DIDEOXYNUCLEOSIDES AS POTENTIAL ANTI-AIDS DRUGS

本实验室发现和开发的抗逆转录病毒药物6-氨基-9-(2，3-二脱氧-2-氟-β-D-苏氨基-呋喃葡萄糖)-9H-嘌呤目前正在进行治疗艾滋病的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洛地诺的替代合成，以提高药物的效率和降低药物的成本。去年报道的新方法包括将相应的6-甲氧基-9-(2-脱氧-2-氟-5-苯甲酰基-β-D-阿拉伯呋喃葡萄糖)-9H-嘌呤的甲基黄原酸酯还原为β-F-Dda，并用异丙醇代替二甘醇作为溶剂和还原剂进行了进一步的改进。新的自由基还原非常有效，避免了使用昂贵和易燃的三丁基锡氢化物，并在6-甲氧基氨解后高产率地生成洛地诺。在机制水平上，一项构象研究表明，尽管α-FddATP具有良好的A-构象(北糖折叠)，但由于氟原子和酪氨酸115之间存在强烈的空间碰撞，因此α-FddATP与其对应的2？-异构体(α-FddA)对接在HIV-1 RT-DNA-dNTP三元复合体的活性部位(用任一种三磷酸类似物取代dNTP)。酪氨酸115是一种高度保守的氨基酸，在HIV-1RT中起着守门人的作用，阻止核糖核苷酸的掺入。事实上，所测量的抑制HIV-1RT的IC50表明，对β-FddATP的效力有4倍的差异。β-F-Dda的亲药递送仍然是绕过腺苷脱氨反应的重要研究途径。初步信息表明，亲药物方法对提高洛丹诺辛的效力非常有益。艾滋病标题：作为逆转录酶抑制剂治疗艾滋病的氟二脱氧核苷。-艾滋病、双脱氧核苷、氟核苷、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,