News and Publications
The Skaggs Institute For Chemical Biology
Scientific Report 1999-2000
Synthesis and Activation of Prodrugs by Antibody Catalysis
S.C. Sinha, R.A. Lerner, J. Sun, S. Dutta, G. Miller
Our research interests include synthetic methods, total synthesis of biologically
important natural products, antibody catalysis, and development of the prodrug
approach for cancer therapy.
Synthesis of Epothilone Analogs Via Antibody Catalysis
Epothilones A-F were isolated from myxobacteria (Sorangium cellulosum strain
90). These compounds have antitumor activity similar to that of paclitaxel. Recently,
we achieved total syntheses of epothilones A-F (Fig. 1). For these syntheses,
we used existing efficient monoclonal catalytic antibodies to prepare multigram
quantities of chiral key precursors. These intermediates were then converted
to the target molecule.
In a continuation of this work, we used the aldolase antibody 84G3 to resolve
several thiazole aldols in more than 99% enantiomeric excess at 50% conversion.
We used these thiazole aldols to synthesize multiple new 13-alkyl analogs of
epothilones (Fig. 1). In collaboration with K.-H. Altmann, Novartis Pharma AG,
Basel, Switzerland, the antitumor properties of these analogs were studied. Some
of these compounds have antitumor activity as high as that of epothilones A and
Antibody 84G3 also catalyzes the resolution of fluoro analogs of thiazole
aldols. A large-scale resolution of fluoroaldols and their conversion to the
fluoro analogs of epothilones are in progress.
The specific elimination of cancer cells by potent chemotherapeutic agents
is limited by the nonspecific toxicity of the agents. Because the agents cannot
reach appropriate targets selectively, normal cells as well as cancer cells are
killed. In order to overcome this limitation, new methods, including prodrug
therapy, are being developed to direct these compounds to an appropriate target.
Using the antibody-directed abzyme prodrug therapy approach, we are collaborating
with C.F. Barbas, the Skaggs Institute, in studies of prodrugs of epothilones,
enediynes, and their analogs.
We synthesized a prodrug (II in Fig. 1) via a known compound (I in
Fig. 1) and tested the toxicity of both the prodrug and the compound on LIM1215
human colon carcinoma cells in vitro in the presence or absence of antibody 38C2.
The results were encouraging; the prodrug and the compound (I) have almost
equal toxicity, and in the presence of a catalytic amount of antibody 38C2, the
prodrug is activated, presumably by conversion to another drug (III in
Fig. 1), and becomes cytotoxic to the LIM1215 cells. Currently, we are synthesizing
prodrugs of other analogs of dynemicin and epothilones.
Avedissian, H., Sinha, S.C., Yazbak, A., Sinha, A., Neogi, P., Sinha,
S.C., Keinan, E. Total synthesis of asimicin and bullatacin. J. Org. Chem.
Sinha, S.C., Dutta, S., Sun, J. Regioselective syntheses of fluoroaldols:
Studies toward fluoroepothilones synthesis via antibody catalysis. Tetrahedron
Lett., in press.
Sinha, S.C., Sinha, S.C., Keinan, E. Total synthesis of squamotacin.
J. Org. Chem. 64:7067, 1999.
Sinha, S.C., Sun, J., Miller, G., Barbas, C.F. III, Lerner, R.A. Sets
of aldolase antibodies with antipodal reactivities: Formal synthesis of epothilone
E by large-scale antibody-catalyzed resolution of thiazole aldol. Org. Lett.
Sinha, S.C., Sun, J., Miller, G.P., Wartmann, M., Lerner, R.A. Catalytic
antibody route to the naturally occurring epothilones: Total synthesis of epothilones
A-F. Chem. Eur. J., in press.
Sinha, S.C., Sun, J., Wartmann, M., Lerner, R.A. Synthesis of multiple
epothilone analogs via antibody catalyzed resolution of thiazole aldol synthons
on a multigram scale: Biological consequences of addition of an alkyl group at
C-13 of epitholones. ChemBioChem, in press.