9-(2-脱氧-2-氟-beta-D-阿拉伯呋喃糖基)-9H-嘌呤-2,6-二胺 | 103884-97-5

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 中文名称: 9-(2-脱氧-2-氟-beta-D-阿拉伯呋喃糖基)-9H-嘌呤-2,6-二胺
• 英文名称: 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-9H-purine-2,6-diamine
• 英文别名: 2,6-diamino-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)purine；2-amino-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine；9-(2’-deoxy-2’-fluoro-β-D-arabinofuranos-1’-yl)-2-amino-6-aminopurine；2,6-Diamino-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-9H-purine；2,6-diamino-9-(2-fluoro-β-D-arabinosyl)purine；(2R,3R,4S,5R)-5-(2,6-diaminopurin-9-yl)-4-fluoro-2-(hydroxymethyl)oxolan-3-ol
• CAS: 103884-97-5
• 化学式: C₁₀H₁₃FN₆O₃
• 分子量: 284.25
• InChiKey: MHWHYOFBOWTAHZ-AYQXTPAHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.4
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  145
• 氢给体数：
  4
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  9-(2-脱氧-2-氟-beta-D-阿拉伯呋喃糖基)-9H-嘌呤-2,6-二胺 在 adenosine deaminase type II 作用下， 反应 16.0h， 以100%的产率得到9-(2-脱氧-2-氟阿拉伯呋喃基)鸟嘌呤
  参考文献：
  名称：

  2'-氟修饰的核苷膦酸酯的合成及其抗HIV活性：GS-9148的类似物。

  摘要：

  合成了GS-9148 [5-（6-氨基-嘌呤-9-基）-4-氟-2,5-二氢呋喃-2-基氧基甲基]-膦酸（2'-Fd4AP）的修饰嘌呤类似物，他们的抗艾滋病毒效力进行了评估。鸟嘌呤类似物（2'-Fd4GP）的抗病毒活性与MT-2细胞中2'-Fd4AP的抗病毒活性相当，但选择性降低。

  DOI：

  10.1016/j.bmcl.2007.11.126
• 作为产物：
  描述：

  2,6-二氯嘌呤 在 叠氮化锂 、 三氟甲磺酸三甲基硅酯 、 氨 、 六甲基二硅氮烷 、 tin(ll) chloride 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 47.33h， 生成 9-(2-脱氧-2-氟-beta-D-阿拉伯呋喃糖基)-9H-嘌呤-2,6-二胺
  参考文献：
  名称：

  Oligonucleotides Containing 9-(2-Deoxy-2-Fluoro-β-D-Arabinofuranosyl)-Adenine and -Guanine: Synthesis, Hybridization and Antisense Properties

  摘要：

  Synthesis of 9-(2-deoxy-2-fluoro-beta -D-arabinofuranosyl)-adenine (7, ara-A(2'F)) and -guanine (12, ara-G(2'F)) was accomplished via the condensation of 2,6-dichloropurine (1) with 2-deoxy-2-fluoro-1,3,5-tri-O-benzoyl-alpha -D-arabinofuranose (2) as a key chemical step. Condensation of silylated N-6-benzoyladenine (6) with 2 gave, after deblocking and chromatographic separation, ara-A(2'F) (7) (14%), it's alpha -anomer 8 (14%) and N-7-alpha -isomer 9 (25%). The PSEUROT analysis of N-9-beta -D-arabinosides 7 and 12 manifested slight preference for the S rotamer (64%) for the former, and an equal population of the N and S rotamers for the latter. The arabinosides 7 and 12 were used for the preparation of the respective phosphoamidite building blocks 13 and 14 for automated oligonucleotide synthesis. Four 15-mer oligonucleotides (ONs) complementary to the initiation codon region of firefly luciferase mRNA were prepared: unmodified 2'-deoxy-ON (AS1) and containing (i) ara-A(2'F) instead of the only A (AS2), (ii) ara-G(2'F) vs. 3-G from the 5'-terminus (AS3), and (iii) both arabinosides at the same positions (AS4). All these ONs display practically the same (i) affinity to both complementary DNA and RNA, and (ii) ability to inhibit a luciferase gene expression in a cell-free transcription-translation system.

  DOI：

  10.1080/15257770008045466

文献信息

• Synthesis and anti-HIV activity of 2′-fluorine modified nucleoside phosphonates: Analogs of GS-9148
  作者：Richard L. Mackman、Kuei-Ying Lin、Constantine G. Boojamra、Hon Hui、Janet Douglas、Deborah Grant、Oleg Petrakovsky、Vidya Prasad、Adrian S. Ray、Tomas Cihlar

  DOI：10.1016/j.bmcl.2007.11.126

  日期：2008.2

  Modified purine analogs of GS-9148 [5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl]-phosphonic acid (2'-Fd4AP) were synthesized and their anti-HIV potency evaluated. The antiviral activity of guanosine analog (2'-Fd4GP) was comparable that of to 2'-Fd4AP in MT-2 cells, but selectivity was reduced.

