Siddiqi S M, Chen X, Rao J, Schneller S W, Ikeda S, Snoeck R, Andrei G, Balzarini J, De Clercq E
Department of Chemistry, University of South Florida, Tampa 33620.
J Med Chem. 1995 Mar 17;38(6):1035-8. doi: 10.1021/jm00006a023.
An enantiospecific synthesis of 3-deaza-5'-noraristeromycin as its dihydrochloride ((-)-6) has been accomplished in six steps beginning with the reaction of (+)-(1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate with 4-chloro-1H-imidazo[4,5-c]pyridine. The preparation of 7-deaza-5'-noraristeromycin ((-)-7) was described previously. Compounds (-)-6 and (-)-7 were evaluated for antiviral activity against a large number of viruses. Compound (-)-6 produced an antiviral activity pattern similar to 5'-noraristeromycin but was less potent. Compound (-)-6 inhibited CEM cell proliferation at a 50% inhibitory concentration of 27 micrograms/mL but proved not inhibitory to HEL cell proliferation and not toxic to E6SM, HeLa, Vero, and MDCK cells at concentrations up to 200 micrograms/mL. While (-)-6 showed inhibition of S-adenosyl-L-homocysteine (AdoHcy) hydrolase, it was less inhibitory than 5'-noraristeromycin. Compound (-)-7 displayed no antiviral properties or inhibitory effects toward AdoHcy hydrolase.
以(+)-(1R,4S)-4-羟基-2-环戊烯-1-基乙酸酯与4-氯-1H-咪唑并[4,5-c]吡啶反应开始，经六步反应完成了3-脱氮-5'-去甲瑞斯托霉素二盐酸盐((-)-6)的对映体特异性合成。7-脱氮-5'-去甲瑞斯托霉素((-)-7)的制备方法先前已有报道。对化合物(-)-6和(-)-7针对大量病毒的抗病毒活性进行了评估。化合物(-)-6产生的抗病毒活性模式与5'-去甲瑞斯托霉素相似，但效力较低。化合物(-)-6在50%抑制浓度为27微克/毫升时抑制CEM细胞增殖，但在浓度高达200微克/毫升时对HEL细胞增殖无抑制作用，对E6SM、HeLa、Vero和MDCK细胞无毒。虽然(-)-6显示出对S-腺苷-L-高半胱氨酸(AdoHcy)水解酶的抑制作用，但其抑制作用比5'-去甲瑞斯托霉素弱。化合物(-)-7没有显示出抗病毒特性或对AdoHcy水解酶的抑制作用。
