Kimball, B. Lawhorn, S. Lee, C. Liu, K. MacMillan, J. Nam, P. Patel, T. Rayl, W. Robertson, A. Romero, Y. Sasaki, M. Schnermann, A. Shaginian, C. Slown, S. Stamm, J. Stover, L. Takaoka, S. Takizawa, H. Tao, M. Tichenor, J. Trzupek, L. Whiby, J. Xie, Y. Zhang, 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.

Fig. 2. Recent total syntheses.

Fig. 3. Additional recent total syntheses.

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.

Publications

Clark, R.C., Pfeiffer, S.S., Boger, D.L. Diastereoselective Diels-Alder reactions of N-sulfonyl-1-aza-1,3-butadienes with optically active enol ethers: an asymmetric variant of the 1-azadiene Diels-Alder reaction. J. Am. Chem. Soc. 128:2587, 2006.

Crowley, B.M., Boger, D.L. Total synthesis and evaluation of [ψ[CH₂NH]Tpg⁴]vancomycin aglycon: reengineering vancomycin for dual D-Ala-D-Ala and D-Ala-D-Lac binding. J. Am. Chem. Soc. 128:2885, 2006.

DeMartino, J.K., Hwang, I., Xu, L., Wilson, I.A., Boger, D.L. Discovery of a potent, nonpolyglutamatable inhibitor of glycinamide ribonucleotide transformylase. J. Med. Chem. 49:2998, 2006.

Elliott, G.I., Fuchs, J.R., Blagg, B.S.J., Ishikawa, H., Tao, H., Yuan, Z.-Q., Boger, D.L. Intramolecular Diels-Alder/1,3-dipolar cycloaddition cascade of 1,3,4-oxadiazoles. J. Am. Chem. Soc. 128:10589, 2006.

Elliott, G.I., Velcicky, J., Ishikawa, H., Li, Y., Boger, D.L. Total synthesis of (–)- and ent-(+)-vindorosine: tandem intramolecular Diels-Alder/1,3-dipolar cycloaddition of 1,3,4-oxadiazoles. Angew. Chem. Int. Ed. 45:620, 2006.

Fang, X., Tiyanont, K., Zhang, Y., Wanner, J., Boger, D., Walker, S. The mechanism of action of ramoplanin and enduracidin, Mol. Biosyst. 2:69, 2006.

Hamasaki, A., Ducray, R., Boger, D.L. Two novel 1,2,4,5-tetrazines that participate in inverse electron demand Diels-Alder reactions with an unexpected regioselectivity. J. Org. Chem. 71:185, 2006.

Ishikawa, H., Elliott, G.I., Velcicky, J., Choi, Y., Boger, D.L. Total synthesis of (–)- and ent-(+)-vindoline and related alkaloids. J. Am. Chem. Soc. 128:10596, 2006.

Lawhorn, B.G., Boga, S.B., Wolkenberg, S.E., Boger, D.L. Total synthesis of cytostatin. Heterocycles 70:65, 2006.

Lawhorn, B.G., Boga, S.B., Wolkenberg, S.E., Colby, D.A., Gauss, C.-M., Swingle, M.R., Amable, L., Honkanen, R.E., Boger, D.L. Total synthesis of cytostatin, its C10-C11 diastereomers and additional key analogues: impact on PP2A inhibition. J. Am. Chem. Soc. 128:16720, 2006.

Romero, F.A., Hwang, I., Boger, D.L. Delineation of a fundamental α-ketoheterocycle substituent effect for use in the design of enzyme inhibitors. J. Am. Chem. Soc. 128:14004, 2006.

Schnermann, M.J., Romero, F.A., Hwang, I., Nakamaru-Ogiso, E., Yagi, T., Boger, D.L. Total synthesis of piericidin A1 and B1 and key analogues. J. Am. Chem. Soc. 128:11799, 2006.

Tichenor, M.S., Trzupek, J.D., Kastrinsky, D.B., Shiga, F., Hwang, I., Boger, D.L. Asymmetric total synthesis of (+)- and ent-(–)-yatakemycin and duocarmycin SA: evaluation of yatakemycin key partial structures and its unnatural enantiomer. J. Am. Chem. Soc. 128:15683, 2006.

Trzupek, J.D., Gottesfeld, J.M., Boger, D.L. Alkylation of duplex DNA in nucleosome core particles by duocarmycin SA and yatakemycin. Nat. Chem. Biol. 2:79, 2006.