  合成了GS-9148 [5-（6-氨基-嘌呤-9-基）-4-氟-2,5-二氢呋喃-2-基氧基甲基]-膦酸（2'-Fd4AP）的修饰嘌呤类似物，他们的抗艾滋病毒效力进行了评估。鸟嘌呤类似物（2'-Fd4GP）的抗病毒活性与MT-2细胞中2'-Fd4AP的抗病毒活性相当，但选择性降低。
• Isolation, Synthesis, and Characterization of Impurities and Degradants from the Clofarabine Process
  作者：Bruce G. Anderson、William E. Bauta、William R. Cantrell, Jr.、Tracy Engles、Dennis P. Lovett

  DOI：10.1021/op800182x

  日期：2008.11.21

  process impurities and their subsequent isolation, synthesis, and characterization is described. Two isomeric process impurities resulting from N6-attachment of a fluoroarabinose to clofarabine were found. Clofarabine’s base degradation products, which were different from the process impurities, were also synthesized and characterized. These compounds resulted from modifications to the sugar moiety, the

  介绍了氯法拉滨工艺杂质的鉴定及其随后的分离，合成和表征。发现了由氟代阿拉伯糖的N 6-附着至氯法拉滨产生的两种异构过程杂质。还合成并表征了与工艺杂质不同的氯法拉滨的碱降解产物。这些化合物是由糖部分，嘌呤环或两者的修饰产生的。提供了用于形成各种工艺杂质和降解产物的机械原理。
• The chemoenzymatic synthesis of clofarabine and related 2′-deoxyfluoroarabinosyl nucleosides: the electronic and stereochemical factors determining substrate recognition by <i>E. coli</i> nucleoside phosphorylases
  作者：Ilja V Fateev、Konstantin V Antonov、Irina D Konstantinova、Tatyana I Muravyova、Frank Seela、Roman S Esipov、Anatoly I Miroshnikov、Igor A Mikhailopulo

  DOI：10.3762/bjoc.10.173

  日期：——

  Two approaches to the synthesis of 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine (1, clofarabine) were studied. The first approach consists in the chemical synthesis of 2-deoxy-2-fluoro-α-D-arabinofuranose-1-phosphate (12a, ^2FAra-1P) via three step conversion of 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinofuranose (9) into the phosphate 12a without isolation of intermediary products. Condensation of 12a with 2-chloroadenine catalyzed by the recombinant E. coli purine nucleoside phosphorylase (PNP) resulted in the formation of clofarabine in 67% yield. The reaction was also studied with a number of purine bases (2-aminoadenine and hypoxanthine), their analogues (5-aza-7-deazaguanine and 8-aza-7-deazahypoxanthine) and thymine. The results were compared with those of a similar reaction with α-D-arabinofuranose-1-phosphate (13a, Ara-1P). Differences of the reactivity of various substrates were analyzed by ab initio calculations in terms of the electronic structure (natural purines vs analogues) and stereochemical features (^2FAra-1P vs Ara-1P) of the studied compounds to determine the substrate recognition by E. coli nucleoside phosphorylases. The second approach starts with the cascade one-pot enzymatic transformation of 2-deoxy-2-fluoro-D-arabinose into the phosphate 12a, followed by its condensation with 2-chloroadenine thereby affording clofarabine in ca. 48% yield in 24 h. The following recombinant E. coli enzymes catalyze the sequential conversion of 2-deoxy-2-fluoro-D-arabinose into the phosphate 12a: ribokinase (2-deoxy-2-fluoro-D-arabinofuranose-5-phosphate), phosphopentomutase (PPN; no 1,6-diphosphates of D-hexoses as co-factors required) (12a), and finally PNP. The substrate activities of D-arabinose, D-ribose and D-xylose in the similar cascade syntheses of the relevant 2-chloroadenine nucleosides were studied and compared with the activities of 2-deoxy-2-fluoro-D-arabinose. As expected, D-ribose exhibited the best substrate activity [90% yield of 2-chloroadenosine (8) in 30 min], D-arabinose reached an equilibrium at a concentration of ca. 1:1 of a starting base and the formed 2-chloro-9-(β-D-arabinofuranosyl)adenine (6) in 45 min, the formation of 2-chloro-9-(β-D-xylofuranosyl)adenine (7) proceeded very slowly attaining ca. 8% yield in 48 h.

