Synthesis of Novel Triazine-Hydrazide Based Nucleoside Analogues and their Activity in 5-Fluorouracil Sensitive or Resistant Colorectal Cancer Cells

Abstract

Cancer continues to be the second leading cause of death worldwide, with colorectal cancer (CRC) being the second most common type. Despite significant advances in cancer therapies, current treatment of CRC remains inefficient. In addition, effectiveness of currently available chemotherapeutic drugs such as 5-Fluorouracil (5FU) is limited owing to developed resistance in CRC. Here, we provide novel schemes for synthesis of four novel nucleoside analogs, as well as describe their effects on proliferation, migration, aggregation, adhesion and de-adhesion of CRC cells, both 5-FU-sensitive and 5-FU-resistant HCT116. In either cell type, our synthesized novel analogs significantly inhibited cell viability in a concentration and time-dependent manner. Importantly, all the four analogues inhibited proliferation at a much lower concentration than that of 5FU, indicating higher potency of these analogs. In addition, these compounds inhibited cell migration in a time-dependent manner. They also inhibited adhesion and de-adhesion of both cell types to collagen, as well as promoted homotypic cell-cell interaction. Levels of ERK1/2, MMP-2 and MMP-9 were diminished by these analogs. Importantly, our analogs significantly inhibited angiogenesis, evident by decreased blood vessel density in Chick Chorioallantoic Membrane (CAM) assay. This was also concomitant with a decrease in the production of nitric oxide (NO) and vascular endothelial growth factor (VEGF). Taken together, by inhibiting these hallmarks of malignancy, our data highlight that the four analogs could act as potent chemotherapeutic drugs against CRC, including the 5-FU-resistant form.