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;3H-TdR掺入法测定了DO-FUdR对U251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。
Abstract
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·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.
关键词
5-氟尿嘧啶脱氧核苷 /
3′ /
5′-二辛酰基-5-氟尿嘧啶脱氧核苷 /
合成路线 /
降解动力学 /
抗肿瘤活性
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Key words
5-fluoro-2′-deoxyuridine /
3′ /
5′-dioctanoyl-5-fluoro-2′-deoxyuridine /
synthesis /
degradation kinetics /
cytotoxicity
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参考文献
[1］Nishizawa Y, Casida JE.3′,5′-diesters of 5- fluoro-2′-deoxyuridine:synthesis and biological activity［J］.Biochem Pharmacol，1965, 14:1605.
[2］Preechagoon D, Brereton I, Staatz C,et al.Ester prodrugs of a potent nalgesic, morphine-6-sulfate: syntheses, spectroscopic and physicochemical properties［J］.Int J Pharm，1998, 163:177.
[3］Nakagawa H, Yamada M, Fukushima M,et al.In vitro study on intrathecal application of 5-fluoro-2′-deoxyuridine(FdUrd) for meningeal dissemination of malignant tumor［J］.No Shinkei Geka，1998, 26(9):787.
[4］Kawaguchi T, Fukushima S, Hayashi,Y,et al.Selective accumulation of 3′,5′-dioctanoyl-5-fluoro-2′-deoxyuridine (FdUrd-C8) and sustained release of its active metabolites in VX-2 rabbit hepatoma following intraarterial administration of FdUrd-C8 solution in lipiodol［J］.Cancer Res，1988, 48:4179.
[5］Fukushima S, Kawaguchi T, Nisida M,et al.Selective antiancer effects of 3′,5′-dioctanoyl-5-fluoro-2′-deoxyuridine,a lipophilic prodrug of 5-fluoro-2′-deoxyuridine, dissolved in an oily lymphographic agent on hepatic cancer of rabbits bearing VX-2 tumor［J］.Cancer Res，1987, 47:1930.
[6］Kawaguchi T, Suzuki Y, Nakahara Y,et al.Activity of esterase in the hydrolysis of 3′,5′-diesters of 5-fluoro-2′-deoxyuridine in relation to the strucure of the diester prodrugs［J］.Chem Pharm Bull,1985, 33(1):301.
[7］于波涛，张志荣，曾仁杰.药质体-一种新型给药系统［J］.中国药学杂志，2000； 35（11）：721.
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脚注
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基金
国家杰出青年科学基金（39925039）、国家自然科学基金（39970877）和教育部高等骨干老师资助计划项目
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