Novel ProTide prodrugs of 5-fluoro-2'-deoxyuridine for the treatment of liver cancer

Eur J Med Chem. 2023 Nov 15:260:115763. doi: 10.1016/j.ejmech.2023.115763.

Leilei Jiang ¹, Ting Pan ², Qin Lv ¹, Wenmin Yuan ¹, Xiaochun Liu ¹, Xianjun Qu ³, Dongdong Luo ⁴, Shengbiao Wan ⁵, Shuxiang Cui ⁶

Affiliations

1 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266071, China.
2 Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, China.
3 Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
4 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266071, China. Electronic address: [email protected].
5 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266071, China. Electronic address: [email protected].
6 Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, China. Electronic address: [email protected].

PMID: 37659196 DOI: 10.1016/j.ejmech.2023.115763

Abstract

ProTide prodrug technology has emerged as a promising way for the development of anti-viral and anti-tumor drugs, whereas, there are fewer applications for the treatment of liver Cancer. Herein, a series of distinct 3'-ester ProTide prodrugs of 5-fluoro-2'-deoxyuridine (FdUR) were synthesized and evaluated for their anti-liver Cancer activity. The most efficient prodrug 11b reached a sub-micromolar activity (IC₅₀ = 0.42 ± 0.13 μM) against HepG2 and over 100-fold and 200-fold improvements compared to 5-FU, respectively. 11b also demonstrated favorable selectivity towards normal liver cells L-02 (IC₅₀ > 100 μM). In vitro metabolic stability studies revealed that 11b is stable in the plasma and could be activated rapidly in the liver, which supported that 11b is liver-targeted. Importantly, to more accurately evaluate the anti-HCC activity of 11b, the liver orthotopic model was built and 11b significantly suppressed tumor growth (TGI = 75.5%) at a dose of 60 mg/kg/2d in vivo without obvious toxicity. Overall, these promising results indicated that 11b could serve as a safe and effective prodrug of 5-FU nucleoside for liver Cancer therapy.

Keywords

5-Fluorouracil; Liver cancer therapy; Mouse orthotopic models; ProTide prodrugs.

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