6-取代氨基-2-烷硫基腺苷化合物的合成及抗血小板凝聚活性

以鸟苷(1)为原料, 经过糖环保护得到2',3',5'-三-O-乙酰基鸟嘌呤核苷(2), 化合物2与三氯氧磷反应得到2-氨基-6-氯-9-(2',3',5'-三-O-乙酰基-β-D-呋喃核糖基)嘌呤(3), 化合物3经重氮化后再与二烷基二硫醚反应得到2-烷硫基-6-氯-9-(2',3',5'-三-O-乙酰基-β-D-呋喃核糖基)嘌呤(4a~4d), 化合物4a~4d与胺进行亲核取代反应后, 脱去糖环保护得到12个新型的6-取代氨基-2-烷硫基腺苷化合物(5a~5l). 采用¹H NMR, ¹³C NMR, IR和高分辨质谱(HRMS)对目标化合物的结构进行了确证, 并对所有化合物进行了体外抗血小板聚集活性测试. 结果表明, 当测试浓度为10 μmol/L时, 化合物5a~5l仍具有一定的抗凝活性, 其中, 6-(3-苯基丙基)氨基-2-丙硫基腺苷(5d)活性最为显著, 抑制率可达90.2%.

Synthesis of 6-Amino-2-alkylthio Adenosine and Their Anti-platelet Aggregation Activity

Some purine derivatives are effective inhibitors of platelet aggregation. Guanosine(1), as the starting material, was protected by acetic anhydride to get 2',3',5' -tri-O-acetyl-guanosine(2), then chlorinated with phosphorus oxychloride to obtain 2-amino-6-chloro-9-(2',3',5'-tri-O-acetyl-β-D-ribofuranosyl)purine(3). Compound 3 was diazotized with isoamyl nitrite and then reacted with dialkyl disulfides to afford 2-alkyl(aryl)thio-6-chloro-9-(2',3',5'-tri-O-acetyl-β-D-ribofuranosyl)purines(4a-4d). 6-Amino-2-alkylthio adenosine(5a-5l) were acquired by aminolysis and deprotection reaction of compounds 4a-4d. The structures of the compounds were identified by ¹H NMR, ¹³C NMR, IR and high resolution mass spectrometer(HRMS). In addition, the platelet aggregation rates(PAR) for the final compounds were measured. The results show that these compounds have a certain anti-platelet aggregation activity under 10 μmol/L. 6-(3-Phenyl propyl)azyl-2-propylthio adenosine has the most significant activity, the PAR was up to 9.8%.