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

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.

Modulation of the ubiquitin‐proteasome system by phytochemicals: Therapeutic implications in malignancies with an emphasis on brain tumors

“…The altered function of these enzymes is attributed to the various aspects of carcinogenesis, for example, cell survival, proliferation, invasion, and drug resistance. [55][56][57][58] Ubiquitin-conjugating enzyme E2 C (UBE2C) is a member of E2s with an essential regulatory function on the cell cycle progression. Accordingly, UBE2C overexpression has been linked with cancer development and chemoresistance in diverse neoplasms, for example, breast, lung, prostate, and gastric malignancies.…”

“…E2s are enzymes with critical functions in labeling target proteins with ubiquitin. The altered function of these enzymes is attributed to the various aspects of carcinogenesis, for example, cell survival, proliferation, invasion, and drug resistance 55–58 . Ubiquitin‐conjugating enzyme E2 C (UBE2C) is a member of E2s with an essential regulatory function on the cell cycle progression.…”

Berberine: Potential preventive and therapeutic strategies for human colorectal cancer

“…Crucially, nanomedicine improves the pharmacokinetic and pharmacodynamic profile of conventional therapies, which optimize the efficacy of existing anticancer compounds 7 . Likewise, synthetic medicinal chemistry has illustrated its potential in defying tumor resistance 8 . However, the safety of them is yet to be fully assessed 9 .…”

“…7 Likewise, synthetic medicinal chemistry has illustrated its potential in defying tumor resistance. 8 However, the safety of them is yet to be fully assessed. 9 Nevertheless, given the limitations of modern cancer treatment and management, researchers are focusing on herbal medicine and natural products, for most of them have multi-target effects and low toxicity.…”