  对2-氯-9-(2-脱氧-2-氟-β-D-阿拉伯呋喃核糖基)腺嘌呤（1，克洛法比林）的合成进行了两种方法的研究。第一种方法包括通过将1,3,5-三-O-苯甲酰基-2-脱氧-2-氟-α-D-阿拉伯呋喃糖（9）经过三步转化成磷酸2-脱氧-2-氟-α-D-阿拉伯呋喃糖（12a，2F Ara-1P）而无需中间产物的分离。使用重组大肠杆菌嘌呤核苷酸磷酸化酶（PNP）催化12a与2-氯腺嘌呤的缩合反应，形成克洛法比林，收率为67%。该反应还与多种嘌呤碱基（2-氨基腺嘌呤和次黄嘌呤）、它们的类似物（5-氮杂-7-脱氮鸟嘌呤和8-氮杂-7-脱氮次黄嘌呤）以及胸腺嘧啶进行了研究。结果与使用α-D-阿拉伯呋喃糖磷酸（13a，Ara-1P）的类似反应进行了比较。通过从头算计算分析了各种底物的反应性差异，考虑了电子结构（天然嘌呤与类似物）和立体化学特征（2F Ara-1P与Ara-1P）来确定大肠杆菌核苷酸磷酸酶对底物的识别。第二种方法从2-脱氧-2-氟-D-阿拉伯糖的级联一锅酶促转化开始，形成磷酸12a，然后与2-氯腺嘌呤缩合，从而在24小时内以约48%的产率制备克洛法比林。下列重组大肠杆菌酶催化了2-脱氧-2-氟-D-阿拉伯糖的顺序转化为磷酸12a：核糖激酶（2-脱氧-2-氟-D-阿拉伯呋喃糖-5-磷酸）、磷酸戊糖异构酶（PPN；不需要D-己糖的1,6-二磷酸作为辅因子）（12a），最后是PNP。研究了D-阿拉伯糖、D-核糖和D-木糖在相关2-氯腺嘌呤核苷的类似级联合成中的底物活性，并将其与2-脱氧-2-氟-D-阿拉伯糖的活性进行了比较。如预期，D-核糖表现出最佳的底物活性（30分钟内2-氯腺苷（8）产率达90%），D-阿拉伯糖在大约45分钟达到浓度平衡，形成2-氯-9-(β-D-阿拉伯呋喃核糖基)腺嘌呤（6），而形成2-氯-9-(β-D-木糖呋喃核糖基)腺嘌呤（7）的过程非常缓慢，在48小时内产率达到约8%。
• 抗Ｂ型肝炎ウイルス剤
  申请人：ダイキン工業株式会社

  公开号：JP2020147532A

  公开（公告）日：2020-09-17

  【課題】核酸アナログを有効成分として含有する、抗Ｂ型肝炎ウイルス剤及びＢ型肝炎ウイルス関連疾患の予防又は治療剤を提供する。【解決手段】抗Ｂ型肝炎ウイルス剤及びＢ型肝炎ウイルス関連疾患の予防又は治療剤は、次式（１）：（式中、Ｒは、ハロゲン原子、アミノ基、メトキシ基、又はシアノ基である。）で表される化合物若しくはそのプロドラッグ、又はそれらの薬学的に許容される塩、或いはそれらの溶媒和物を有効成分として含有する。【選択図】なし

  提供含有核酸类似物作为有效成分的抗乙型肝炎病毒药物，以及用于预防或治疗乙型肝炎病毒相关疾病的药物。抗乙型肝炎病毒药物和乙型肝炎病毒相关疾病的预防或治疗药物包含以下式（1）所示的化合物或其前体（其中，R代表卤原子、氨基、甲氧基或氰基），或其药学上可接受的盐，或它们的溶剂物。【选择图】无
• Anti-HCV nucleoside derivatives
  申请人：——

  公开号：US20030083307A1

  公开（公告）日：2003-05-01

  The present invention comprises nucleoside derivatives for use in the treatment or prophylaxis of hepatitis C virus infections. In particular, the present invention discloses the novel use of known 2′-deoxy-2′-fluoro nucleoside derivatives as inhibitors of hepatitis C virus (HCV) RNA replication and pharmaceutical compositions of such compounds. The compounds of this invention have potential use as therapeutic agents for the treatment of HCV infections.

  本发明涉及用于治疗或预防丙型肝炎病毒感染的核苷酸衍生物。特别地，本发明揭示了已知的2'-脱氧-2'-氟核苷酸衍生物作为丙型肝炎病毒（HCV）RNA复制抑制剂的新用途，并且揭示了这些化合物的制药组合物。本发明的化合物具有作为治疗HCV感染的治疗剂的潜在用途。