SBIR Phase I:Ring Contraction Metathesis Reaction for the Generation of Novel Polyene Macrolides

This Small Business Innovation Research (SBIR) Phase I project will develop a process for modifying macrolide natural products in general and Rapamycin in particular using a relatively new chemical transformation called the ring contraction metathesis reaction. The modified compounds will contain a novel contracted core that is inaccessible by conventional methods in a cost effective way. Rapamycin is an immunosuppressant used widely in transplantation, autoimmune and oncological diseases and drug coated stents. The major draw back of rapamycin is its extremely long half-life (63h) which leads to tolerability issues. The novel synthetic transformation outlined in this Phase I Research will allow for the synthesis of a novel new rapamycin analogs with improved pharmacological properties, such as shorter half-life.
The broader impacts of this research are the following: First, development of this reaction into a general synthetic process will allow for the generation of a variety of new and novel compounds which cannot be prepared in any other way. The ring contraction process will generate novel natural product structures that could function as new chemical probes to better understand biological processes. Furthermore, novel macrolide compounds could advance national health concerns by providing new drugs with an improved therapeutic profile. Secondly, the generation of novel Rapamycin analogs will improve the health and quality of life of organ transplant patients as well as form the basis for ongoing research in oncology and auto immune diseases.