The long-term objectives of this research are to develop practical methods for preparation of stereopure antisense phosphorothioates as potentially improved second-generation antiviral and anticancer agents to replace, if warranted, the current first-generation of stereorandom antisense phosphorothioates under investigation by Lynx (and other antisense drug discovery companies). The particular disease targets for Lynx include acute and chronic myelogenous leukemias (AML and CML), malignant melanoma, colorectal carcinoma, and infection by human immunodeficiency virus, type (HIV-1), and hepatitis B and C virus (HBV and HCV). Optimization of automated solid-phase synthesis by the recently explored oxathiaphospholane method will be studied in parallel with optimal shortening of current lead compounds using cell culture assays for HIV-1, AML, and CML. Synthesis parameters to be studied include nucleobase protection, phosphorothioate capping, stronger base catalyst, more resistant solid support, and 5' hydroxyl capping. Cell culture assays will be conducted in the context of existing collaborations at the National Cancer Institute Laboratory of Tumor Cell Biology (HIV-1), the University of Nebraska Medical Center (AML), and the Thomas Jefferson University Cancer Institute (CML).
