Cottam H B, Kazimierczuk Z, Geary S, McKernan P A, Revankar G R, Robins R K
J Med Chem. 1985 Oct;28(10):1461-7. doi: 10.1021/jm00148a015.
A number of 6-substituted and 2,6-disubstituted pyrrolo[2,3-d]pyrimidine 2'-deoxyribonucleosides were prepared by the direct stereospecific sodium salt glycosylation procedure. Reaction of the sodium salt of 4-chloro-6-methyl-2-(methylthio)pyrrolo[2,3-d]pyrimidine (6a) or 4,6-dichloro-2-(methylthio)pyrrolo[2,3-d]pyrimidine (6b) with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-alpha-D-erythro-pentofuranose (9) provided the corresponding N7 2'-deoxy-beta-D-ribofuranosyl blocked derivatives (8a and 8c) which, on ammonolysis, gave 4-amino-6-methyl-2-(methylthio)-7-(2-deoxy-beta-D-erythro-pentofuranosyl )pyrrolo[2,3-d]pyrimidine (11a) and 4-amino-6-chloro-2-(methylthio)-7-(2-deoxy-beta-D-erythro-pentofuranosyl )pyrrolo[2,3-d]pyrimidine (11b), respectively. Dethiation of 11a and 11b afforded 6-methyl-2'-deoxytubercidin (10a) and 6-chloro-2'-deoxytubercidin (10b), respectively. Dehalogenation of 10b provided an alternate route to the reported 2'-deoxytubercidin (3a). Application of this glycosylation procedure to 4,6-dichloro and 4,6-dichloro-2-methyl derivatives of pyrrolo[2,3-d]pyrimidine (15a and 15b) gave the corresponding blocked 2'-deoxyribonucleosides (18a and 18b), which on ammonolysis furnished 10b and 4-amino-6-chloro-2-methyl-7-(2-deoxy-beta-D-erythro- pentofuranosyl)pyrrolo[2,3-d]pyrimidine (17), respectively. This stereospecific attachment of the 2-deoxy-beta-D-ribofuranosyl moiety appears to be due to a Walden inversion at the C1 carbon by the anionic heterocyclic nitrogen. Controlled deacylation of 4-chloro-7-(2-deoxy-3,5-di-O-p-toluoyl-beta-D-erythro-pentofuranosyl) pyrrolo[2,3-d]pyrimidine (20a) gave 4-chloro-7-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrrolo[2,3-d] pyrimidine (20b). Dehalogenation of 20b gave the 2'-deoxynebularin analogue 7-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrimidine (19), and reaction of 20b with thiourea gave 7-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrimidine-4(3H)- thione (21). All of these compounds were tested in vitro against certain viruses and tumor cells. Only compounds 12a, 20b, and 21 showed significant activity against measles in vitro, and the activity is comparable to that of ribavirin. Although compounds 3a and 12b are slightly more active than ribavirin against HSV-2 in vitro, they are relatively more toxic to Vero cells. Compounds 3a and 20b exhibited moderate cytostatic activity against L1210 and P388 leukemia in vitro but are considerably less active than 2-chloro-2'-deoxyadenosine (1).
通过直接立体定向的钠盐糖基化方法制备了多种6-取代和2,6-二取代的吡咯并[2,3-d]嘧啶2'-脱氧核糖核苷。4-氯-6-甲基-2-(甲硫基)吡咯并[2,3-d]嘧啶(6a)或4,6-二氯-2-(甲硫基)吡咯并[2,3-d]嘧啶(6b)的钠盐与1-氯-2-脱氧-3,5-二-O-对甲苯甲酰基-α-D-赤藓糖戊呋喃糖(9)反应，得到相应的N7 2'-脱氧-β-D-核糖呋喃糖基封闭衍生物(8a和8c)，经氨解后分别得到4-氨基-6-甲基-2-(甲硫基)-7-(2-脱氧-β-D-赤藓糖戊呋喃糖基)吡咯并[2,3-d]嘧啶(11a)和4-氨基-6-氯-2-(甲硫基)-7-(2-脱氧-β-D-赤藓糖戊呋喃糖基)吡咯并[2,3-d]嘧啶(11b)。11a和11b的脱硫反应分别得到6-甲基-2'-脱氧结核菌素(10a)和6-氯-2'-脱氧结核菌素(10b)。10b的脱卤反应为报道的2'-脱氧结核菌素(3a)提供了另一条合成路线。将该糖基化方法应用于吡咯并[2,3-d]嘧啶的4,6-二氯和4,6-二氯-2-甲基衍生物(15a和15b)，得到相应的封闭2'-脱氧核糖核苷(18a和18b)，经氨解后分别得到10b和4-氨基-6-氯-2-甲基-7-(2-脱氧-β-D-赤藓糖戊呋喃糖基)吡咯并[2,3-d]嘧啶(17)。2-脱氧-β-D-核糖呋喃糖基部分的这种立体定向连接似乎是由于阴离子杂环氮在C1碳上的瓦尔登反转。4-氯-7-(2-脱氧-3,5-二-O-对甲苯甲酰基-β-D-赤藓糖戊呋喃糖基)吡咯并[2,3-d]嘧啶(20a)的可控脱酰反应得到4-氯-7-(2-脱氧-β-D-赤藓糖戊呋喃糖基)吡咯并[2,3-d]嘧啶(20b)。20b的脱卤反应得到2'-脱氧新制癌菌素类似物7-(2-脱氧-β-D-赤藓糖戊呋喃糖基)吡咯并[2,3-d]嘧啶(19)，20b与硫脲反应得到7-(2-脱氧-β-D-赤藓糖戊呋喃糖基)吡咯并[2,3-d]嘧啶-4(3H)-硫酮(21)。所有这些化合物都在体外针对某些病毒和肿瘤细胞进行了测试。只有化合物12a、20b和21在体外对麻疹显示出显著活性，且活性与利巴韦林相当。虽然化合物3a和12b在体外对单纯疱疹病毒2型的活性略高于利巴韦林，但它们对Vero细胞的毒性相对较大。化合物3a和20b在体外对L1210和P388白血病表现出中等的细胞生长抑制活性，但活性远低于2-氯-2'-脱氧腺苷(1)。
