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Outline
Based on the ProTide technology, structural modification was performed on the 3′-hydroxyl group of 2′-deoxy-5-fluorouridine (FdUR) to design and synthesize a series of novel 5-FU phosphoramidate diester dual prodrugs (A1-A10). The structures of all compounds were confirmed by spectroscopic techniques, and their anti-hepatocellular carcinoma activity was evaluated using the MTT assay. The results indicated that several compounds exhibited significant anti-liver tumor activity. Among them, compound A6 showed the most potent activity with IC50 values of 0.15 μmol·L-1 (against HepG2 cells) and 0.34 μmol·L-1 (against Huh7 cells), which were superior to the positive control 11b. It also demonstrated good selectivity towards normal cells. Mechanistic studies revealed that ³¹P NMR monitoring confirmed that A6 follows the classic ProTide activation pathway and can be hydrolyzed by carboxypeptidase Y to remove the carboxylate ester. In vitro metabolic stability studies indicated that A6 remained stable in rat plasma for up to 48 h, whereas it underwent rapid activation in liver homogenate. Further in vivo experiments confirmed that in a mouse orthotopic Huh7 xenograft model, A6 (45 mg·kg-1, administered every 2 days) achieved a tumor inhibition rate of 55.84%, which was significantly higher than that of the sorafenib control group (38.98%), without causing significant changes in body weight. The animal protocols were approved by the Animal Ethics Committee of Capital Medical University (No. AEEI-2025-536). This study successfully developed a class of 5-FU dual prodrug candidates with significant anti-HCC activity. Among them, A6 exhibited excellent in vitro activity, metabolic stability, and in vivo antitumor efficacy. Its activation mechanism aligned with the designed pathway, providing a valuable lead compound and theoretical support for anti-HCC drug development.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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