Scientific Report 2008
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.
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).
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.
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
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,
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,
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.