ELUCIDATION OF THE PANCRATISTATIN CYTOTOXIC PHARMACOPHORE

点击翻译按钮获取中文摘要

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 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 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 year of the INBRE project we developed a highly diastereoselective arylcuprate addition to ?-alkoxy-?,?-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. In the current year we further studied this method from a theoretical perspective and developed a novel reductive elimination-based model to predict the stereochemical outcome of such processes. This model is expected to be of general use in synthetic organocuprate chemistry. We applied this method to the construction of a library of pancratistatin ring B analogues and evaluated these compounds for anticancer activity. The conclusion of this study is the requirement for the integrity of ring B to retain the potency of the natural compound. Further Study Since no activity was found with pancratistatin analogues with the open ring B, our further efforts in this area will focus on the synthesis of the ring C analogues. This will be accomplished both through totally synthetic and semisynthetic approaches. The latter will be based on isolation of narciclasine, a congener of pancratistatin, and its conversion to pancratistatin-related structures.