Delyar Khosroabadi, & Dr. Amed Awad
Pancreatic ductal adenocarcinoma (PDAC), the most prevalent type of pancreatic cancer with a high mortality rate due to a lack of early detection techniques leading to diagnosis at a terminal stage which limits treatment options. The current standard chemotherapeutic for pancreatic cancer is a drug called Gemcitabine. The diphosphorylated form of this prodrug covalently binds within the catalytic site and inhibits the activity of ribonucleotide reductase (RNR), while the triphosphorylated form of the drug gets directly incorporated into the DNA sequence, inhibiting DNA polymerase. The problem with gemcitabine is that it faces drug resistance which hinders its chemotherapeutic potential. This is mainly due to the presence of cytidine deaminase in cells which inactivates most of the drug upon entry. Gemcitabine is also commonly administered alongside other medications possessing iron or zinc chelating properties, resulting in additional side effects. Our goal is to modify the chemical structure of gemcitabine to increase its chemotherapeutic potential. Our proposed nucleosides feature an OH group on the 4’ nitrogen of the base of the nucleoside, inhibiting cytidine deaminase from inactivating the drug which increases its bioavailability. Another modification that we are introducing is the addition of a zinc and iron chelator at the 2’ carbon of the ribose sugar. To achieve these objectives, we use multi-step organic synthesis under inert conditions. Some of the named reactions we use include the Mitsunobu reaction and Yamaguchi esterification reaction. Our computational studies of the analogs include molecular docking, SWISSADME, and PASS prediction. The molecular docking studies are performed using internal coordinate mechanics algorithm (ICM) which allows analysis of the edock score, root mean square deviation (RMSD), and H-bonding formation of the analogs in the catalytic site of RNR. The results of these computational studies support the potential of these compounds as RNR inhibitors.