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The Skaggs Institute for Chemical Biology
Scientific Report 1999-2000


Synthetic, Medicinal, and Bioorganic Chemistry


D.L. Boger, Y. Ambroise, B. Aquila, B. Blagg, P. Bounaud, C. Boyce, S. Brunette, S. Castle, Y. Chen, D. Ellis, R. Fecik, R. Garbaccio, C. Gauss, J. Goldberg, M. Hedrick, J. Hong, T. Hughes, S. Ichikawa, T. Ishii, W. Jiang, Q. Jin, H. Keim, S. Kim, P. Krenitsky, M. Lall, M. Ledeboer, J.K. Lee, R. Lee, E. Lerner, B. Lewis, D. Lewy, O. Loiseleur, T. Marsilje, T. Matsuzaki, J. McAtee, P. Meier, H. Miyauchi, S. Miyazaki, D. O'Neill, S. Pollack, L. Resnick, O. Rogel, A. Santillán, H. Sato, S. Satoh, R. Schaum, H. Schmitt, C. Sehon, D. Soenen, H. Strittmatter, W. Tse, J. Weng, G. Wilke, S. Wolkenberg, C. Woods, W. Zhong

The research interests of our group include the total synthesis of biologically active natural products, the development of new synthetic methods, heterocyclic chemistry, bioorganic and medicinal chemistry, combinatorial 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 agents in efforts to understand the origin of the biological properties of the agents.

Natural Products

A powerful complement to the examination of the naturally derived agents themselves is the preparation and subsequent examination of key partial structures, agents containing deep-seated structural modifications, and the corresponding unnatural enantiomers of the natural products. Well-conceived deep-seated structural modifications can be used to address the structural basis of the interactions of the natural products with biological targets and to define fundamental relationships between structure, functional reactivity, and properties. In these studies we address the challenging problem of understanding the beautiful solutions and subtle design elements provided in the form of a natural product and work to extend the solution through rational design elements to provide more selective, more efficacious, or more potent agents designed specifically for the problem or target under investigation.

In the past year, we completed total syntheses of the natural products vancomycin aglycon (an antibiotic); ningalin A, lamerlarin O, lukianol A, and permethyl storniamide (multidrug resistance reversal agents); luzopeptins A-C (antitumor compounds); quinoxapeptins (HIV reverse transcriptase inhibitors); phormazarin; HUN-7293 (an anti-inflammatory compound); and key analogs, including those of the antitumor compounds CC-1065, duocarmycin, and bleomycin A2.

Central to such studies are the development of dependable synthetic strategies and the advent of new synthetic methods for preparation of the natural products, key partial structures, and analogs incorporating deep-seated structural changes. The resulting efforts have reduced many difficult or intractable synthetic challenges to manageable problems and have provided an approach not only to the natural product but also to a series of structural analogs. Our research enabled us to fully explore the origin of the properties of the natural products and to devise agents with improved selectivity and efficacy.

Oleamide

Oleamide, a fatty acid primary amide with physiologic sleep-inducing properties, is a prototypical member of a new class of endogenous chemical messengers.

Study of this amide led to the identification of an enzyme, fatty acid amide hydrolase, responsible for the degradation and regulation of oleamide; characterization of an endogenous inhibitor of the enzyme (2-octyl-γ-bromoacetoacetate); and the discovery of potential sites of action. Exceptionally potent inhibitors of fatty acid amide hydrolase, which also degrades anandamide, have been prepared and characterized and are being investigated in the treatment of sleep disorders and as novel analgesics.

Signal Transduction

Receptor activation by homodimerization, heterodimerization, and higher order homo- and hetero-oligomerization has emerged as a general mechanism of initiating intracellular signal transduction. We are investigating the fundamental principles and structural features embodied in activation of the receptor for erythropoietin. Additional targets under examination include ErbB-2, Myc-Max, LEF-1/ß-catenin, the androgen receptor, and angiogenesis inhibitors (αvß3 and αvß5), including those that inhibit binding of matrix metalloproteinase 2 to αvß3 (Fig. 1).

