N2-异丁酰-2'-氟脱氧鸟苷 | 80681-25-0

• 物质功能分类: 医药中间体 - 原料药中间体
• 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: N2-异丁酰-2'-氟脱氧鸟苷
• 中文别名: N2-异丁酰-2'-氟-2'-脱氧鸟苷
• 英文名称: N-isobutyryl-2'-deoxy-2'-fluoroguanosine
• 英文别名: 2’-fluoro-N2-isobutyryl-2’-deoxyguanosine；2'-deoxy-2'-fluoro-N2-isobutyrylguanosine；N-[9-[(2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-6-oxo-1H-purin-2-yl]-2-methyl-propanamide；N2-Isobutyryl-2'-fluoro-2'-deoxyguanosine；N-[9-[(2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-oxo-1H-purin-2-yl]-2-methylpropanamide
• CAS: 80681-25-0
• 化学式: C₁₄H₁₈FN₅O₅
• 分子量: 355.326
• InChiKey: SLHADUUWJSVYGQ-HTFXMJNNSA-N

物化性质

• 密度：
  1.78±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  138
• 氢给体数：
  4
• 氢受体数：
  8

安全信息

• 危险性防范说明：
  P261,P280,P301+P312,P302+P352,P305+P351+P338
• 危险性描述：
  H302,H315,H320,H335

反应信息

• 作为反应物：
  描述：

  N2-异丁酰-2'-氟脱氧鸟苷 在 氨 作用下， 反应 16.0h， 以80%的产率得到2'-脱氧-2'-氟鸟苷
  参考文献：
  名称：

  Uniformly modified 2'-deoxy-2'-fluoro-phosphorothioate oligonucleotides as nuclease-resistant antisense compounds with high affinity and specificity for RNA targets

  摘要：

  均一化修饰的磷酸二酯或硫代磷酸酯寡核苷酸，包含2'-脱氧-2'-氟腺苷、-鸟苷、-尿苷和-胞苷，首次在此报道，当它们与RNA杂交时，表现出一致的叠加性稳定性提升，同时不会影响碱基配对的特异性。2'-脱氧-2'-氟修饰的寡核苷酸与RNA杂交的圆二色光谱表明，杂交双链呈现完全的A型构象。以磷酸二酯形式存在的2'-脱氧-2'-氟修饰的寡核苷酸对核酸酶不具抵抗力；然而，以硫代磷酸酯形式存在的修饰寡核苷酸则具有极高的核酸酶抗性，并且保留了对RNA靶标的卓越结合亲和力。2'-脱氧-2'-氟修饰对RNA-DNA双链的稳定化效果被证明优于2'-O-甲基核糖的替代。与均一化2'-脱氧-2'-氟修饰寡核苷酸形成的RNA杂交双链不支持HeLa细胞中RNase H活性；然而，将修饰引入到“嵌合”寡核苷酸中已被证明可以激活哺乳动物的RNase H。均一化修饰的2'-脱氧-2'-氟硫代磷酸酯寡核苷酸提供了反义分子，具有（1）对RNA靶标的高结合亲和力和选择性，以及（2）对核酸酶的稳定性。

  DOI：

  10.1021/jm00059a007
• 作为产物：
  描述：

  9-Β-D-糖呋喃鸟嘌呤 在 吡啶 、 4-二甲氨基吡啶 、 ammonium hydroxide 、 sodium hydroxide 、 三甲基氯硅烷 、 Dowex-50 、 四丁基氟化铵 、 对甲苯磺酸 、 氟化氢吡啶 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 吡啶 、 甲醇 、 二氯甲烷 为溶剂， 生成 N2-异丁酰-2'-氟脱氧鸟苷
  参考文献：
  名称：

  An Efficient and Scalable Synthesis of Arabinosylguanine and 2′-Deoxy-2′-Fluoro-guanosine

  摘要：

  An efficient conversion from commercially available 2,6-diaminopurine-2',3',5'-tri-O-benzyl arabinoside to arabinosylguanine and its further transformation to 2'-deoxy-2'-fluoro-guanosine is outlined. This process has been used to produce more than one hundred grams of final product.

  DOI：

  10.1080/07328319708006246

文献信息

• 3'3' CYCLIC DINUCLEOTIDES WITH AN ALKENYLENE
  申请人：Institute of Organic Chemistry and Biochemistry ASCR, V.V.I.

  公开号：EP3936514A1

  公开（公告）日：2022-01-12

  The present disclosure relates to 3'3' cyclic phosphonate dinucleotides of general formula (J), their pharmaceutically acceptable salts, their pharmaceutical composition and combinations of said substances and other medicaments or pharmaceuticals. The disclosure also relates to the use of said compounds for the treatment or prevention of diseases or conditions modifiable by STING protein modulation, such as cancer or viral, allergic and inflammatory diseases. In addition, these substances can be used as adjuvants in vaccines.

