DIDEOXYNUCLEOSIDES AS POTENTIAL ANTI-AIDS DRUGS

开发了一种新的、更方便的合成方法 2‘-氟-β-D-苏脱氧核苷被成功地扩展到 一系列新的嘌呤和嘧啶类似物。在新的 1-(2，3-二脱氧-2-氟-β-D-苏氨酸)类似物的合成 胞苷及其5-氟胞嘧啶类似物表现良好 抗艾滋病病毒的活动。所有的尿嘧啶衍生物都没有活性。其中 嘌呤类，9-(2，3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)-6- 氯嘌呤作为活性次黄嘌呤核苷的前体药物 被腺苷脱氨酶激活后。最后，弱抗艾滋病毒 9-的活动 (2，3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)guanosine曾经是 与肌苷联合使用时显著增加 单磷酸脱氢酶抑制剂，如噻唑呋喃或利巴韦林。 几种抗HIV活性发酵的扩环类似物 合成了产物oxetanocin A，目的是评价 额外的羟甲基侧链在抗HIV中的重要性 活动。由此产生的一些双脱氧碳二糖和碳环 合成的核苷代表了新的化学结构。它们的生物学特性 评估正在进行中。 作为底物的6-取代-2‘-氟脱氧嘌呤核苷 由于腺苷脱氨酶(ADA)是以前药形式合成的 F-DDI和F-DDG。6-氯和6-氯的体外抗HIV活性 发现N6-甲氨基类似物被ADA废除 抑制剂，2‘-脱氧辅酶A，并通过添加ADA来增强 培养基质地。这些前药被设计成亲脂性的 有可能转移到艾滋病毒庇护所的分子，如 CNS，在ADA激活之前。

The new and more expedient method developed for the synthesis of 2'-fluoro-beta-D-threo-dideoxy nucleosides was successfully extended to a series of new purine and pyrimidine analogues. Among the new pyrimidine analogues prepared, 1-(2,3-dideoxy-2-fluoro-beta-D-threo- pentofuranosyl)cytosine and its 5-fluorocytosine analogue displayed good anti-HIV activity. None of the uracil derivatives were active. Among the purines, 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)-6- chloropurine behaved as a prodrug of the active hypoxanthine nucleoside after activation by adenosine deaminase. Finally, the weak anti-HIV activity of 9- (2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)guanosine was increased significantly when used in combination with inosine monophosphate dehydrogenase inhibitors such as tiazofurin or ribavirin. A number of ring-enlarged analogues of the anti-HIV-active fermentation product oxetanocin A have been synthesized with the intent of assessing the importance of the extra hydroxymethyl side chain to the anti-HIV activity. Some of the resulting dideoxyapiose and carbocyclic nucleosides made represent new chemical structures. Their biological evaluation is in progress. 6-Substituted-2'-fluoro-dideoxy purine nucleosides which are substrates for adenosine deaminase (ADA) are being synthesized as prodrug forms of F-ddI and F-ddG. The in vitro anti-HIV activities of the 6-chloro and N6-methylamino analogues were found to be abolished by the ADA inhibitor, 2'-deoxycoformycin, and augmented by the addition of ADA to the culture medium. These prodrugs are being designed as lipophilic molecules with potential for transport to HIV sanctuaries, such as the CNS, prior to activation by ADA.