[(2R,3S,5R)-5-(5-氟-2,4-二氧代嘧啶-1-基)-3-羟基四氢呋喃-2-基]磷酸二氢甲酯 | 134-46-3

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷酸
• 中文名称: [(2R,3S,5R)-5-(5-氟-2,4-二氧代嘧啶-1-基)-3-羟基四氢呋喃-2-基]磷酸二氢甲酯
• 中文别名: 2'-脱氧-5-氟-5'-尿苷酸
• 英文名称: 5-fluoro-2'-deoxyuridine-5'-O-monophosphate
• 英文别名: 5-fluoro-2′-deoxyuridine 5′-monophosphate；5-fluoro-2’-deoxyuridine-5'-O-monophosphate；5-fluoro-2′-deoxyuridine monophosphate；5-fluoro-2'-deoxyuridine 5'-monophosphate；5-fluoro-2'-deoxyuridine-5'-monophosphate；5-fluoro-2'-deoxyuridine monophosphate；[(2R,3S,5R)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-3-hydroxyoxolan-2-yl]methyl dihydrogen phosphate
• CAS: 134-46-3
• 化学式: C₉H₁₂FN₂O₈P
• 分子量: 326.175
• InChiKey: HFEKDTCAMMOLQP-RRKCRQDMSA-N

物化性质

• 密度：
  1.81±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO（少许）、水（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  -2.8
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  146
• 氢给体数：
  4
• 氢受体数：
  9

制备方法与用途

2',5'-二脱氧-5'-氟尿苷三乙铵是一种嘌呤核苷类似物，具有广泛的抗肿瘤活性，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来实现。

反应信息

• 作为反应物：
  描述：

  [(2R,3S,5R)-5-(5-氟-2,4-二氧代嘧啶-1-基)-3-羟基四氢呋喃-2-基]磷酸二氢甲酯 在 Mycobacterium tuberculosis 、 5’-三磷酸腺苷 作用下， 生成 5-Fluorodeoxyuridine diphosphate
  参考文献：
  名称：

  胸苷和胸苷5'-O-单磷酸酯类似物可作为结核分枝杆菌胸苷酸激酶的抑制剂。

  摘要：

  评估了一系列2'，3'-和5-修饰的胸苷类似物对结核分枝杆菌胸苷单磷酸激酶（TMPKmt）的亲和力。几种非磷酸化类似物的亲和力与其磷酸化同类物的亲和力处于相同的数量级。考虑到与磷酸化化合物有关的药物传递问题，这些“游离”核苷似乎在寻找TMPKmt抑制剂作为新型抗结核药方面更具前景。

  DOI：

  10.1016/s0960-894x(03)00643-7
• 作为产物：
  描述：

  5-氟-2'-脱氧脲核苷 在 吡啶 、 lithium hydroxide 、 溶剂黄146 、 N,N'-二环己基碳二亚胺 作用下， 以 甲醇 为溶剂， 反应 100.33h， 生成 [(2R,3S,5R)-5-(5-氟-2,4-二氧代嘧啶-1-基)-3-羟基四氢呋喃-2-基]磷酸二氢甲酯
  参考文献：
  名称：

  Synthesis and Biological Activity of Aromatic Amino Acid Phosphoramidates of 5-Fluoro-2‘-deoxyuridine and 1-β-Arabinofuranosylcytosine:  Evidence of Phosphoramidase Activity

  摘要：

  The amino acid phosphoramidate diesters of FUdR (2) and Ara-C (6), 5-fluoro-2'-deoxy-5'-uridyl N-(1-carbomethoxy-2-phenylethyl)phosphor (5a), 5-fluoro-2'-deoxy-5'-uridyl N-(1-carbomethoxy-2-indolylethyl)phosphoramidate (5b), 1-beta-arabinofuranosylcytosine 5'-N-(1-carbomethoxy-2-phenylethyl)phosphoramidate (8a), and 1-beta-arabinofuranosylcytosine 5'-N-(1-carbomethoxy-2-indolylethyl)phosphoramidate (8b), were synthesized and tested for their antitumor activity against L1210 mouse lymphocytic leukemia cells and CCRF-CEM human T-cell lymphoblastic leukemia cells. Ara-C phosphoramidates 8a,b were found to be inactive at a concentration of 100 mu M, while the FUdR conjugates 5a,b exhibited IC50 values within a range of 0.30-0.40 mu M. Stability studies revealed that >99% of the phosphoramidates remained intact after incubation for >2 days in 20% calf or 20% human serum. Intracellular thymidylate synthase (TS) inhibition studies revealed that treatment of L1210 and CCRF-CEM cells with 5a or 5b resulted in significant inhibition of TS in intact and permeabilized cells, while treatment of L929 TK- cells with these compounds did not result in inhibition of TS activity in intact cells. However, permeabilization of L929 TK- cells enhanced the activity of 5a,b toward intracellular TS by 900- and 1500-fold, respectively. In addition, incubation of cell-free extracts of CEM cells with radiolabeled 5b resulted in the rapid production of FUdR 5'-monophosphate and a lag in the generation of FUdR. Consequently, it is proposed that the metabolism of the phosphoramidate diesters of FUdR in proliferating tissue proceeds through two separate enzymatic steps involving P-N bond cleavage by an unknown phosphoramidase followed by P-O bond cleavage by phosphatases such as 5'-nucleotidase.

