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

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

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.

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. CH3OH 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） -N3-（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.