DIDEOXYNUCLEOSIDES AS POTENTIAL ANTI-AIDS DRUGS

碘腺苷，6-氨基-9-（2，3-二脱氧-2-氟-β-D-苏型-戊呋喃糖基）-9H-嘌呤，是本实验室发现和开发的抗逆转录病毒药物，目前正处于治疗艾滋病的I/II期临床试验（http：//www.aegis.com/pub/beta/1998/BE981003.html）。LMC目前有兴趣开发新的替代合成洛腺苷，以提高效率并降低药物成本。去年报道的新方法包括将6-甲氧基-9-（2-脱氧-2-氟-5-苯甲酰基β-D-阿拉伯呋喃糖基）-9H-嘌呤的相应甲基黄原酸酯还原为β-F-ddA，通过使用异丙醇作为溶剂和还原剂而不是二甘醇二甲醚，进一步改进了该方法。新的自由基还原是非常有效的，避免了使用昂贵和易燃的氢化三丁基锡，并在6-甲氧基氨解后以高产率生产碘腺苷。在机理水平上，研究了三磷酸碘腺苷及其相应的2？异头物（α-FddA）对接在HIV-1 RT-DNA- dNTP的三元复合物的活性位点（通过用三磷酸类似物替换dNTP）强烈表明，尽管α-FddATP具有有利的A-构象（North糖皱褶），但由于氟原子和酪氨酸115之间的强烈空间冲突，其不如β-FddATP有效。酪氨酸115是一种高度保守的氨基酸，在HIV-1 RT中作为门控员发挥作用，以防止核糖核苷酸的掺入。实际上，测量的抑制HIV-1 RT的IC 50证明，在效力方面存在4倍差异，有利于β-FddATP。β-F-ddA的前体药物递送仍然是绕过腺苷脱氨的重要研究途径。初步信息表明，前体药物的方法是非常有益的，在提高效力的lodenosine。艾滋病标题：氟二脱氧核苷作为逆转录酶抑制剂治疗艾滋病。- 艾滋病，双脱氧核苷，荧光素，艾滋病毒，逆转录酶，

Lodenosine, 6-Amino-9-(2,3-dideoxy-2-fluoro-beta-D-threo- pentofuranosyl)-9H-purine, an antiretroviral agent discovered and developed in this laboratory is currently in Phase I/II clinical trials (http://www.aegis.com/pub/beta/1998/BE981003.html) for the treatment of AIDS. The LMC is currently interested in developing new, alternative synthesis of lodenosine to improve efficiency and lower the cost of the drug. The new approach reported last year, which consisted in the reduction of the corresponding methyl xanthate of 6-methoxy-9-(2-deoxy- 2-fluoro-5-benzoyl beta-D-arabinofuranosyl)-9H-purine to beta-F-ddA, was further improved by using isopropanol as solvent and reducing agent instead of diglyme. The new radical reduction is very efficient, avoids the use of the expensive and flammable tributyltin hydride, and produces lodenosine in high yield after ammonolysis of the 6-methoxy group. At the mechanistic level, a conformational study where the triphosphate of lodenosine and its corresponding 2?-anomer (alpha-FddA) were docked at the active site of the ternary complex of HIV-1 RT-DNA- dNTP (by replacing the dNTP with either triphosphate analogue) strongly suggests that the alpha-FddATP, despite having a favorable A- conformation (North sugar pucker), is less effective than beta-FddATP due to a strong steric clash between the fluorine atom and Tyrosine 115. Tyrosine 115 is a highly conserved amino acid that functions as a gate keeper in HIV-1 RT to prevent the incorporation of ribonucleotides. Indeed the measured IC50 for inhibiting HIV-1 RT demonstrated that there is a 4-fold difference in potency favoring the beta-FddATP. Pro-drug delivery of beta-F-ddA continues to be an important avenue of research to by-pass adenosine deamination. Preliminary information indicates that the pro-drug approach is highly beneficial in improving the potency of lodenosine.AIDS title: Fluorodideoxynucleosides as Reverse Transcriptase Inhibitors for the Treatment of AIDS. - AIDS, dideoxynucleosides, fluoronucleosides, HIV, Reverse Transcriptase,