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The Skaggs Institute for Chemical Biology
Scientific Report 1998-1999


Synthetic and Bioorganic Chemistry


D.L. Boger, C. Andersson, B. Aquila, B. Austin, R. Beresis, P. Bounaud, C. Boyce, S. Brunette, H. Cai, S. Castle, R. Castro, W. Chai, Y. Chen, P. Ducray, R. Fecik, B. Fink, R. Garbaccio, C. Gauss, J. Goldberg, M. Hedrick, J. Hong, S. Ichikawa, T. Ishii, W. Jiang, Q. Jin, H. Keim, S. Kim, P. Krenitsky, M. Kume, M. Labroli, M. Ledeboer, J.K. Lee, R. Lee, E. Lerner, B. Lewis, D. Lewy, O. Loiseleur, T. Matsuzaki, S. Miyazaki, D. O'Neill, L. Resnick, A. Santillán, H. Sato, S. Satoh, R. Schaum, G. Schüle, M. Searcey, C. Sehon, D. Soenen, W. Tse, J. Weng, G. Wilke, S. Wolkenberg, J. Wu, 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.

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 of and opportunities for providing unique solutions to complex biological problems have increased. 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 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.

Oleamide

Oleamide (Fig. 1), a fatty acid primary amide with sleep-inducing properties, is a prototypical member of a new class of endogenous chemical messengers. Continued 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 the potential sites of action involved in inhibition of gap junction cell-cell communication or potentiated activation of serotonin receptors. Effective inhibitors of fatty acid amide hydrolase, which also degrades anandamide, have been prepared and characterized and should aid in the examination of the effects of oleamide.

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 (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).

Solution-Phase Combinatorial Chemistry

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).

Transformylases

In collaboration with I.A. Wilson, the Skaggs Institute, we are examining the x-ray crystallographic structures of (1) the apo forms of glycinamide ribonucleotide transformylase and aminoimidazole carboxamide transformylase and (2) complexes of the enzymes with their substrates (glycinamide ribonucleotide and aminoimidazole carboxamide ribonucleotide), folate cofactors, and inhibitors. Our goals are the novo design and examination of potential potent enzyme inhibitors as antineoplastic agents (Fig. 4).

DNA-Drug Interactions

We are also exploring and defining the structural basis for the sequence-selective recognition of duplex DNA by a series of naturally occurring antitumor antibiotics, including CC-1065 and the duocarmycins, bleomycin A2, sandramycin and the luzopeptins, isochrysohermidin, and distamycin A. In each instance, synthetic deep-seated structural changes in the natural product are used to probe the basis for the recognition or ensuing chemical reaction with duplex DNA.

Publications

Boger, D.L. Heterocyclic and acyclic azadiene Diels-Alder reactions: Total synthesis of nothapodytine B. J. Heterocyclic Chem. 35:1003, 1998.

Boger, D.L., Beresis, R.T., Loiseleur, O., Wu, J.H., Castle, S.L. Synthesis of the vancomycin CDE ring system. Bioorg. Med. Chem. Lett. 8:721, 1998.

Boger, D.L., Boyce, C.W., Garbaccio, R.M., Searcey, M. Synthesis of CC-1065/duocarmycin analogs via intramolecular aryl radical cyclization of a tethered vinyl chloride. Tetrahedron Lett. 39:2227, 1998.

Boger, D.L., Chai, W. Solution-phase combinatorial synthesis: Convergent multiplication of diversity via the olefin metathesis reaction. Tetrahedron 54:3955, 1998.

Boger, D.L., Chai, W., Jin, Q. Multistep convergent solution-phase combinatorial synthesis and deletion synthesis deconvolution. J. Am. Chem. Soc. 120:7220, 1998.

Boger, D.L., Chen, J.-H., Saionz, K.W., Jin, Q. Synthesis of key sandramycin analogs: Systematic examination of the intercalation chromophore. Bioorg. Med. Chem. 6:85, 1998.

Boger, D.L., Ducray, P., Chai, W., Jiang, W., Goldberg, J. Higher order iminodiacetic acid libraries for probing protein-protein interactions. Bioorg. Med. Chem. Lett. 8:2339, 1998.

Boger, D.L., Goldberg, J., Jiang, W., Chai, W., Ducray, P., Lee, J.K., Ozer, R.S., Andersson, C.-M. Higher order iminodiacetic acid libraries for probing protein-protein interactions. Bioorg. Med. Chem. 6:1347, 1998.

