DIDEOXYNUCLEOSIDES AS POTENTIAL ANTI-AIDS DRUGS

今天，LMCH的6-氨基-9-(2，3-氨基-9-(2，3-))一期临床试验一年后 二脱氧-2-氟-b-D-硫代呋喃糖基)-9H-嘌呤(β-F-Dda) 即将完成的是一项更雄心勃勃的议定书，其中包括另外两项 将实施抗逆转录病毒药物。这将增加需求。 对于更多的药物和开发更有效和便利的需要 β-FddA的合成我们发现了一种很有前途的方法 从市售的阿拉伯呋喃糖基腺嘌呤(Ara-A)开始。 从Ara-A(适当保护)可以引入氟原子 很容易找到糖份，但字母字母“错”了 立体化学(所有尝试引入氟与 来自腺苷类似物的“正确的”β立体化学失败，因为 从文献和我们自己的研究中得到证实)。的反转 到所需的β立体化学的阿尔法立体化学是 通过形成中间体甲烷磺酸酯来实现 经过准备好的消除反应，得到相应的6-氨基-9-(5- O-单甲氧基三丁基-2-氟-2，3-二脱氧-b-D-甘油-戊二烯-2- 腺嘌呤(关键的氟乙烯中间体！)催化作用 双键的氢化，并同时去除 单甲氧基三苯基得到了所需的β-FddA，其中的苏基- 配置，成品率高。精致的立体选择性 减少促使我们寻找更有效的方法来达到 关键的氟乙烯中间体。其他生产方法 所需的消除产品而不考虑初始 正在对氟的立体化学进行研究。可得性 对于α-FddA异构体，一种完全不起作用的化合物 HIV在体外，启发我们调查其不活跃的原因。 合适的非活性α-FddA的亲药结构，可以提供 通过绕过最初的磷酸化步骤，单磷酸盐显示 EC50低的CEM/O淋巴细胞具有显著的抗HIV活性 为2微米。这次调查的最终目的是试图 关联构型(并因此关联构象) 核苷与其能力有效发挥作用的每个 从最初的磷酸化到最终的磷酸化的中间步骤 与逆转录酶(RT)的相互作用。三种化合物的合成 α-FddA的三磷酸刚刚完成，其活性 将对RT进行调查。 艾滋病标题：作为逆转录酶抑制剂的氟二脱氧核苷 用于治疗艾滋病。

Today, a year after the phase I clinical trial of LMCh's 6-amino-9-(2,3- dideoxy-2-fluoro-b-D threo-pentofuranosyl)-9H-purine (beta-F-ddA) has nearly concluded, a more ambitious protocol that includes two other antiretroviral agents will be implemented. This will increase the demand for more drug and the need to develop more efficient and expedient syntheses of beta-FddA. We have discovered a promising method that starts from commercially available arabinofuranosyl adenine (ara-A). From ara-A (suitably protected), the fluorine atom can be introduced readily onto the sugar moiety, but with the "wrong" alpha stereochemistry (all attempts to introduce the fluorine with the "correct" beta stereochemistry from adenosine analogues failed, as substantiated from the literature and our own research). Inversion of the alpha stereochemistry to the desired beta stereochemistry was achieved via the formation of an intermediate methanesulfonate ester that underwent ready elimination to give the corresponding 6-amino-9-(5- O-monomethoxytrityl-2 fluoro-2,3-dideoxy-b-D-glycero-pent-2- enofuranosyl)adenine (the key vinyl fluoride intermediate!). Catalytic hydrogenation of the double bond, and the simultaneous removal of the monomethoxytrityl group gave the desired beta-FddA, with the threo- configuration, in good yield. The exquisite stereoselectivity of the reduction has prompted us to look for more efficient ways to get to the critical vinyl fluoride intermediate. Additional methods of producing the desired elimination product regardless of the initial stereochemistry of the fluorine are being investigated. The availability of the alpha-FddA isomer, a compound that is completely inactive against HIV in vitro, inspired us to investigate the reasons for its inactivity. Suitable pro-drug constructs of the inactive alpha-FddA, which deliver the monophosphate by bypassing the initial phosphorylation step, showed remarkable activity against HIV in CEM/O lymphocytes with EC50s as low as 2 microM. The ultimate goal of this investigation is to try to correlate the configuration (and hence the conformation) of the nucleoside with its capacity to function effectively at each of the intervening steps from the initial phosphorylation to its final interaction with reverse transcriptase (RT). The syntheses of the triphosphate of alpha-FddA has just been completed and its activity against RT will be investigated. AIDS title: Fluorodideoxynucleosides as Reverse Transcriptase Inhibitors for the Treatment of AIDS.