News and Publications
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 (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.
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).
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).
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.
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,
Boger, D.L., Chai, W., Jin, Q. Multistep convergent solution-phase
combinatorial synthesis and deletion synthesis deconvolution. J. Am. Chem. Soc.
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,
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.
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.