ELUCIDATION OF THE PANCRATISTATIN CYTOTOXIC PHARMACOPHORE

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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. Background and Rationale 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 alkaloids 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 analogues. Therefore, the discovery of an efficient and flexible chemical route enabling preparation of not only the natural product itself, but also a diverse library of its analogues will tremendously facilitate further development of this lead compound, hence it has been a long-sought objective of the scientific community. Methods This work focuses on a practical synthesis of pancratistatin-based series of compounds with variable truncated portions of the molecule. Once synthesized, the compounds are evaluated for in vitro and in vivo anticancer activity. Based on the obtained SAR information the pancratistatin pharmacophore is 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. Results In the previous years of the INBRE project we developed a highly diastereoselective arylcuprate addition to g-alkoxy-a,b-enoates, explored its scope and found that its potential applicability is not limited to this project, but rather has a general utility in synthetic organic chemistry. We have further studied this method from a theoretical perspective and developed a novel reductive elimination-based model to predict the stereochemical outcome of such processes. Using the model we predicted that g-amino-a,b-enoates would give the addition products with high preponderance of the syn isomer. We systematically studied such process with two different L-serine-derived enoates and found that this process indeed proceeds as expected. The methodology is complementary to reactions of g-alkoxy-a,b-enoates and directly applicable to the synthesis of structurally simplified analogs of pancratistatin. This work was published. The INBRE funds also allowed us to identify several potent biologically active compounds through screening efforts using highly focused compound libraries. This work, which involves a great number of students and educates them about the drug discovery process, was published as well. Further Study Utilization of the developed methodologies for the synthesis of simplified pancratistatin analogues as well as further discoveries of the drug discovery group, involving a large number of students, will be actively pursued.