DIDEOXYNUCLEOSIDES AS POTENTIAL ANTI-AIDS DRUGS

今天，在LMCh的6-氨基-9-（2，3-二氨基苯并[d]噻吩-4-基）-N-甲基-N-苯并[d]噻吩-4-基的I期临床试验一年后， 双脱氧-2-氟-b-D苏式-戊呋喃糖基）-9H-嘌呤（beta-F-ddA）具有 一个更雄心勃勃的协议，其中包括两个其他 将使用抗逆转录病毒药物。这将增加需求 更多的药物和需要开发更有效和方便的 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（适当保护的），可以引入氟原子 很容易连接到糖基上，但是用的是“错误的”α 立体化学（所有试图引入氟与氟的立体化学的尝试）。 腺苷类似物的“正确”β立体化学失败， 从文献和我们自己的研究证实）。反演 α立体化学与所需的β立体化学之比为 通过形成中间体甲磺酸酯来实现 将其进行快速消除，得到相应的6-氨基-9-（5-氨基苯基）-N-甲基-N-（2-氨基苯基）-N-甲基-N- O-单甲氧基三苯甲基-2-氟-2，3-二脱氧-b-D-甘油基-β-D-吡喃-2-酮 烯呋喃糖基）腺嘌呤（关键的氟乙烯中间体！）。催化 双键的氢化，和同时除去双键， 单甲氧基三苯甲基得到所需的β-FddA，苏型- 配置，产量良好。的精致立体选择性 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 所需的消除产物，无论初始 氟的立体化学正在研究中。的可用性 alpha-FddA异构体，一种完全对 艾滋病毒在体外，启发我们调查其不活动的原因。 合适的非活性α-FddA的前药构建体，其递送 通过绕过初始磷酸化步骤， 在CEM/O淋巴细胞中具有显著的抗HIV活性，EC 50较低 为2 μ M。这次调查的最终目的是 （1）结构（conformity） 核苷与其能力，有效地发挥作用，在每一个 从最初的磷酸化到最终的磷酸化 与逆转录酶（RT）相互作用。合成了 alpha-FddA的三磷酸刚刚完成，其活性 将对RT进行调查。 AIDS标题：作为逆转录酶抑制剂的氟代二脱氧核苷 艾滋病的治疗。

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.