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The Skaggs Institute For Chemical Biology
Scientific Report 1997-1998


Synthetic and Bioorganic Chemistry


D.L. Boger, C. Andersson, B. Aquila, B. Austin, R. Beresis, C. Boyce, H. Cai, S. Castle, R. Castro, W. Chai, P. Ducray, B. Fink, R. Garbaccio, J. Goldberg, J. Hong, W. Jiang, Q. Jin, Y.-S. Jung, H. Keim, M. Kume, M. Labroli, M. Ledeboer, J.K. Lee, R. Lee, E. Lerner, B. Lewis, O. Loiseleur, T. Matsuzaki, S. Miyazaki, J. Patterson, M. Pattricelli, H. Purkey, L. Resnick, K. Saionz, A. Santillán, H. Sato, S. Satoh, R. Schaum, G. Schüle, M. Searcey, C. Sehon, P. Turnbull, A. Vaupel, G. Wilke, J. Wu

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.

As exploration of the properties of complex natural products becomes increasingly more sophisticated with the technologic advances in screening and evaluation, and as structural details of the products' interactions with biological targets become more accessible, the importance and opportunities for providing unique solutions to complex biological problems have increased. A powerful complement to 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 that Nature has provided in the form of a natural product and work to extend the solutions through rational design elements to provide more selective, more efficacious, or more potent agents designed specifically for the problem or target under investigation.

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 has enabled us to fully explore the origin of the properties of the natural products and to devise agents with improved selectivity and efficacy.

Since the discovery of oleamide (Fig. 1), a fatty acid primary amide with sleep-inducing properties, continued study of this prototypical member of a new class of endogenous chemical messengers led to the identification of an enzyme, fatty acid amide hydrolase, responsible for the degradation and regulation of oleamide. In addition, the 2 potential sites of action at which inhibition of cell-to-cell communication at the gap junction or potentiation of activation of serotonin receptors occurs have been discovered. Effective inhibitors of fatty acid amide hydrolase have been designed, prepared, and characterized and should continue to aid in the study of the effects of oleamide.

Receptor activation by homodimerization, heterodimerization, and higher order homo- and hetero-oligomerization has emerged as a general mechanism of initiating intracellular signal transduction (Fig. 2). Studies are under way to investigate the fundamental principles and structural features embodied in activation of the receptor for erythropoietin. Additional targets under examination include ErbB-2, Myc-Max, the androgen receptor, and angiogenesis inhibitors (αvß3 and αvß5).

As a complement to the emerging techniques of solid-phase combinatorial chemistry for advancing drug discovery, we are developing solution-phase approaches to the multistep preparation of combinatorial libraries that, for the proper applications, 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. 3).

In collaboration with I.A. Wilson, Department of Molecular Biology, 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, aminoimidazole carboxamide ribonucleotide), folate cofactors, and inhibitors. Our goals are the de novo design and examination of potent enzyme inhibitors as antineoplastic agents.

Publications

Boger, D.L., Garbaccio, R.M., Jin, Q. Synthesis and evaluation of CC-1065 and duocarmycin analogs incorporating the iso-CI and iso-CBI alkylation subunits: Impact of relocation of the C-4 carbonyl. J. Org. Chem. 62:8875, 1997.

Boger, D.L., Loiseleur, O., Castle, S.L., Beresis, R.T., Wu, J.H. Thermal atropisomerism of fully functionalized vancomycin CD, DE, and CDE ring systems. Bioorg. Med. Chem. Lett. 7:3199, 1997.

Guan, X., Cravatt, B.F., Ehring, G.R., Hall, J.E., Boger, D.L., Lerner, R.A., Gilula, N.B. The sleep-inducing lipid oleamide deconvolutes gap junction communication and calcium wave transmission in glial cells. J. Cell Biol. 139:1785, 1997.

 

 







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