News and Publications

Synthesis and Activation of Prodrugs by Antibody Catalysis

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 C.

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.

Prodrugs

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.

Publications

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. 65:6035, 2000.

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. 1:1623, 1999.

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.