  DOI：

  10.1021/jm9603680

文献信息

• [EN] HETEROCYCLIC AMIDES USEFUL AS PROTEIN MODULATORS<br/>[FR] AMIDES HÉTÉROCYCLIQUES UTILES EN TANT QUE MODULATEURS DE PROTÉINE
  申请人：GLAXOSMITHKLINE IP DEV LTD

  公开号：WO2017175147A1

  公开（公告）日：2017-10-12

  Disclosed are compounds having the formula (I-N), wherein q, r, s, A, B, C, RA1, RA2, RB1, RB2, RC1, RC2, R3, R4, R5, R6, R14, R15, R16, and R17, are as defined herein, or a tautomer thereof, or a salt, particularly a pharmaceutically acceptable salt, thereof.

  揭示了具有化学式（I-N）的化合物，其中q、r、s、A、B、C、RA1、RA2、RB1、RB2、RC1、RC2、R3、R4、R5、R6、R14、R15、R16和R17如本文所定义，或其互变异构体，或其盐，特别是其药用可接受盐。
• [EN] MODULATORS OF STIMULATOR OF INTERFERON GENES (STING) USEFUL IN TREATING HIV<br/>[FR] MODULATEURS DE STIMULATEUR DES GÈNES (STING) D'INTERFÉRON UTILES DANS LE TRAITEMENT DU VIH
  申请人：GLAXOSMITHKLINE IP DEV LTD

  公开号：WO2019069269A1

  公开（公告）日：2019-04-11

  Disclosed are compounds having the formula: (I-N) wherein q, r, s, A, B, C, RA1, RA2, RB1, RB2, RC1, RC2, R3, R4, R5, R6, R14, R15, R16, and R17, are as defined herein, or a tautomer thereof, or a salt, particularly a pharmaceutically acceptable salt, thereof, along with combinations thereof, all of which are useful in HIV therapies.

  揭示了具有以下式的化合物：(I-N)其中q、r、s、A、B、C、RA1、RA2、RB1、RB2、RC1、RC2、R3、R4、R5、R6、R14、R15、R16和R17如本文所定义，或其互变异构体，或其盐，特别是其药用可接受盐，以及其组合物，所有这些在HIV疗法中是有用的。
• ANTI-B7-H3 ANTIBODIES AND ANTIBODY DRUG CONJUGATES
  申请人：AbbVie Inc.

  公开号：US20170355769A1

  公开（公告）日：2017-12-14

  The invention relates to B7 homology 3 protein (B7-H3) antibodies and antibody drug conjugates (ADCs), including compositions and methods of using said antibodies and ADCs.

  这项发明涉及B7同源物3蛋白（B7-H3）抗体和抗体药物结合物（ADCs），包括使用所述抗体和ADCs的组合物和方法。
• [EN] AMIDOIMIDAZOPYRIDAZINES AS MKNK-1 KINASE INHIBITORS<br/>[FR] AMIDOIMIDAZOPYRIDAZINES À TITRE D'INHIBITEURS DE KINASES MKNK-1
  申请人：BAYER PHARMA AG

  公开号：WO2014118135A1

  公开（公告）日：2014-08-07

  The present invention relates to amido-substituted imidazopyridazine compounds of general formula (I) : in which A, R1, R2, R3, R4 and n are as defined in the claims, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper- proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.

  本发明涉及一般式(I)的酰胺取代咪唑吡啶化合物，其中A、R1、R2、R3、R4和n如权利要求中所定义，以及制备所述化合物的方法，用于制备所述化合物的有用中间体化合物，包括所述化合物的药物组合物和组合物，以及利用所述化合物制造用于治疗或预防疾病的药物组合物，特别是用作唯一药剂或与其他活性成分结合。
• [EN] INDOLYL-THIENO`3,4-B!PYRAZIN-3-ONE DERIVATIVES USEFUL FOR TREATING HYPER-PROLIFERATIVE DISORDERS AND DISEASES ASSOCIATED WITH ANGIOGENESIS<br/>[FR] DERIVES D'INDOLYL-THIENO`3,4-B!PYRAZIN-3-ONE UTILISES POUR TRAITER LES MALADIES ET LES TROUBLES HYPER-PROLIFERATIFS ASSOCIES A L'ANGIOGENESE
  申请人：BAYER PHARMACEUTICALS CORP

  公开号：WO2005051957A1

  公开（公告）日：2005-06-09

  This invention relates to a compound of Formula (I): (I) and its use in treating hyper-proliferative disorders and diseases associated with angiogenesis.

  这项发明涉及到化合物的公式(I)：(I)及其在治疗与血管生成有关的高增殖性疾病和疾病中的应用。