We are also developing peptidomimetic inhibitors, cytotoxic natural products, and their conjugates, which can be combined with the aldolase antibody 38C2–based technology to further improve the efficacy of the compounds by a combination therapy. These compounds include protease inhibitors and anticancer adjacent bis-tetrahydrofuran annonaceous acetogenins. Numerous proteases are overexpressed in several cancer cell lines and are highly implicated in tumor growth and metastases. Inhibition of such proteases has potential application in cancer therapy. In collaboration with C. Liu, Scripps Research, we are developing inhibitors of legumain protease, which is highly expressed in a number of cancer cell lines, including prostate and breast cancer cells.
Annonaceous acetogenins are among the most cytotoxic compounds. Each acetogenin can have as many as 64 stereoisomers because of the bis-tetrahydrofuran fragment alone flanked by a hydroxy function on each side. In order to understand the structure-activity relationship of these compounds and carry out comprehensive biological studies, total synthesis of all 64 stereoisomers is required. This synthesis has been the focus of research for several years, not only by us but also by many others. However, despite a continued effort, synthesis of all 64 stereoisomers of asimicin or bullatacin, which are among the most cytotoxic adjacent bis-tetrahydrofuran acetogenins, has not yet been achieved. We have now prepared 8 adjacent bis-tetrahydrofuran acetogenins via 2 bis-tetrahydrofuran precursors. We have also prepared 27-hydroxybullatacin, which is highly active against pancreatic cancer cells, and the 15-epimer of 27-hydroxybullatacin (Fig. 1). Biological evaluations of these compounds will be done in collaboration with F. Valeriote, Henry Ford Health System, Detroit, Michigan.
Abraham, S., Guo, F., Li, L.-S., Rader, C., Liu, C., Barbas, C.F. III, Lerner, R.A. Sinha, S.C. Synthesis of the
next-generation therapeutic antibodies that combine cell targeting and antibody-catalyzed prodrug activation. Proc. Natl. Acad. Sci.
Das, S., Abraham, S., Sinha, S.C. Studies toward the total synthesis of sorangiolides and their analogs: a convergent stereoselective synthesis of the macrocyclic lactone precursors. Org. Lett. 9:2273, 2007.
Lo, H.C., Han, H., D'Souza, L.J., Sinha, S.C., Keinan, E. Rhenium(VII) oxide-catalyzed heteroacylative ring-opening dimerization of tetrahydrofuran. J. Am. Chem. Soc. 129:1246, 2007.
Sinha, S.C., Das, S., Li, L.-S., Lerner, R.A., Barbas, C.F. III. Preparation of integrin αvβ3-targeting Ab 38C2 constructs. Nat. Protoc. 2:449, 2007.