2-Nucleobase-substituted 4,6-Diaminotriazine Analogs: Synthesis and Anti-cancer Activity in 5-Fluorouracil-sensitive and Resistant Colorectal Cancer Cells

Khalil Hamze, Rola H. Abdallah, Nour K. Younis, Manal Fardoun, Nadine Darwiche, Firas Kobeissy, Rabah Iratni, Kamal Bouhadir, Ali H. Eid

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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 nu-cleobase 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.

Original languageEnglish
Pages (from-to)3032-3049
Number of pages18
JournalCurrent Medicinal Chemistry
Volume30
Issue number26
DOIs
Publication statusPublished - 2023

Keywords

  • 2-nucleobase-substituted 4,6-diamino-s-triazine analogues
  • 5-fluorouracil
  • Colorectal cancer
  • analogs
  • malignancy
  • nucleobase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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