Synthesis/In Vivo Activity of Cyclocinamide A

DESCRIPTION (provided by applicant): Metastatic solid tumors (colon, breast, ovary, lung and prostate) comprise 50% of all human cancers and account for half of all the mortality in the population of the United States. 21st Century Therapeutics, Inc (21CTI) is an anticancer drug discovery and development company whose focus is to discover, develop and license (to large pharmaceutical companies) new anti-solid tumor selective agents derived from natural product or other sources. To answer the need for solid tumor selective chemotherapeutic agents, the research presented here will focus on the synthesis of the cyclic anti-tumor peptide cyclocinamide A (CA). The goal of this project is to determine if CA is a suitable candidate for further clinical development. We have already shown that CA possesses excellent in vitro activity. Demonstration of its in vivo activity will allow for CA to move forward into the second phase of clinical development (Phase 2 SBIR). This project will unequivocally establish the relative and absolute stereochemistry of CA (novel structure and composition of matter patent position) and simultaneously establish a viable synthetic route that will be used for the preparation of analogs (Phase 2 SBIR). Molecular modeling and dynamics simulations have been used to establish the lowest energy conformation of CA and this information (along with a body of preliminary synthetic results) has been used to determine the relative stereochemistry of naturally occurring CA. In the pharmacology phase, new compounds identified as possessing selective in vitro antiproliferative activity for solid tumors proceeds to clonogenic concentration-survival studies. CA will be entered in the early in vivo pharmacologic development and therapeutic assessment trials with the aim of identifying clinical utility and forecasting the parameters of late preclinical and early clinical development. The commercial viability of this project lies in the fact that the results obtained during this funding period will allow the compound to be moved forward to a Phase 2 SBIR. Subsequent successful drug development will result in an "added-value" agent that can then be licensed to a large pharmaceutical company.