Solution-Phase Combinatorial Chemistry

As a complement to the techniques of solid-phase combinatorial chemistry for advancing drug discovery, we are developing solution-phase approaches to the multistep preparation of combinatorial libraries that offer substantial advantages. For example, direct dimerization linkage of combinatorial libraries of iminodiacetic acid diamides, which is precluded by solid-phase techniques, provides a unique approach to the discovery of agonists for the receptor dimerization and activation events detailed in the preceding paragraph (Fig. 2).

Transformylases

In collaboration with I.A. Wilson, the Skaggs Institute, we are examining x-ray crystallographic structures of (1) the apo forms of glycinamide ribonucleotide transformylase and aminoimidazole carboxamide ribonucleotide transformylase and (2) complexes of the enzymes with their substrates (glycinamide ribonucleotide and aminoimidazole carboxamide ribonucleotide), folate cofactors, and inhibitors. Our goals are the de novo design and examination of potential potent enzyme inhibitors as antineoplastic agents.

DNA-Drug Interactions

Considerable efforts have been devoted to exploring and defining the structural basis for the sequence-selective recognition of duplex DNA by a series of naturally occurring antitumor antibiotics, including (1) CC-1065 and the duocarmycins; (2) bleomycin A2; (3) sandramycin, the luzopeptins, quinoxapeptins, thiocoraline, and BE-22179; (4) isochrysohermidin; and (5) distamycin A. In each instance, synthetic deep-seated structural changes in the natural product are used to probe the basis for the recognition of or ensuing chemical reaction with duplex DNA. Large combinatorial libraries of potential DNA-binding agents have been prepared, and new technology for high-throughput screening for DNA-binding affinity and selectivity has been developed (Fig. 3).

Publications

Baraldi, P.G., Cacciari, B., Romagnoli, R., Spalluto, G., Boyce, C.W., Boger, D.L. Resolution of a CPzI precursor, synthesis and biological evaluation of (+)- and (-)-NBoc-CPzI: A further validation of the relationship between chemical solvolytic stability and cytotoxicity. Bioorg. Med. Chem. Lett. 9:3087, 1999.

Boger, D.L., Boyce, C.W., Garbaccio, R.M., Searcey, M., Jin, Q. CBI prodrug analogs of CC-1065 and the duocarmycins. Synthesis 1505, 1999.

Boger, D.L., Boyce, C.W., Labroli, M.A., Sehon, C.A., Jin, Q. Total syntheses of ningalin A, lamellarin O, lukianol A, and permethyl storniamide A utilizing heterocyclic azadiene Diels-Alder reactions. J. Am. Chem. Soc. 121:54, 1999.

Boger, D.L., Cai, H. Bleomycin: Synthetic and mechanistic studies. Angew. Chem. Int. Ed. 38:448, 1999.

Boger, D.L., Castle, S.L., Miyazaki, S,. Wu, J.H., Beresis, R.T., Loiseleur, O. Vancomycin CD and DE macrocyclization and atropisomerism studies. J. Org. Chem. 64:70 1999.

Boger, D.L., Garbaccio, R.M. Are the duocarmycin and CC-1065 DNA alkylation reactions acid catalyzed? Solvolysis pH rate profiles suggest they are not. J. Org. Chem. 64:5666, 1999.

Boger, D.L., Garbaccio, R.M. A novel class of CC-1065 and duocarmycin analogs subject to mitomycin-related reductive activation. J. Org. Chem. 64:8350, 1999.

Boger, D.L., Garbaccio, R.M. Shape-dependent catalysis: Insights into the source of catalysis for the CC-1065 and duocarmycin DNA alkylation reaction. Acc. Chem. Res. 32:1043, 1999.

Boger, D.L., Goldberg, J., Andersson, C.M. Solution phase combinatorial synthesis of biaryl libraries employing heterogeneous conditions for catalysis and isolation with size exclusion chromatography for purification. J. Org. Chem. 64:2422, 1999.

