This grant application describes a research program directed towards the total synthesis of the newly discovered cytotoxic agent apoptolidin (1). Isolated from actinomycete Nocardiopsis sp., apoptolidin shows remarkable cytotoxicty (IC50 11 ng/mL) against rat glia cells transformed with the adenovirus El A while not affecting normal glia cells or normal fibroblasts (IC50 greater than 100microg/mL). Its mechanism of action involves apoptosis as evidenced by the appearance of condensed chromatin and fragmented nuclei. Due to the striking selectivity exhibited by this substance against tranformed versus normal cells, the proposed chemistry will be extended to the synthesis of designed analogs for biological investigations. Both solution and solid phase strategies will be explored for the synthesis of the proposed compounds. The approach will involve construction of the macrocyclic core followed by attachment of the carbohydrate moieties via stereocontrolled reactions. The proposed work is expected to have significant impact in the area of cancer chemotherapy and should provide enabling technologies and tools for biology and medicine.
