News and Publications

Antibody Catalysis and Organic Synthesis

S.C. Sinha, R.A. Lerner, J. Sun, S. Dutta

Our research interests involve synthetic methods, total synthesis of biologically important natural products, antibody catalysis, and development of the prodrug and targeting approaches for cancer therapy. In the past year, we focused on the syntheses of 13-alkyl analogs of epothilones and prodrugs of epothilones and enediynes.

EPOTHILONES AND THEIR ANALOGS

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-E (Fig. 1). To synthesize these complex molecules, we used existing efficient monoclonal catalytic antibodies to prepare multigram amounts of chiral key precursors. These intermediates were then converted to the target molecule.

In a continuation of this work, we completed the synthesis of epothilone F and several new analogs of 13-alkyl epothilone C and studied their antitumor properties in collaboration with K.-H. Altmann and M. Wartmann, Novartis Pharma AG, Basel, Switzerland.

PRODRUG THERAPY

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 emerging that can be used to direct these compounds to an appropriate target. Using the antibody-directed abzyme prodrug therapy approach, we are collaborating with C. Barbas and C. Rader, Department of Molecular Biology, to study prodrugs of epothilones, enediynes, and their analogs. Currently, we are synthesizing prodrugs of epothilones and calicheamicinone and analogs of dynemicin, doxorubicin, and camptothecin. The catalytic aldolase antibody 38C2 will be used as the abzyme component of our approach. The targeting antibody component is being developed by Drs. Barbas and Rader.

We are also developing a small molecule-directed abzyme prodrug therapy approach in which small-molecule antagonists of the integrin a;_vß₃ will be used to replace the targeting antibody component of the antibody-directed abzyme prodrug therapy approach. Because a;_vß₃ is overexpressed on tumor blood vessels, an antagonist of the integrin is a practical substitute for the targeting antibody.

SYNTHESIS OF ANNONACEOUS ACETOGENINS

In a joint effort with E. Keinan, Department of Molecular Biology, we are using rhenium(VII) oxide-mediated oxidative cyclizations of bishomoallylic alcohols to synthesize tetrahydrofuran compounds and annonaceous acetogenins. These compounds have high antitumor activity. Several annonaceous acetogenins, including ones with adjacent bis-tetrahydrofuran rings, such as asimicin, bullatacin, trilobacin, trilobin, and squamotacin, have been synthesized. We also synthesized rollidecins C and D.

PUBLICATIONS
D'Souza, L.J., Sinha, S.C., Lu, S.-F., Keinan, E., Sinha, S.C. Oxidative polycyclization with rhenium(VII) oxides: Application of the stereoselectivity rules in the total synthesis of rollidecins C and D. Tetrahedron, in press.

Sinha, S.C., Dutta, S., Sun, J. Regioselective syntheses of fluoroepothilones: Syntheses via antibody catalysis. Tetrahedron Lett. 41:8243, 2000.

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. Chemistry 7:1691, 2001.

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 epothilones. ChemBioChem, in press.