Title:2-Nucleobase-substituted 4,6-Diaminotriazine Analogs: Synthesis and
Anti-cancer Activity in 5-Fluorouracil-sensitive and Resistant Colorectal
Cancer Cells
Volume: 30
Issue: 26
Author(s): Khalil Hamze, Rola H. Abdallah, Nour K Younis, Manal Fardoun, Nadine Darwiche, Firas Kobeissy, Rabah Iratni, Kamal Bouhadir*Ali H. Eid*
Affiliation:
- Department of Chemistry, American University of Beirut, P.O. Box 11-0236, 1107-2020, Beirut, Lebanon
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar
University, Doha, P.O. Box2713, Qatar
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, P.O.
Box2713, Qatar
Keywords:
Colorectal cancer, 5-fluorouracil, nucleobase, analogs, 2-nucleobase-substituted 4, 6-diamino-s-triazine analogues, malignancy.
Abstract:
Background: Cancer continues to be the second leading cause of death worldwide, with
colorectal cancer (CRC) being the third most common type. Despite significant advances in cancer
therapies, the current treatment of CRC remains suboptimal. In addition, the effectiveness of available
chemotherapeutic drugs such as 5-Fluorouracil (5-FU) is limited by CRC-acquired resistance.
Methods: In this study, we provide innovative approaches employed in synthesizing four novel nucleobase
analogs. Equally, we describe the effects of these compounds on proliferation, migration,
aggregation, and adhesion of 5-FU-sensitive (HCT116) and -resistant (5-FU-R-HCT116) human
CRC cells. In either cell type, our synthesized novel analogs significantly inhibited cell viability in
a concentration- and time-dependent manner. This highlights the higher potency of these novel
analogs. In addition, these compounds attenuated migration and adhesion of both cell types while
they promoted homotypic cell-cell interaction.
Results: These changes were reflected by the downregulation of matrix metalloproteases (MMP-2
and MMP-9). Furthermore, our analogs exhibited potent anti-angiogenic activity in vivo.
Conclusion: These novel nucleobase analogs reduced the level of secreted vascular endothelial
growth factor (VEGF) and nitric oxide (NO) production in both 5-FU-sensitive and -resistant CRC
cells. Taken together, our data highlight the potential chemotherapeutic properties of our novel
analogs against CRC, including the 5-FU-resistant form.