Alexander Kornienko, PhD New Mexico Tech akornien@nmt.edu Phone:(505) 835-5884 Personal Website

Title: Elucidation of the Pancratistatin Cytotoxic Pharmacophore

Project Description:

The long-term goal of this project is to generate medicinally useful analogs of the pancratistatin family of amaryllidaceae antitumor alkaloids. 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, these studies have been put on hold due to the limited quantity of material available from isolation. Although a number of total syntheses of both (+)-pancratistatin and its naturally occurring analog, (+)-7-deoxypancratistatin, have been reported, a practical route for the large-scale synthesis of these targets has not yet been uncovered. The synthetic complexity of these phenantridone-based structures has also plagued efforts directed towards the generation of pancratistatin analogs and the derivation of systematic structure-activity relationships (SAR). The reported limited SAR data clearly show that the trans-fused lactam portion of the molecule is essential, while the perturbations of the cyclitol ring do not necessarily result in decreased activity. No investigation of the structural requirements of the aromatic ring has been reported to date. The work proposed in this application 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. Once synthesized, the compounds will be evaluated in vitro in the NCI-administered 60 cell line anticancer screen, followed by further testing of promising structures in vivo in various mouse models. Based on the obtained SAR information the pancratistatin pharmacophore will be constructed and used for the development of a series 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.