Synthesis of Novel Pyrimidine Analog Gemcitabine-Decitabine Dimer

Abstract

Nucleotide substitutions play a critical role in cancer development and therapeutic response, with antimetabolites like gemcitabine and decitabine commonly targeting DNA synthesis and epigenetic regulation. This study reports the synthesis and preliminary evaluation of a novel gemcitabine-decitabine dimer (Gem-Dec dimer) as a potential chemotherapeutic agent. The dimer was synthesized using a modified guadecitabine synthesis pathway that omits amine protection, improving efficiency and minimizing structural degradation. Its chemical integrity was confirmed via thin-layer chromatography, which demonstrated stability across various culture media. Cytotoxicity assays using colorectal cancer cell lines HCT116 and LS174T revealed that the dimer retains anticancer activity, particularly in HCT116 cells, though with slightly reduced potency compared to monomeric gemcitabine. Combination treatment studies showed synergistic cytotoxic effects in HCT116 cells, with up to 36% greater inhibition of cell viability compared to either drug alone, suggesting mechanistic complementarity. LS174T cells, however, demonstrated minimal responsiveness. These findings confirm that gemcitabine and decitabine can be chemically conjugated to form a stable, bioactive compound and suggest that the Gem-Dec dimer merits further investigation in cancer types where its constituent drugs have proven efficacy. This work establishes a foundation for developing novel, dual-action nucleoside analog-based therapies that target both DNA replication and epigenetic dysregulation in cancer.