Boger, D.L., Hong, J., Hikota, M., Ishida, M. Total synthesis of phomazarin. J. Am. Chem. Soc. 121:2471, 1999.

Boger, D.L., Jiang, W., Goldberg, J. Convergent solution phase synthesis of combinatorial libraries through rigid biaryl or diacetylene couplings. J. Org. Chem. 64:7094, 1999.

Boger, D.L., Keim, H., Oberhauser, B., Schreiner, E.P., Foster, C.A. Total synthesis of HUN-7293. J. Am. Chem. Soc. 121:6197, 1999.

Boger, D.L., Ledeboer, M.W., Kume, M. Total synthesis of luzopeptins A-C. J. Am. Chem. Soc. 121:1198, 1999.

Boger, D.L., Ledeboer, M.W., Kume, M., Jin, Q. Total synthesis of quinoxapeptin A-C: Establishment of absolute stereochemistry. Angew. Chem. Int. Ed. 38:2424, 1999.

Boger, D.L., Ledeboer, M.W., Kume, M., Searcey, M., Jin, Q. Total synthesis and comparative evaluation of luzopeptin A-C and quinoxapeptin A-C. J. Am. Chem. Soc. 121:11375, 1999.

Boger, D.L., Miyazaki, S., Kim, S.H., Wu, J.H., Castle, S.L., Loiseleur, O., Jin, Q. Total synthesis of the vancomycin aglycon. J. Am. Chem. Soc. 121:10004, 1999.

Boger, D.L., Miyazaki, S., Kim, S.H., Wu, J.H., Loiseleur, O., Castle. S.L. Diastereoselective total synthesis of the vancomycin aglycon with ordered atropisomer equilibrations. J. Am. Chem. Soc. 121:3226, 1999.

Boger, D.L., Saionz, K.W. DNA binding properties of key sandramycin analogues: Systematic examination of the intercalation chromophore. Bioorg. Med. Chem. 7:315, 1999.

Boger, D.L., Santillán, A., Jr., Searcey, M, Jin, Q. Synthesis and evaluation of duocarmycin and CC-1065 analogues containing modifications in the subunit linking amide. J. Org. Chem. 64:5241, 1999.

Boger, D.L., Sato, H., Lerner, A.E., Austin, B.J., Patterson, J.E., Patricelli, M.B., Cravatt, B.F. Trifluoromethyl ketone inhibitors of fatty acid amide hydrolase: A probe of structural and conformational features contributing to inhibition. Bioorg. Med. Chem. Lett. 9:167, 1999.

Boger, D.L., Sato, H., Lerner, A.E., Guan, X., Gilula, N.B. Arachidonic acid amide inhibitors of gap junction cell-cell communication. Bioorg. Med. Chem. Lett. 9:1151, 1999.

Greasley, S.M., Yamashita, M.M., Cai, H., Benkovic, S.J., Boger, D.L, Wilson, I.A. New insights into inhibitor design from the crystal structure and NMR studies of Escherichia coli GAR transformylase in complex with ß-GAR and 10-formyl-5,8,10-trideazafolic acid. Biochemistry 38:16783, 1999.

Schnell, J.R., Ketchem, R.R., Boger, D.L., Chazin, W.J. DNA binding-induced alkylation: Insights from the structure of a DNA duplex alkylated by the indole derivative of duocarmycin SA. J. Am. Chem. Soc. 121:5645, 1999.

Wilcox, B.J., Ritenour-Rodgers, K.J., Asser, A.S., Baumgart, L.E., Baumgart, M.A., Boger, D.L., Patterson, J.E., DeBlassio, J.L., deLong, M.A., Glufke, U., Henz, M.E., King, L. III, Merkler, K.A., Robleski, J.J., Vederas, J.C., Merkler, D.J. N-Acylglycine amidation: Implications for the biosynthesis of fatty acid primary amides. Biochemistry 38:3235, 1999.

 

 







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