This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project is aimed at the ultimate goal of providing new therapeutic agents for the treatment of cancer. The alkaloid (+)-pancratistatin, extracted from Pancratium littorale bulbs, displays promising antineoplastic and antiviral activity and is currently undergoing preclinical evaluation by the US National Cancer Institute. However, the studies have been put on hold due to the limited quantity of material available from isolation. The alkaloid's limited availability has also plagued efforts towards the elucidation of its mechanism of action as well as structure ?activity studies, which could be crucial for the identification of more potent and/or less toxic analogs. Therefore, the discovery of an efficient and flexible chemical route enabling preparation of (+)-pancratistatin and its analogs will tremendously facilitate further development of this lead compound, hence it has been a long-sought objective of the scientific community. This project focuses on a practical synthesis of pancratistatin-based series of compounds with (a) variable structure of the aromatic moiety and (b) truncated cyclitol portion of the molecule. Both series are evaluated for antitumor activity and the active compounds are further tested in vivo in appropriate mouse models. The utilized chemistry is based on the previously developed in this laboratory synthesis of novel 2-deoxy-2-arylconduritols F and a highly diastereoselective arylcuprate addition to ?-alkoxy-?,?-enoates. The long-term objective of this work involves the refinement of the pancratistatin cytotoxic pharmacophore for the development of analogs with (a) improved activity/toxicity profiles, (b) improved water solubility, and (c) simplified structures, amenable to a large-scale production for the forthcoming clinical trials.
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