Boger, D.L., Henriksen, S.J., Cravatt, B.F. Oleamide: An endogenous sleep-inducing lipid and prototypical member of a new class of biological signaling molecules. Curr. Pharm. Des. 4:303, 1998.

Boger, D.L., Hong, J. Total synthesis of nothapodytine B and (­)-mappicine. J. Am. Chem. Soc. 120:1218, 1998.

Boger, D.L., Kochanny, M.J., Cai, H., Wyatt, D., Kitos, P.A., Warren, M.S., Ramcharan, J., Gooljarsingh, L.T., Benkovic, S.J. Design, synthesis, and evaluation of potential GAR and AICAR inhibitors. Bioorg. Med. Chem. 6:643, 1998.

Boger, D.L., Miyazaki, S., Loiseleur, O., Beresis, R.T., Castle, S.L., Wu, J.H., Jin, Q. Thermal atropisomerism of aglucovancomycin derivatives: Preparation of (M,M,M)- and (P,M,M)-aglucovancomycin, J. Am. Chem. Soc. 120:8920, 1998.

Boger, D.L., Patterson, J.E., Guan, X., Cravatt, B.F., Lerner, R.A., Gilula, N.B. Chemical requirements for inhibition of gap junction communication by the biologically active lipid oleamide. Proc. Natl. Acad. Sci. U. S. A. 95:4810, 1998.

Boger, D.L., Patterson, J.E., Jin, Q. Structural requirements for 5-HT2A and 5-HT1A receptor potentiation by the biologically active lipid oleamide. Proc. Natl. Acad. Sci. U. S. A. 95:4102, 1998.

Boger, D.L., Ramsey, T.M., Cai, H., Hoehn, S.T., Stubbe, J. Definition of the effect and role of the bleomycin A2 valerate substituents: Preorganization of a rigid, compact conformation implicated in sequence selective DNA cleavage. J. Am. Chem. Soc. 120:9149, 1998.

Boger, D.L., Ramsey, T.M., Cai, H., Hoehn, S.T., Stubbe, J. A systematic evaluation of the bleomycin A2 l-threonine side chain: Its role in preorganization of a compact conformation implicated in sequence selective DNA cleavage. J. Am. Chem. Soc. 120:9139, 1998.

Boger, D.L., Santillán, A., Jr., Searcey, M., Jin, Q. The critical role of the linking amide in CC-1065 and the duocarmycins: Implications on the source of DNA alkylation catalysis. J. Am. Chem. Soc. 120:11554, 1998.

Boger, D.L., Schaum, R.P., Garbaccio, R.M. Regioselective inverse electron demand Diels-Alder reactions of N-acyl 6-amino-3-methylthio-1,2,4,5-tetrazines. J. Org. Chem. 63:6329, 1998.

Boger, D.L., Schüle, G. Synthesis of acyclic precursors to (3S,4S)-4-hydroxy-2,3,4,5-tetrahydropyridazine-3-carboxylic acid and incorporation into a luzopeptin/quinoxapeptin dipeptide. J. Org. Chem. 63:6421, 1998.

Boger, D.L., Turnbull, P. Synthesis and evaluation of a carbocyclic analog of the CC-1065 and duocarmycin alkylation subunits: Role of the vinylogous amide and implications on DNA alkylation catalysis. J. Org. Chem. 63:8004, 1998.

Patricelli, M.P., Patterson, J.E., Boger, D.L., Cravatt, B.F. An endogenous REM sleep inducing compound is a potent competitive inhibitor of fatty acid amide hydrolase (FAAH). Bioorg. Med. Chem. Lett. 8:613, 1998.

Ramsey, T.M., Cai, H., Hoehn, S.T., Kozarich, J.W., Stubbe, J., Boger, D.L. Assessment of the role of the bleomycin A2 pyrimidoblamic acid C4 amino group. J. Am. Chem. Soc. 120:53, 1998.

Wu, W., Vanderwall, D.E., Teramoto, S., Lui, S.M., Hoehn, S.T., Tang, X.-J., Turner, C.J., Boger, D.L., Kozarich, J.W., Stubbe, J. NMR studies of Co*deglycobleomycin A2 green and its complex with oligonucleotide d(CCAGGCCTGG)2. J. Am. Chem. Soc. 120:2239, 1998.

 

 







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