Krenitsky T A, Rideout J L, Chao E Y, Koszalka G W, Gurney F, Crouch R C, Cohn N K, Wolberg G, Vinegar R
J Med Chem. 1986 Jan;29(1):138-43. doi: 10.1021/jm00151a022.
A variety of imidazo[4,5-c]pyridines (3-deazapurines) were synthesized. With use of these aglycons as pentosyl acceptors, the corresponding ribonucleosides and 2'-deoxyribonucleosides were prepared by an enzymatic method involving transfer of the pentosyl moiety from appropriate pyrimidine nucleosides. With most of the imidazo[4,5-c]pyridines, the products obtained from the enzyme-catalyzed reactions were pentosylated exclusively in the 1-position. However, some 3-pentosylation occurred with aglycons that had H or N3 in the 4-position. In addition to the 2'-deoxy congener of the ribonucleoside of 4-amino-1H-imidazo[4,5-c]pyridine, the 5'-deoxy and 2',5'-dideoxy congeners were synthesized. All of the aglycons and their nucleosides were tested for toxicity to mammalian cells in culture. None were markedly cytotoxic. These compounds were also evaluated for their ability to inhibit lymphocyte-mediated cytolysis in vitro. 3-Deazaadenosine (23) and its 2'-deoxy congener (38) were the most potent inhibitors (ED50 = 20 microM). In addition to these two in vitro tests, in vivo inhibition of the inflammatory response in the rat carregeenan pleurisy model was determined. 3-Deazaadenosine (23) was the most potent compound (ED50 = 3 mg/kg) in this in vivo test.
合成了多种咪唑并[4,5-c]吡啶（3-脱氮嘌呤）。以这些糖苷配基作为戊糖基受体，通过一种酶促方法制备了相应的核糖核苷和2'-脱氧核糖核苷，该方法涉及从合适的嘧啶核苷转移戊糖基部分。对于大多数咪唑并[4,5-c]吡啶，酶催化反应得到的产物仅在1-位发生戊糖基化。然而，4-位含有氢或N3的糖苷配基会发生一些3-戊糖基化。除了4-氨基-1H-咪唑并[4,5-c]吡啶核糖核苷的2'-脱氧类似物外，还合成了5'-脱氧和2',5'-二脱氧类似物。对所有糖苷配基及其核苷进行了对培养的哺乳动物细胞的毒性测试。均无明显细胞毒性。还评估了这些化合物在体外抑制淋巴细胞介导的细胞溶解的能力。3-脱氮腺苷（23）及其2'-脱氧类似物（38）是最有效的抑制剂（ED50 = 20 microM）。除了这两项体外测试外，还测定了在大鼠角叉菜胶胸膜炎模型中体内对炎症反应的抑制作用。在该体内测试中，3-脱氮腺苷（23）是最有效的化合物（ED50 = 3 mg/kg）。
