4.6 Article

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

期刊

CURRENT MEDICINAL CHEMISTRY
卷 30, 期 26, 页码 3032-3049

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BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/0929867329666220914112042

关键词

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

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In this study, we synthesized four novel nucleobase analogs and investigated their effects on CRC cells. The results showed that these analogs significantly inhibited cell viability, attenuated cell migration and adhesion, and promoted cell-cell interaction. Additionally, these compounds exhibited anti-angiogenic activity in vivo.
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.

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