2-amino-6-chloro-9-(2,3-dideoxy-β-D-glycero-pent-enofuranosyl)-9H-purine | 141684-95-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: 2-amino-6-chloro-9-(2,3-dideoxy-β-D-glycero-pent-enofuranosyl)-9H-purine
• 英文别名: 2-amino-6-chloro-9-(2,3-dideoxy-β-D-glycero-pent-2-enofuranosyl)purine；[(2S,5R)-5-(2-amino-6-chloropurin-9-yl)-2,5-dihydrofuran-2-yl]methanol
• CAS: 141684-95-9
• 化学式: C₁₀H₁₀ClN₅O₂
• 分子量: 267.675
• InChiKey: CTLWYNHRDFXPOU-NTSWFWBYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  99.1
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-amino-6-chloro-9-(2,3-dideoxy-β-D-glycero-pent-enofuranosyl)-9H-purine 在 氨基甲醇 作用下， 以 乙醇 为溶剂， 反应 24.0h， 以66%的产率得到2,6-diamino-9-(2',3'-dideoxy-β-D-glyceropent-2-eno-furanosyl)purine
  参考文献：
  名称：

  一系列6-修饰的2'，3'-Dideoxyguanosine和2'，3'-Didehydro-2'，3'-dideoxyguanosine类似物的合成和抗HIV活性

  摘要：

  为寻找潜在的2'，3'-双脱氧鸟苷（ddG）和2'，3'-双脱氢-2'，3'-双脱氧鸟苷（D4G）前药，合成了一系列6-修饰的ddG，D4G类似物，并对其进行了评估。在基于细胞的测定中具有抗HIV活性和细胞毒性。所有类似物均显示出低细胞毒性，其中一些表现出良性的抗HIV活性。体内的活性三磷酸形式ddGTP和D4TTP也通过新颖且简便的“一锅法”合成。用非放射性方法研究了掺入DNA / RNA链中的Taq，Therminater DNA聚合酶和HIV逆转录酶（RT）对ddGTP和D4TTP的识别，并确定了K m。

  DOI：

  10.1002/cjoc.201300440
• 作为产物：
  描述：

  2-氟-6-氯嘌呤 在 吡啶 、 ammonium sulfate 、 三氟甲磺酸三甲基硅酯 、 四丁基氟化铵 、 氨 、 双氧水 、 六甲基二硅氮烷 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 二氯甲烷 为溶剂， 反应 21.5h， 生成 2-amino-6-chloro-9-(2,3-dideoxy-β-D-glycero-pent-enofuranosyl)-9H-purine
  参考文献：
  名称：

  A highly stereoselective synthesis of anti-HIV 2',3'-dideoxy- and 2',3'-didehydro-2',3'-dideoxynucleosides

  摘要：

  A general total synthetic method for the stereocontrolled synthesis of 2',3'-dideoxy- as well as 2',3'-didehydro-2',3'-dideoxynucleosides is presented. Introduction of an alpha-phenylselenenyl group at the 2-position of 2,3-dideoxyribosyl acetate directs the glycosyl bond formation to give greater-than-or-equal-to 95% beta-isomer. This 2'-phenylselenenyl nucleoside may be converted to either the 2',3'-dideoxynucleoside by treatment with n-Bu3SnH and Et3B at room temperature or to the unsaturated derivative by treatment with H2O2/cat. pyridine. The application of this method to the syntheses of pyrimidines (ddU, ddT, ddC), 6-substituted purines (ddA, ddI, 6-chloro-ddP, N6-Me-ddA), and 2,6-disubstituted purines (2-F-ddA, 6-chloro-2-amino-ddP) as well as selected 2',3'-didehydro-2',3'-dideoxy derivatives is reported.

  DOI：

  10.1021/jo00040a031

文献信息

• Novel Use of a Guanosine Prodrug Approach To Convert 2',3'-Didehydro-2',3'-Dideoxyguanosine into a Viable Antiviral Agent
  作者：Adrian S. Ray、Zhenjun Yang、Chung K. Chu、Karen S. Anderson

  DOI：10.1128/aac.46.3.887-891.2002

  日期：2002.3

  Transient kinetic studies with human immunodeficiency virus (HIV) type 1 reverse transcriptase suggest that nucleotide analogs containing the 2',3'-didehydro-2',3'-dideoxy ribose ring structure present in D4T (stavudine) triphosphate are among the most effective alternative substrates. For unclear reasons, however, the corresponding purine nucleoside, 2',3'-didehydro-2',3'-dideoxyguanosine (D4G), was found to be inactive in cell culture. We have found that the previously reported lack of activity of D4G is primarily due to solution instability, and in this report we describe a novel use of a guanosine prodrug approach to stabilize the nucleoside. D4G was modified at the 6 position of the purine ring to contain a cyclopropylamino group yielding the prodrug, cyclo-D4G. An evaluation of cyclo-D4G revealed that the prodrug possessed anti-HIV activity. In addition, cyclo-D4G had increased stability, lipophilicity, and solubility, as well as decreased toxicity relative to D4G, suggesting that further study is warranted.

