6-amino-9-<5-O-(tert-butyldimethylsilyl)-2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl>-9H-purine | 125542-18-9

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 英文名称: 6-amino-9-<5-O-(tert-butyldimethylsilyl)-2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl>-9H-purine
• 英文别名: 9-[(2R,3S,5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-fluorooxolan-2-yl]purin-6-amine
• CAS: 125542-18-9
• 化学式: C₁₆H₂₆FN₅O₂Si
• 分子量: 367.499
• InChiKey: KGCDMCAOVLAKJM-ZIBATOQPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.06
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  88.1
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  6-amino-9-<5-O-(tert-butyldimethylsilyl)-2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl>-9H-purine 在 亚硝酸特丁酯 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 生成 9-[5'-O-(tert-butyldimethylsilyl)-2',3'-dideoxy-2'-fluoro-β-D-arabinofuranosyl]-9H-purine
  参考文献：
  名称：

  Potential anti-AIDS drugs. Lipophilic, adenosine deaminase-activated prodrugs

  摘要：

  Selected acid-stable (2'-fluoro-2',3'-dideoxyarabinofuranosyl)adenine nucleosides containing methyl groups and other lipophilic functions at various positions in the adenine ring were prepared and evaluated as anti-HIV agents. The N6-methyl (1f), N6-benzoyl (1g), and 6-chloro (li) analogues had modest activity, giving 30-50% protection to ATH8 cells infected with HIV. 2-Methyl (1d), 8-methyl (1h), and 2,N6-dimethyl (1e) substitution, as well as N1-oxide (21) formation, abolished the activity of the parent compound (1a). Several of these compounds, originally designed as agents for treating HIV in the central nervous system, were further investigated as substrates for adenosine deaminase (ADA). Kinetic experiments showed that ADA catalyzed the formation of the anti-HIV active inosine compound 1b from the N6-methyl analogue 1f in a quantitative manner. The anti-HIV activity of 1f and 1i was abolished when the ADA inhibitor, 2'-deoxycoformycin, was added to the test mixture. In contrast, the activity of 1f was significantly enhanced when ADA was added to the test system. These data indicate that 1f and 1i are prodrug forms of 1b in systems containing ADA.

  DOI：

  10.1021/jm00109a018
• 作为产物：
  描述：

  9-[5-O-(tert-butyldimethylsilyl)-2-deoxy-2-fluoro-3-O-(phenoxythiocarbonyl)-β-D-arabinofuranosyl]adenine 在 偶氮二异丁腈 、 三正丁基氢锡 作用下， 以 甲苯 为溶剂， 反应 0.5h， 以71%的产率得到6-amino-9-<5-O-(tert-butyldimethylsilyl)-2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl>-9H-purine
  参考文献：
  名称：

  Acid-stable 2'-fluoro purine dideoxynucleosides as active agents against HIV

  摘要：

  2',3'-Dideoxy purine nucleosides have anti-HIV activity in vitro and the inosine analogue is being clinically evaluated. The instability of these compounds toward acidic conditions complicates oral administration. The effect of the addition of a fluorine atom to the 2'-position was investigated by preparing the fluorine-containing 2'-erythro and 2'-threo isomers of ddA and the threo isomer of ddI. All fluorine-containing compounds were indefinitely stable to acidic conditions which completely decomposed ddI (1) and ddA (2) in minutes. While the fluorine-containing erythro isomer, 5, was inactive, the threo isomers, 2'-F-dd-ara-A (3) and 2'-F-dd-ara-I (4), were just as potent and active in protecting CD4+ ATH8 cells from the cytopathogenic effects of HIV-1 as the parent drugs. Exposure to pH 1 at 37 degrees C prior to testing destroyed the activity of ddA and ddI but left the anti-HIV properties of 3 and 4 unchanged. The fluorinated analogues also protected cells exposed to HIV-2 and inhibited gag gene product expression but not as effectively as the parent compounds. The fluorine-containing analogues appear to be somewhat more toxic in vitro to the antigen- and mitogen-driven proliferation of immunocompetent cells than their corresponding parent compounds.

  DOI：

  10.1021/jm00165a015

文献信息

• Lipophilic, Acid-Stable, Adenosine Deaminase-Activated Anti-HIV Prodrugs for Central Nervous System Delivery. 2. 6-Halo- and 6-Alkoxy Prodrugs of 2'-.beta.-Fluoro-2',3'-dideoxyinosine
  作者：Harry Ford、Maqbool Siddiqui、John S. Driscoll、Victor E. Marquez、James A. Kelley、Hiroaki Mitsuya、Takuma Shirasaka

  DOI：10.1021/jm00007a015

  日期：1995.3

  and 6-alkoxy-(OMe-, OEt-) 9-(2,3-dideoxy-2-fluoro-beta-D-threopentofuranosyl) purines (F-ddN) have been synthesized and characterized with the objective of finding compounds which might be superior to existing drugs for the treatment of HIV in the central nervous system. These compounds, which contain lipophilic 6-substituents, were chosen as acid-stable prodrugs for the anti-HIV-active F-ddN, 9-(2,3

