Scientific Report 2006

Chemistry

Synthetic and Bioorganic Chemistry

D.L. Boger, S.B. Boga, K. Bunker, R. Clark, D. Colby, J. Cottell, B. Crowley, J. DeMartino, G. Elliott, J. Elsner, C. Ezzili, J. Fuchs, J. Garfunkle, A. Hamasaki, W. Han, N. Haq, S. Hong, D. Horne, I. Hwang, H. Ishikawa, W. Jin, D. Kato, D. Kastrinsky, M. Kelso, G. Kim, F.S. Kimball, B. Lawhorn, S. Lee, C. Liu, K. MacMillan, J. Nam, P. Patel, A. Romero, M. Schnermann, A. Shaginian, C. Slown, L. Takaoka, H. Tao, M. Tichenor, J. Trzupek, J. Velcicky, L. Whiby, Y. Zhang

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).

Fig. 2. Recent total syntheses.

Fig. 3. Additional recent total syntheses.

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.

Publications

Boger, D.L., Miyauchi, H., Du, W., Hardouin, C., Fecik, R.A., Cheng, H., Hwang, I., Hedrick, M.P., Leung, D., Acevedo, O., Guimarães, C.R.W., Jorgensen, W.L., Cravatt, B.F. Discovery of a potent, selective, and efficacious class of reversible α-ketoheterocycle inhibitors of fatty acid amide hydrolase effective as analgesics. J. Med. Chem. 48:1849, 2005.

Capps, K.J., Humiston, J., Dominique, R., Hwang, I., Boger, D.L. Discovery of AICAR Tfase inhibitors that disrupt requisite enzyme dimerization. Bioorg. Med. Chem. Lett. 15:2840, 2005.

Cheng, H., Chong, Y., Hwang, I., Tavassoli, A., Zhang, Y., Wilson, I.A., Benkovic, S.J., Boger, D.L. Design, synthesis, and evaluation of 10-methanesulfonyl-DDACTHF, 10-methanesulfonyl-5-DACTHF, and 10-methylthio-DDACTHF as potent inhibitors of GAR Tfase and the de novo purine biosynthetic pathway. Bioorg. Med. Chem. 13:3577, 2005.

Cheng, H., Hwang, I., Chong, Y., Tavassoli, A., Webb, M.E., Zhang, Y., Wilson, I.A., Benkovic, S.J., Boger, D.L. Synthesis and biological evaluation of N-{4-[5-(2,4-diamino-6-oxo-6-dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway. Bioorg. Med. Chem. 13:3593, 2005.

Choi, Y., Ishikawa, H., Velcicky, J., Elliott, G.I., Miller, M.M., Boger, D.L. Total synthesis of (–)- and ent-(+)-vindoline. Org. Lett. 7:4539, 2005.

Chong, Y., Hwang, I., Tavassoli, A., Zhang, Y., Wilson, I.A., Benkovic, S.J, Boger, D.L. Synthesis and biological evaluation of α- and γ-carboxamide derivatives of 10-CF₃CO-DDACTHF. Bioorg. Med. Chem. 13:3587, 2005.

Chou, T.-C., Gaun, Y., Soenen, D.R., Danishefsky, S.J., Boger, D.L. Potent reversal of multidrug resistance by ningalin and its use in drug combinations against human colon carcinoma xenografts in nude mice. Cancer Chemother. Pharmacol. 56:379, 2005.

Du, W., Hardouin, C., Cheng, H., Hwang, I., Boger, D.L. Heterocyclic sulfoxide and sulfone inhibitors of fatty acid amide hydrolase. Bioorg. Med. Chem. Lett. 15:103, 2005.

Guimarães, C.R.W., Boger, D.L., Jorgensen, W.L. Elucidation of fatty acid amide hydrolase inhibition by potent α-ketoheterocycle derivatives from Monte Carlo simulations. J. Am. Chem. Soc. 127:17377, 2005.

Hamasaki, A., Zimpleman, J.M., Hwang, I., Boger, D.L. Total synthesis of ningalin D. J. Am. Chem. Soc. 127:10767, 2005.

Leung, D., Du, W., Hardouin, C., Cheng, H., Hwang, I., Cravatt, B.F., Boger, D.L. Discovery of an exceptionally potent and selective class of fatty acid amide hydrolase inhibitors enlisting proteome-wide selectivity screening: concurrent optimization of enzyme inhibitor potency and selectivity. Bioorg. Med. Chem. Lett. 15:1423, 2005.

Schnermann, M.J., Boger, D.L. Total synthesis of piercidin A1 and B1. J. Am. Chem. Soc. 127:15704, 2005.

Tse, W.C., Boger, D.L. A fluorescent intercalator displacement (FID) assay for establishing DNA binding selectivity and affinity. In: Current Protocols in Nucleic Acid Chemistry. Beaucage, S.L., et al. (Eds.). Wiley & Sons, New York, in press.

Walker, S., Chen, L., Hu, Y., Rew, Y., Shin, D., Boger, D.L. Chemistry and biology of ramoplanin: a lipoglycodepsipeptide with potent antibiotic activity. Chem. Rev. 105:449, 2005.

Yuan, Z., Ishikawa, H., Boger, D.L. Total synthesis of natural (+)- and ent-(–)-4-desacetoxy-6,7-dihydrovindorosine [corrected] and natural and ent-minovine: oxadiazole tandem intramolecular Diels-Alder/1,3-dipolar cycloaddition reaction [published correction appears in Org. Lett. 7:2079, 2005]. Org. Lett. 7:741, 2005.