甘油骨架上含芳硒基的替加氟硫代磷脂缀合物的合成及生物活性

以O-(2-邻苯二甲酰亚氨基)乙基-1,3,2-二氧磷杂环戊烷硫代磷酸酯1及2-邻苯二甲酰亚氨基乙醇环甘油硫代磷脂缀合物2为模型,研究开环反应的条件.结果表明,在室温下,甲醇对化合物1中1,3,2-二氧磷杂环戊烷中的磷原子的亲核进攻,生成O-甲基-O-羟乙基-O-(2-邻苯二甲酰亚氨基)乙基硫代磷酸酯3,但是在此条件下,甲醇与化合物2不反应.在室温下,以异丙醇作溶剂,苯硒酚与化合物2不反应.在氢氧化钾存在下,以异丙醇/水作溶剂(体积比20:1),在室温下,硒酚可以有效地进攻中化合物2中1,3,2-二氧磷杂环戊烷中的碳原子生成相应的开环产物.按照这一反应条件,顺利实现了硒酚对N¹-(2-呋喃基)-N³-羟烷基-5-氟脲嘧啶硫代环甘油磷脂缀合物的亲核开环,生成甘油骨架的端碳原子上带有芳硒基新颖的磷脂核苷缀合物.对开环反应的机理进行了探讨.体外细胞毒性试验结果表明:产物对膀胱癌细胞T-24、胃癌细胞BGC-823的恶性增殖抑制效果优于替加氟;但对正常肝上皮细胞毒性也大于替加氟.

Synthesis and Biologic Activities of Glycerothiophospholipid Conjugate of Tegafur Containing Aryl-selenium Group in the Glycerol Skeleton

2-Phthalimidoethyl-2-sulfur-1,3,2-dioxaphopholane(1) and cyclic glycerothiophospholipid conjugate of phahalimidoethanol(2) were used as model compounds to investigate the selectivity and reaction conditions of nucleophilic opening ring by heteroatomic function groups.CH-3OH could attack the phosphor atom in 1,3,2-dioxaphopholane of compiound(1) to give O-methyl O-hydroxyethyl-O-phthalimidoethyl thiophosphate in 85% yield;in the presence of potassium hydroxide aryl selenol could attack the carbon atom in 1,3,2-dioxaphopholane of the cyclic phospholipid conjugate of N~1-(2-furanidyl)-N~3-(hydroxyalkyl)-5-fluorouracil to give the corresponding product of ring-opening in high yields.It was indicated through in vitro biological assays by using MTT that the title compound exhibited higher inhibitory effect on the malignant proliferation of bladder cancer cell T-24 and stomach cancer cell BGC-823 than tegafur,but on the other hand it showed a higher toxicity on the normal liver epithelial cell L-02.