The Design, Development, and Computational Studies of Nucleoside Analogues as Therapeutics for Pancreatic Cancer  

Aleksya Drobshoff, Jacob Ruiz, and Dr. Ahmed Awad 

Abstract

Pancreatic cancer is the fourth leading cause of death in the United States. The 5-year survival rate after diagnosis currently sits at 8.5%. The dismal survival rate of pancreatic cancer is mainly due to late detection at an advanced stage in the pancreas. The standard treatment at this late stage is chemotherapy with the drug Gemcitabine. The metabolism of Gemcitabine involves phosphorylation by deoxycytidine kinase to its diphosphate and triphosphate forms. The triphosphate form of gemcitabine inhibits DNA polymerases by incorporation into DNA, while the diphosphate form binds within the catalytic site of the enzyme ribonucleotide reductase (RNR) and irreversibly inhibits its activity by disrupting the catalytic pathway. Our research project involves the design and development of gemcitabine analogues, the most common and effective modified nucleoside analogue used in the chemotherapy treatment of pancreatic cancer. Our current and most tested modification made to gemcitabine was adding a Poly Ethylene Glycol Amino (PEGA) chain to the 2’ position on cytidine. The PEGA modification was proposed to act as a chelating site for the zinc ion, the metal ion required for the RNR function, which may lead to a decrease in its activity. The previously tested enzymatic-target binding affinity and positive correlation to anticancer and antimicrobial properties gives the PEGA-nucleoside a good potential to serve as a strong RNR inhibitor. We tested this molecule through a series of computational docking studies to test the binding affinity of our molecule with RNR. The results we have achieved thus far demonstrate the positive potential of the PEGA modification as an anticancer nucleoside analogue with the next step of leading into to our transition into performing synthesis in the lab.

Presentation

Session 1 – 1:30p.m. – 2:45p.m.

Room D – Sierra 2422  

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