Design, Synthesis, and Biological Evaluation of Novel 3′-Deoxy-3′-[1,4-Disubstituted-1,2,3-Triazolyl] Uridine Analogues Using CuAAC as Potential Human RNR Inhibitors

Abstract

Ribonucleotide reductases (RNRs) are overexpressed in various types of cancers, and they affect the deoxyribonucleotide concentration in the cells through the catalytic removal of 2′-OH in the ribonucleotides. This shows their importance in cancer cell rapid division and playing a vital role in the cellular life cycle. Here, we report the synthesis of 2 novel uridine analogues bearing 1,4-disubstituted-1,2,3-triazole at the 3′-C. Molecular docking analysis of all proposed analogues showed binding affinity between −7.8 and −8.8 kcal/mol. Analysis of the ligand–protein interactions indicated that the added functional groups formed additional interactions with the enzyme including H-bonding between the 1,2,3-tirazole and CYS218. Biological testing of the synthesized analogues via MTT and wound healing assays proved the potential anticancer activity carried by the introduction of the 1,2,3-triazole ring at the 3′-C. The analogues had cytotoxic activity represented in a reduction in cell viability for up to 74.18% viable cells at 100 µM against H292 and MCF7 cancer cells and anti-metastatic activity against A549 cancer cells. This anticancer activity is hypothesized to be enhanced after the introduction of a monophosphate group at 5′-C due to reduced first phosphorylation of nucleoside analogues.