  摘要 对人类免疫缺陷病毒（HIV）1 型逆转录酶的瞬时动力学研究表明，D4T（司他夫定）三磷酸中含有 2',3'-二脱氢-2',3'-二脱氧核糖环结构的核苷酸类似物是最有效的替代底物之一。然而，由于不明原因，人们发现相应的嘌呤核苷--2',3'-双脱氢-2',3'-双脱氧鸟苷（D4G）在细胞培养中没有活性。我们发现，之前报道的 D4G 缺乏活性的主要原因是溶液的不稳定性，在本报告中，我们介绍了一种利用鸟苷原药稳定核苷的新方法。D4G 在嘌呤环的 6 位被修饰成含有环丙基氨基，从而产生了环-D4G 原药。对环-D4G 的评估显示，该原药具有抗艾滋病毒的活性。此外，与 D4G 相比，环-D4G 的稳定性、亲油性和可溶性都有所提高，毒性也有所降低，这表明有必要对其进行进一步研究。
• 6-羟基双脱氧鸟嘌呤核苷磷酸酯制备和用途
  申请人：南京济群医药科技股份有限公司

  公开号：CN104211748B

  公开（公告）日：2017-05-31

  本发明属于药物研究领域，提供了一种下式化合物或其盐：其中R1和R2为可选为烷基、芳基或者氢原子等，R3为烃基或芳基等，X为O或NH；以及其制备方法、制备中间体及其药物组合物。本发明提供的6‑羟基‑2’,3’‑双脱氧鸟嘌呤核苷磷酸酯衍生物具有良好的肝脏靶向性、体内药物稳定并且活性高、对其他器官毒性低、成药性良好等特点。
• Novel compounds and methods for inhibiting/treating HIV infections and AIDS related symptoms
  申请人：——

  公开号：US20030018015A1

  公开（公告）日：2003-01-23

  The present invention relates to novel compounds, compositions and methods for inhibiting the growth, elaboration and/or replication of HIV in human patients and to the prevention and treatment of human acquired immunodeficiency syndrome (AIDS) and other diseases caused by retroviral infection. More particularly, in preferred aspects, the present invention provides a method for the use of novel prodrug forms of 9-(2,3-Dideoxy-&bgr;-D-glycero-pent-2-enofuranosyl)guanine (d4G) for the prevention and treatment of both wild type and drug-resistant Human Immunodeficiency Virus (HIV), the causative pathogen of AIDS.

  本发明涉及新型化合物、组合物和方法，用于抑制HIV在人体内的生长、扩散和/或复制，并预防和治疗由逆转录病毒感染引起的人类获得性免疫缺陷综合症（AIDS）和其他疾病。更具体地说，在首选方面，本发明提供了一种使用新型前药形式的9-（2,3-二脱氧-β-D-葡萄糖醇-2-烯呋喃基）鸟嘌呤（d4G）的方法，用于预防和治疗野生型和耐药性人类免疫缺陷病毒（HIV）的感染，该病毒是AIDS的病原体。
• 2′,3′-Dideoxynucleoside 5′-β,γ-(Difluoromethylene) Triphosphates With α-<i>P</i>-Thio or α-<i>P</i>-Seleno Modifications: Synthesis and Their Inhibition of HIV-1 Reverse Transcriptase
  作者：Nicholas A. Boyle、Patrick Fagan、Jennifer L. Brooks、Marija Prhavc、John Lambert、P. Dan Cook

  DOI：10.1080/15257770500267055

  日期：2005.9.1

  Nucleoside reverse transcriptase inhibitors (NRTIs) are prodrugs which require three intracellular phosphorylation steps to yield their corresponding, biologically active, nucleoside triphosphate. In order to circumvent this often inefficient phosphorylation cascade, a plausible approach is to provide the active species directly in the form of a stabilized nucleoside triphosphate mimic. We have previously shown that such a mimic, namely 5'-alpha-R-p-borano-beta,gamma-(difluoromethylene) triphosphate (5'-alpha BCF2TP) is a generic triphosphate mimic that is biologically stable and can render antiviral ddNs with potent inhibitory activity against HIV-1 RT.([1,2]) Herein we report the synthesis and activity against HIV-1 RT of several ddN 5'-alpha-modified-beta,gamma-(difluoromethylene) triphosphate mimics with either a non-bridging alpha-P-thio (5'-alpha SCF2TP) or alpha-P-seleno (5'-alpha SeCF2TP) modification. One compound, namely, AZT-5'-alpha-P-seleno-beta,gamma-(difluoromethylene) triphosphate (diastereomer I), was identified as a potent inhibitor of HIV-1 RT (K-i = 64 nM) and represents the first report of HIV-1 RT inhibition data for a nucleotide bearing an alpha-P-seleno modification. These triphosphate mimics may be useful in the investigation of enzyme mechanism and may have interesting properties with respect to drug resistance and polymerase selectivity.
• Robins, Morris J.; Wilson, John S.; Madej, Danuta, Journal of Heterocyclic Chemistry, 2001, vol. 38, # 6, p. 1297 - 1306
  作者：Robins, Morris J.、Wilson, John S.、Madej, Danuta、Tyrrell, D. Lorne J.、Gati, Wendy P.、Lindmark、Wnuk, Stanislaw F.

  DOI：——

  日期：——