5-Fu多级前体药物的设计合成与体内抗肿瘤作用

Multiple-grade prodrugs of 5-flulorouracil:synthesis and anti-tumor activities in mice

目的:设计合成5-Fu的多级前体药物,并进行小鼠体内抗肿瘤作用研究。方法:在5-Fu的N_1和N_3位引入邻甲苯甲酰基,分别合成氟尿嘧啶的邻甲苯甲酰基的单取代(TFu)和双取代(DTFu)前体药物,并考察目标化合物对小鼠S_(180)实体瘤和肝癌实体瘤的抑瘤作用。结果:在相同的给药剂量下(按100 mg·kg^(-1)给药时)DTFu和TFu对的小鼠S_(180)实体瘤的抑瘤率分别为55．88%和57．84%,优于对照药FT-207(抑瘤率为44．12%)。对肝癌实体瘤实验,DTFu抑瘤率与剂量成相关性,50,100和200 mg·kg^(-1)时的抑瘤率分别为37．74%,58．14%和88．74%。DTFu对小鼠灌胃给药的LD_(50)为3 165．77 mg·kg^(-1)。结论:TFu和DTFu具较强抗肿瘤活性且毒性较低。

Objective ： To synthesize single substituted （TFu） and double substituted （DTFu） prodrugs of 5-flulorouracil, and to study their anticancer activities in mice. Methods： TFu and DTFu were synthesized by introducing an O-methyl benzoic group at N1 and N3 positions of 5-flulorouracil. The anticancer activity of TFu and DTFu were evaluated based on their inhibitory rate against Sis0 solid carcinoma and hepatoma solid carcinoma of mice. Results：The DTFu and TFu showed a better inhibitory rate against S180 solid carcinoma at the dose of 100 mg·kg^-1 （55.88% vs. 57.84% ） than the positive control drug FT-207 （44. 12% ）. The DTFu had inhibitory rates of 37.74%, 58.14% and 88.74% against hepatoma solid carcinoma at the dosage of 50, 100 and 200 mg·kg^-1, respectively, in a dose-dependent manner. The LDs0 of DTFu was 3 165.77mg·kg^-1 Conclusion：Both DTFu and TFu are of anti-tumor activities against mice S180 solid carcinoma and hepatoma solid carcinoma with low toxicity.