9-(2-脱氧-2-氟-beta-D-阿拉伯呋喃糖基)-1,9-二氢-6H-嘌呤-6-酮 | 98983-40-5

• 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)-1,9-二氢-6H-嘌呤-6-酮
• 英文名称: 9-(2-Deoxy-2-fluoro-β-D-arabinofuranosyl)hypoxanthine
• 英文别名: 9-(2-Deoxy-2-fluoro-beta-D-arabinofuranosyl)-1,9-dihydro-6H-purin-6-one；9-[(2R,3S,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1H-purin-6-one
• CAS: 98983-40-5
• 化学式: C₁₀H₁₁FN₄O₄
• 分子量: 270.22
• InChiKey: NRVOTDBYJXFINS-GQTRHBFLSA-N

物化性质

• 密度：
  2.01

计算性质

• 辛醇/水分配系数(LogP)：
  -0.3
• 重原子数：
  19
• 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：
  109
• 氢给体数：
  3
• 氢受体数：
  7

制备方法与用途

2'-脱氧-2'-氟阿拉伯肌苷是一种嘌呤核苷类似物，这类化合物具有广泛抗肿瘤活性，特别是针对惰性淋巴系统恶性肿瘤。其抗癌机制主要通过抑制DNA合成和诱导细胞凋亡实现。

反应信息

• 作为产物：
  描述：

  N6-苯甲酰基腺嘌呤 在 molecular sieve 、 sodium methylate 、 sodium nitrite 作用下， 以 二氯甲烷 、 溶剂黄146 为溶剂， 反应 125.0h， 生成 9-(2-脱氧-2-氟-beta-D-阿拉伯呋喃糖基)-1,9-二氢-6H-嘌呤-6-酮
  参考文献：
  名称：

  核苷。CXXXV。一些9-（2-脱氧-2-氟-β-D-阿拉伯呋喃糖基）-9H-嘌呤的合成及其生物学活性。

  摘要：

  合成了含有2'-脱氧-2'-氟-β-D-阿拉伯呋喃糖基部分的七个嘌呤核苷，并测试了它们的抗肿瘤活性。3-O-乙酰基-5-O-苯甲酰基-2-脱氧-2-氟-D-阿拉伯呋喃糖基溴化物（1）与N6-苯甲酰腺嘌呤在CH2Cl2中的直接缩合，然后将产物皂化，得到腺嘌呤核苷（I，2 -F-ara-A）。用HOAc中的NaNO 2脱除I，得到次黄嘌呤类似物（II，2'-F-ara-H）。通过汞法将1与6-氯嘌呤缩合，然后进行硫脲处理和产物皂化，制备6-硫嘌呤核苷（III，2'-F-ara-6MP）。III的甲基化得到6-SCH3类似物（IV）。III的阮内镍脱硫得到未取代的嘌呤核苷（V，2'-F-ara-P）。通过甲硅烷基方法将1-与2-乙酰氨基-6-氯嘌呤缩合，得到被保护的2-乙酰氨基-6-氯嘌呤核苷，其可用作鸟嘌呤和6-硫代鸟嘌呤核苷的前体（VI，2'-F-ara- G和VII，分别为2'-F-ara

  DOI：

  10.1248/cpb.37.336

文献信息

• 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%。
• A synthesis of 9-(2-deoxy-2-fluoro-.beta.-D-arabinofuranosyl)adenine and -hypoxanthine. An effect of C3'-endo to C2'-endo conformational shift on the reaction course of 2'-hydroxyl group with DAST
  作者：Krzysztof W. Pankiewicz、Jacek Krzeminski、Lech A. Ciszewski、Wu Yon Ren、Kyoichi A. Watanabe

  DOI：10.1021/jo00028a030

  日期：1992.1

  O3',O5',N6-Tritrityladenosine (6), 3',5'-di-O-trityl-N1-benzylinosine (15), and 3',5'-di-O-tritylinosine (18) were prepared and subjected to nucleophilic reaction with DAST. Thus, 6 afforded 2'-beta-fluorine-substituted nucleoside 11 along with the isomeric 2-deoxy-2-(N-trityladenin-3-yl)-3,5-di-O-trityl-alpha-D-arabinofuranosyl fluoride (12). Nucleoside 15, under the same treatment with DAST, gave the desired 2'-fluoroarabino derivative 16 exclusively in high yield. Although 18 was converted into the 2'-beta-fluoro product 19 under the similar conditions, the yield was low. A plausible mechanism of formation of 12 is discussed. Deprotection of 11 and 16 afforded the desired 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine (1) and -hypoxanthine (2), respectively, in high yield. The conformational influence of sugar protecting groups on the rate of nucleophilic substitution against elimination is discussed. Treatment of O3',O5',N1-benzylinosine (20) with DAST afforded only the elimination products 9-(3',5'-di-O-benzyl-beta-D-erythro-pent-2-enofuranosyl)-1-benzylhypoxanthine (22) and 3-(benzyloxy)-2-[(benzyloxy)methyl]furan (23). On the other hand, 9-(3,5-di-O-trityl-beta-D-arabinofuranosyl)adenine (26) (prepared from 6 by triflyation followed by NaOAc treatment and deacetylation) afforded a mixture from which 2'-deoxy-2'-fluoroadenosine (27) and 9-(2-deoxy-3,5-di-O-trityl-D-erythro-pent-1-enofuranosyl)-N6-trityladenine (28) were isolated in 60 and 30% yield, respectively. O2',O5',N6-Tritrityladenosine (7) was selectively detritylated with HCO2H/Et2O to give O2',N6-ditrityladenosine (30), which, upon treatment with benzyl chloride/KOH, afforded 3',5'-di-O-benzyl-O2',N6-ditrityladenosine (31). 9-(3,5-Di-O-benzyl-beta-D-arabinofuranosyl)adenine (35) was prepared from 31 by further detritylation with CF3CO2H/CHCl3 and triflyation followed by NaOAc treatment and deacetylation of the product. Treatment of 35 with DAST followed by hydrogenolytic debenzylation afforded 2'-deoxy-2'-fluoroadenosine (3) in high yield. The three-step synthesis described herein, albeit about 10% overall yield, is far superior to the currently available multistep procedures which give the desired 2'-fluoroarabinosylpurines in much less overall yields.
• US5840743A
  申请人：——

  公开号：US5840743A

  公开（公告）日：1998-11-24