Discipline: Chemistry and Chemical Sciences
Subcategory: Cancer Research
Osvaldo Cossio - University of Arkansas at Little Rock
Co-Author(s): Darin E. Jones and Sreevishnu Cheerla, University of Arkansas at Little Rock
The synthesis and turnover of poly(ADP-ribose) (PAR) by poly(ADP-ribose) polymerase (PARP) and poly(ADP-ribose) glycohydrolase (PARG) are required for normal responses to DNA damage. Genetic knockdown of PARG impairs DNA repair, sensitizes cancer cells to chemotherapeutics agents and radiation, and specifically kills BRCA-deficient breast tumors. The role of PARG activity and the mechanism explaining the requirement for PAR degradation during PARP-dependent repair of DNA is unknown. We therefore initiated a medicinal chemistry program targeting PARG with small molecule inhibitors to study the effects of PAR metabolism in BRCA-deficient breast cancer cells. To study the effects of small molecule inhibitors, we synthesized a series of analogs to study the structure-activity relationship (SAR) with the protein. Here, the majority of the analogs synthesized have xanthine as their core structure with modifications at the oxo position and addition of different R group at carbon 8. The method utilized to analyze and validate the synthesis of all the small molecule inhibitors synthesized in this project was done via 1H and 13C Nuclear Magnetic Resonance (NMR) results analysis. Through the structure-based drug design of the series of analog synthesized in this project, these small molecules could represent novel therapeutic agents that could serve as inhibitors of PARG. Our future studies will involve synthesizing more small molecules that are structurally different (new modification) to see how this would effect the inhibitors activity.
Funder Acknowledgement(s): University of Arkansas at Little Rock, Chemistry ; National Institute of Health, NIH
Faculty Advisor: Darin E. Jones, firstname.lastname@example.org
Role: The part I played in this research mainly relates to the organic synthesis of the xanthine scheme template. Here, enough starting material of xanthine template had to be synthesize through the nitration, reduction, and cyclization reactions to be use for the modification and addition of different R group at the carbon 8 position of the xanthine template synthesized. Here in this project, I also validated the synthesis of the compounds I synthesized involved in each step describe above via 1H and 13C Nuclear Magnetic Resonance (NMR).