  本公开涉及一般式（J）的3'3'环磷酸二核苷酸，其药用盐，其药物组合物以及所述物质与其他药物或药品的组合物。该公开还涉及利用所述化合物治疗或预防可通过STING蛋白调节改变的疾病或症状，如癌症或病毒性、过敏性和炎症性疾病。此外，这些物质可用作疫苗的辅助剂。
• Uniformly modified 2'-deoxy-2'-fluoro-phosphorothioate oligonucleotides as nuclease-resistant antisense compounds with high affinity and specificity for RNA targets
  作者：Andrew M. Kawasaki、Martin D. Casper、Susan M. Freier、Elena A. Lesnik、Maryann C. Zounes、Lendell L. Cummins、Carolyn Gonzalez、P. Dan Cook

  DOI：10.1021/jm00059a007

  日期：1993.4

  ''Uniformly'' modified phosphodiester or phosphorothioate oligonucleotides incorporating 2'-deoxy-2'-fluoroadenosine, -guanosine, -uridine, and -cytidine, reported herein for the first time, when hybridized with RNA afforded consistent additive enhancement of duplex stability without compromising base-pair specificity. CD spectra of the 2'-deoxy-2'-fluoro-modified oligonucleotides hybridized with RNA indicated that the duplex adopts a fully A-form conformation. The 2'-deoxy-2'-fluoro-modified oligonucleotides in phosphodiester form were not resistant to nucleases; however, the modified phosphorothioate oligonucleotides were highly nuclease resistant and retained exceptional binding affinity to the RNA targets. The stabilizing effects of the 2'-deoxy-2'-fluoro modifications on RNA-DNA duplexes were shown to be superior to those of the 2'-O-methylribo substitutions. RNA hybrid duplexes with uniformly 2'-deoxy-2'-fluoro-modified oligonucleotides did not support HeLa RNase H activity; however, incorporation of the modifications into ''chimeric'' oligonucleotides has been shown to activate mammalian RNase H. ''Uniformly'' modified 2'-deoxy-2'-fluoro phosphorothioate oligonucleotides afforded antisense molecules with (1) high binding affinity and selectivity for the RNA target and (2) stability toward nucleases.

  均一化修饰的磷酸二酯或硫代磷酸酯寡核苷酸，包含2'-脱氧-2'-氟腺苷、-鸟苷、-尿苷和-胞苷，首次在此报道，当它们与RNA杂交时，表现出一致的叠加性稳定性提升，同时不会影响碱基配对的特异性。2'-脱氧-2'-氟修饰的寡核苷酸与RNA杂交的圆二色光谱表明，杂交双链呈现完全的A型构象。以磷酸二酯形式存在的2'-脱氧-2'-氟修饰的寡核苷酸对核酸酶不具抵抗力；然而，以硫代磷酸酯形式存在的修饰寡核苷酸则具有极高的核酸酶抗性，并且保留了对RNA靶标的卓越结合亲和力。2'-脱氧-2'-氟修饰对RNA-DNA双链的稳定化效果被证明优于2'-O-甲基核糖的替代。与均一化2'-脱氧-2'-氟修饰寡核苷酸形成的RNA杂交双链不支持HeLa细胞中RNase H活性；然而，将修饰引入到“嵌合”寡核苷酸中已被证明可以激活哺乳动物的RNase H。均一化修饰的2'-脱氧-2'-氟硫代磷酸酯寡核苷酸提供了反义分子，具有（1）对RNA靶标的高结合亲和力和选择性，以及（2）对核酸酶的稳定性。
• 2′-Fluoro-c-di-GMP as an oral vaccine adjuvant
  作者：Jia Li、Rhonda Kuo Lee、Wangxue Chen、Hongbin Yan

  DOI：10.1039/c9ra08310c

  日期：——

  2′-F-c-di-GMP was synthesized through the modified H-phosphonate chemistry. 2′-F-c-di-GMP was found to be an effective mucosal vaccine adjuvant, both intranasally and orally.

  2'-F-c-di-GMP是通过改良的H-膦酸酯化学合成的。 2'-F-c-di-GMP被发现是一种有效的粘膜疫苗佐剂，可以通过鼻腔和口服途径使用。
• Vinylphosphonate-based cyclic dinucleotides enhance STING-mediated cancer immunotherapy
  作者：Milan Dejmek、Andrea Brazdova、Tomáš Otava、Marketa Pimkova Polidarova、Martin Klíma、Miroslav Smola、Zdenek Vavrina、Miloš Buděšínský、Martin Dračínský、Radek Liboska、Evzen Boura、Gabriel Birkuš、Radim Nencka

  DOI：10.1016/j.ejmech.2023.115685

  日期：2023.11

  designed a novel class of CDNs containing vinylphosphonate based on a STING-affinity screening assay. In vitro, acyloxymethyl phosphate/phosphonate prodrugs of these vinylphosphonate CDNs were up to 1000-fold more potent than the clinical candidate ADU-S100. In vivo, the lead prodrug induced tumor-specific T cell priming and facilitated tumor regression in the 4T1 syngeneic mouse model of breast cancer

  环状二核苷酸 (CDN) 触发干扰素基因环 GMP-AMP 合酶刺激剂 (cGAS-STING) 途径，该途径在胞质 DNA 传感中发挥着关键作用，从而在针对感染、细胞损伤和癌症的免疫调节中发挥着关键作用。然而，CDN 的癌症免疫治疗试验显示免疫激活，但肿瘤并未完全消退。尽管如此，我们还是基于 STING 亲和力筛选试验设计了一类含有乙烯基膦酸酯的新型 CDN。在体外，这些乙烯基膦酸酯 CDN 的酰氧基甲基磷酸酯/膦酸酯前药的效力比临床候选 ADU-S100 强 1000 倍。在体内，先导前药诱导肿瘤特异性 T 细胞启动，并促进 4T1 同基因小鼠乳腺癌模型中的肿瘤消退。此外，我们还解析了与 STING 蛋白结合的配体的晶体结构。因此，我们的研究结果不仅验证了乙烯基膦酸酯 CDN 的治疗潜力，而且还为桥接先天免疫和适应性免疫的癌症免疫治疗药物开发开辟了机会。
• WO2020016782A5
  申请人：——

  公开号：WO2020016782A5

  公开（公告）日：2022-07-14