3′,5′-二辛酰基-5-氟尿嘧啶脱氧核苷的合成及性质研究

Study on synthesis and properties of 3′,5′-dioctanoyl-5-fluoro-2 ′-deoxyuridine

目的 研究 5 氟尿嘧啶脱氧核苷 (FUdR)的前体药物 3′ ,5′ 二辛酰基 5 氟尿嘧啶脱氧核苷 (DO FUdR)的合成路线、降解规律和体外抗肿瘤细胞增殖活性。方法 通过酯化反应合成了DO FUdR ,采用MS ,NMR等进行了鉴定 ;HPLC测定DO FUdR在不同pH值缓冲液和小鼠组织匀浆中浓度的变化 ,计算其在不同介质中的降解速率常数 ,并测定了DO FUdR的溶解度和分配系数 ;3 H TdR掺入法测定了DO FUdR对U2 5 1星型胶质瘤细胞体外增殖活性的抑制作用。结果 合成化合物为DO FUdR ;其在缓冲溶液和组织匀浆中的降解过程符合表观一级反应 ;与FUdR具有相似的抗胶质瘤细胞增殖活性。结论 DO FUdR是一种值得进行进一步研究和开发的前体药物。

OBJECTIVE: to investigate the synthesis route, solubility, lipophicity, degradation kinetics and cytotoxicity of 3′, 5′-dioctanoyl-5-fluoro-2′-deoxyuridine(DO-FUdR). METHODS: DO-FUdR was synthesized and its structure was confirmed by mass spectrometry, IR spectrophotometry and detailed 1H and 13C-NMR, respectively. The solubility and lipophicity of the compound were assessed. The hydrolysis of DO-FUdR in different buffers and tissue homogenates was determined by HPLC. The inhibition effect on the proliferation of human U251 Astrocytic Glioma cells of DO-FUdR was compared with that of 5-fluoro-2′-deoxyuridine(FUdR). RESULTS: DO-FUdR was synthesized successfully and its solubility was found to be 5.52 × 10-5 mol &middot L-1. The hydrolysis of DO-FUdR was found to occur in buffers and the faster rate of enzymatic hydrolysis of it in 10% plasma and 4% tissue homogenates were observed with the apparent first order hydrolysis kinetics. The inhibition effect of DO-FUdR on the proliferation of tumor cells was almost as the same as that of FUdR. CONCLUSION: DO-FUdR is a potential prodrug to be studied further.