  一系列6卤代（F-，Cl-，Br-，I-）和6-烷氧基-（OMe-，OEt-）9-（2,3-二脱氧-2-氟-β-D-叔戊基呋喃糖基）嘌呤（F-ddN）已被合成和表征，目的是发现在中枢神经系统中治疗HIV可能优于现有药物的化合物。这些含有亲脂性6位取代基的化合物被选作抗HIV活性F-ddN，9-（2,3-二脱氧-2-氟-β-D-苏-五呋喃糖基）次黄嘌呤的酸稳定前药（F-ddI），因为相对于F-ddI，它们具有增加血脑屏障渗透的潜力。所有新化合物均比目前批准的抗艾滋病药物更具亲脂性。相对于二羟肌苷（ddI），对于6-氯-和6-乙氧基类似物，分配系数增加了30倍和110倍。2' -氟取代消除了pH 1，核苷糖基键的酸催化裂解。然而，在pH 1时，观察到6-氟取代基的酸催化水解产生F-ddI的速率约为t1 / 2（0.54 h）。比其他前药快40-170倍。F-ddN作为F-ddI的前药的效用取决
• Deoxyfluoronucleoside process
  申请人：Bristol-Myers Squibb Company

  公开号：EP0428109A3

  公开（公告）日：1991-09-11

  There is disclosed a process for synthesizing 2′-­fluoro-2′,3′-dideoxyarabinofuranose derivatives of inosine and adenine on a large scale which involves coupling of a fluorosugar derivative and a purine reactant to provide a purine nucleoside intermediate which is then deoxygenated. 6-Chloro or 6-benzamidopurine and 1,3,5-tri-O-benzoyl-2-­deoxy-2-fluoroarabinofuranose are used as starting materials.

  揭示了一种合成肌苷和腺嘌呤的2'-氟-2',3'-二去氧阿拉伯呋喃糖衍生物的大规模过程，涉及将氟糖衍生物和嘌呤试剂偶联以提供嘌呤核苷中间体，然后对其进行脱氧。6-氯或6-苯甲酰基嘌呤和1,3,5-三-O-苯甲酰-2-脱氧-2-氟阿拉伯呋喃糖被用作起始物质。
• Lipophilic, Acid-Stable, Adenosine Deaminase-Activated Anti-HIV Prodrugs for Central Nervous System Delivery. 3. 6-Amino Prodrugs of 2‘-β-Fluoro-2‘,3‘-dideoxyinosine
  作者：John S. Driscoll、Maqbool A. Siddiqui、Harry Ford,、James A. Kelley、Jeri S. Roth、Hiroaki Mitsuya、Masatoshi Tanaka、Victor E. Marquez

  DOI：10.1021/jm9509197

  日期：1996.1.1

  dimethylamino compounds are ca. 100 times more lipophilic than ddI or F-ddI. As expected, 2'-fluoro substitution protects the compounds from acid-catalyzed glycosylic cleavage. Only the hydroxylamino and nitro analogs underwent any nonenzymatic hydrolysis at pH 1.0 or 7.4. This reaction, however, results in hydrolysis of the group in the 6-position rather than glycosylic bond cleavage. ADA catalyzes

  合成并表征了一系列9-（2,3-二脱氧-2-氟-β-D-苏-五氟呋喃糖基）嘌呤（F-ddN）的6个取代氨基类似物，目的是发现可能是在治疗中枢神经系统中的HIV方面优于现有药物。这些化合物比目前批准的抗HIV药物具有更高的亲脂性，可以更好地渗透血脑屏障。随后腺苷脱氨酶（ADA）催化的这些前药在大脑中的水解可产生抗HIV药物9-（2,3-二脱氧-2-氟-β-D-苏-五呋喃糖基）次黄嘌呤（F- ddI）。由相应的6-氯类似物合成的新化合物包括F-ddN，其中含有甲基氨基，乙基氨基，二甲基氨基，羟基氨基，甲氧基氨基，苄氧基氨基，肼基，和在6-位的硝基取代基。在制备6-氯衍生物的过程中，以意外产物的形式分离了6-硝基类似物。在具有抗HIV活性的类似物中，乙氨基和二甲氨基化合物为约。亲脂性比ddI或F-ddI高100倍。如所预期的，2'-氟取代保护化合物免受酸催化的糖基裂解。在pH 1.0或7.4下，
• The “β-Fluorine Effect” in the Non-Metal Hydride Radical Deoxygenation of Fluorine-Containing Nucleoside Xanthates
  作者：Maqbool A. Siddiqui、John S. Driscoll、Elie Abushanab、James A. Kelley、Joseph J. Barchi、Victor E. Marquez

  DOI：10.1080/15257770008032993

  日期：2000.1

  An alternative method to conduct a Barton-McCombie deoxygenation in nucleosides Is described. The utility of the procedure is limited to structures with an electronegative substituent, particularly fluorine, in the beta-position relative to the radical center. The process is radical in nature and triggered by peroxides. The abstraction of hydrogen from the solvent is favorably influenced by the presence of a beta-fluorine.
• MARQUEZ, VICTOR E.;TSENG, CHRISTOPHER K. -H.;MITSUYA, HIROAKI;AOKI, SHIZU+, J. MED. CHEM., 33,(1990) N, C. 978-985
  作者：MARQUEZ, VICTOR E.、TSENG, CHRISTOPHER K. -H.、MITSUYA, HIROAKI、AOKI, SHIZU+

  DOI：——

  日期：——