Development of Small Molecule Proteasome Inhibitors

Erica R. Tabakin,  Chemistry (2nd from right in photo)

Faculty Mentor: Dr. David Hunt

              Proteasomes are cellular organs which break down regulatory proteins that are no longer needed in a cell.  However in a cancerous cell, when the proteasome is blocked, the cell undergoes apoptosis, or programmed cell death, since it is poisoned by waste products which cannot be eliminated.  This is a significant area of research because it could assist in the development of new chemotherapeutic agents toward a relatively new biological target. 

              The strategy towards the development of synthetic proteasome inhibitors originates from the combination of specific functional groups located at pharmacophoric sites of naturally occurring proteasome inhibitors.  More specifically, the target molecule utilizes the pyrrolidinone structure from NPI-0052 and the carbonyl adjacent to the epoxide from epoxomicin.

              Reactions carried out this summer included: acylations, Mitsubobu reactions, epoxidations, and second order nucleophilic substitutions.  Similar to medicinal chemistry research in an industrial setting, all reactions were performed twice, once with each enantiomer because one stereoisomer may be active while the other is not.   Each compound synthesized was purified by flash chromatography and was characterized by proton nuclear magnetic resonance, carbon nuclear magnetic resonance, infrared spectroscopy, and gas chromatography/ mass spectroscopy.  To date, seven compounds have been synthesized and are currently being tested for proteasome inhibition on Caenorhabditis elegans in Dr. Sudhir Nayak’s lab of TCNJ’s Biology Department.  Positive signals will provide a basis for the development of a SAR (structure-activity relationship), thereby providing a rationale for modifying certain sites on the molecule to maximize the effectiveness of inhibition. 

Personal Statement

              The Summer Undergraduate Research Program has provided me an invaluable opportunity to work in a laboratory, gain knowledge in the area of organic synthesis and medicinal chemistry research methods, and develop good laboratory technique.  This experience has opened my eyes to the approaches used in research and development labs in pharmaceutical companies.  Having a strong chemistry background, I feel that I am a step closer to pursuing a career in medicine, where I can do medical research and clinical trials.  Working on an independent project in part of a larger research group has helped me become more confident with my experiments, but still confer with other students.  The SURP lunch gatherings have allowed me to meet other students outside of my courses and learn about other types of research which is not scientifically based.