Bouton Jakob, Van Hecke Kristof, Van Calenbergh Serge
Laboratory for Medicinal Chemistry, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
XStruct, Department of Inorganic and Physical Chemistry, Ghent University, Krijgslaan 281 S3, 9000 Ghent, Belgium.
Tetrahedron. 2017 Jul 27;73(30):4307-4316. doi: 10.1016/j.tet.2017.05.083. Epub 2017 May 29.
Azanucleosides, sugar-modified nucleoside analogues containing a 4' nitrogen atom, have shown a lot of therapeutic potential, e.g. as anti-cancer and antiviral agents. We report the synthesis of a series of 2'-homoazanucleosides, in which the nucleobase is attached to the 2'-position of the pyrrolidine ring via a methylene linker. A suitable orthogonally protected iminosugar was synthesized by ring closing metathesis and dihydroxylation as key steps and further converted to a series of 8 nucleoside analogues through Mitsunobu reaction with suitably protected nucleobases. The 5' position of the adenine analogue was then further derivatized with thiols to afford 2 additional compounds. The final compounds were evaluated for biological activity.
氮杂核苷是一类含有4'氮原子的糖修饰核苷类似物，已显示出许多治疗潜力，例如作为抗癌和抗病毒药物。我们报道了一系列2'-高氮杂核苷的合成，其中核苷碱基通过亚甲基连接基连接到吡咯烷环的2'-位。通过关环复分解和二羟基化作为关键步骤合成了一种合适的正交保护亚氨基糖，并通过与适当保护的核苷碱基的 Mitsunobu 反应进一步转化为一系列8种核苷类似物。然后用硫醇对腺嘌呤类似物的5'位进行进一步衍生化，得到另外2种化合物。对最终化合物进行了生物活性评估。
