News and Publications
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.
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.
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,