News and Publications
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.
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, 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.
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.
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).
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.
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).
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,
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,
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.
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.
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.