Phosphoric acid mono-[(2R,3S,5R)-3-hydroxy-5-(5-[1,4]oxathian-2-yl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-tetrahydro-furan-2-ylmethyl] ester | 88145-42-0

• 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
• 英文名称: Phosphoric acid mono-[(2R,3S,5R)-3-hydroxy-5-(5-[1,4]oxathian-2-yl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-tetrahydro-furan-2-ylmethyl] ester
• 英文别名: 2'-Deoxy-5-(1,4-oxathian-2-yl)uridine 5'-(dihydrogen phosphate)；[(2R,3S,5R)-3-hydroxy-5-[5-(1,4-oxathian-2-yl)-2,4-dioxopyrimidin-1-yl]oxolan-2-yl]methyl dihydrogen phosphate
• CAS: 88145-42-0
• 化学式: C₁₃H₁₉N₂O₉PS
• 分子量: 410.342
• InChiKey: ABEFHZPSTVFJDV-FPTZPQHFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3.1
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  180
• 氢给体数：
  4
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  2-巯基乙醇 、 (E)-5-(2-bromovinyl)-2'-deoxyuridine 5'-monophosphate 在 human thymidylate synthase 作用下， 以 水 为溶剂， 生成 Phosphoric acid mono-[(2R,3S,5R)-3-hydroxy-5-(2-oxo-6-propylsulfanyl-2H-furo[2,3-d]pyrimidin-3-yl)-tetrahydro-furan-2-ylmethyl] ester 、 Phosphoric acid mono-[(2R,3S,5R)-3-hydroxy-5-(5-[1,4]oxathian-2-yl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-tetrahydro-furan-2-ylmethyl] ester
  参考文献：
  名称：

  Enzyme-catalyzed therapeutic agent (ECTA) design: activation of the antitumor ECTA compound NB1011 by thymidylate synthase11Abbreviations: BVdU, (E)-5-(2-bromovinyl)-2′-deoxyuridine; BVdUMP, (E)-5-(2-bromovinyl)-2′-deoxyuridine 5′-monophosphate; NB1011, (E)-5-(2-bromovinyl)-2′-deoxy-5′-uridyl phenyl l-methoxyalaninylphosphoramidate; COSY, correlated spectroscopy; DCI, direct current ionization; DMF, N,N-dimethylformamide; dUMP, 2′-deoxyuridine 5′-monophosphate; ECTA, enzyme-catalyzed therapeutic agent; 5-FU, 5-fluorouracil; 5-FdUMP, 5-fluoro-2′-deoxyuridine 5′-monophosphate; RFU, relative fluorescence units; THF, N5,N10-methylene tetrahydrofolate; TBDMS, tert-butyldimethylsilyl; and TS, thymidylate synthase (EC 2.1.1.45).

  摘要：

  The in vivo administration of enzyme-inhibiting drugs for cancer and infectious disease often results in overexpression of the targeted enzyme. We have developed an enzyme-catalyzed therapeutic agent (ECTA) approach in which an enzyme overexpressed within the resistant cells is recruited as an intracellular catalyst for converting a relatively non-toxic substrate to a toxic product. We have investigated the potential of the ECTA approach to circumvent the thymidylate synthase (TS) overexpression-based resistance of tumor cells to conventional fluoropyrimidine [i.e., 5-fluorouracil (5-FU)] cancer chemotherapy. (E)-5-(2-Bromovinyl)-2'-deoxy-5'-uridyl phenyl L-methoxyalaninylphosphoramidate (NB1011) is a pronucleotide analogue of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVdU), an antiviral agent known to be a substrate for TS when in the 5'-monophosphorylated form. NB1011 was synthesized and found to be at least 10-fold more cytotoxic to 5-FU-resistant, TS-overexpressing colorectal tumor cells than to normal cells. This finding demonstrates that the ECTA approach to the design of novel chemotherapeutics results in compounds that are selectively cytotoxic to tumor cell lines that overexpress the target enzyme, TS, and therefore may be useful in the treatment of fluoropyrimidine-resistant cancer. (C) 2001 Elsevier Science Inc. All rights reserved.

  DOI：

  10.1016/s0006-2952(00)00542-6

文献信息

• Enzyme-catalyzed therapeutic agent (ECTA) design: activation of the antitumor ECTA compound NB1011 by thymidylate synthase11Abbreviations: BVdU, (E)-5-(2-bromovinyl)-2′-deoxyuridine; BVdUMP, (E)-5-(2-bromovinyl)-2′-deoxyuridine 5′-monophosphate; NB1011, (E)-5-(2-bromovinyl)-2′-deoxy-5′-uridyl phenyl l-methoxyalaninylphosphoramidate; COSY, correlated spectroscopy; DCI, direct current ionization; DMF, N,N-dimethylformamide; dUMP, 2′-deoxyuridine 5′-monophosphate; ECTA, enzyme-catalyzed therapeutic agent; 5-FU, 5-fluorouracil; 5-FdUMP, 5-fluoro-2′-deoxyuridine 5′-monophosphate; RFU, relative fluorescence units; THF, N5,N10-methylene tetrahydrofolate; TBDMS, tert-butyldimethylsilyl; and TS, thymidylate synthase (EC 2.1.1.45).
  作者：David B. Lackey、Michael P. Groziak、Maria Sergeeva、Malgorzata Beryt、Christopher Boyer、Robert M. Stroud、Peter Sayre、John W. Park、Patrick Johnston、Dennis Slamon、H.Michael Shepard、Mark Pegram

  DOI：10.1016/s0006-2952(00)00542-6

  日期：2001.1

  The in vivo administration of enzyme-inhibiting drugs for cancer and infectious disease often results in overexpression of the targeted enzyme. We have developed an enzyme-catalyzed therapeutic agent (ECTA) approach in which an enzyme overexpressed within the resistant cells is recruited as an intracellular catalyst for converting a relatively non-toxic substrate to a toxic product. We have investigated the potential of the ECTA approach to circumvent the thymidylate synthase (TS) overexpression-based resistance of tumor cells to conventional fluoropyrimidine [i.e., 5-fluorouracil (5-FU)] cancer chemotherapy. (E)-5-(2-Bromovinyl)-2'-deoxy-5'-uridyl phenyl L-methoxyalaninylphosphoramidate (NB1011) is a pronucleotide analogue of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVdU), an antiviral agent known to be a substrate for TS when in the 5'-monophosphorylated form. NB1011 was synthesized and found to be at least 10-fold more cytotoxic to 5-FU-resistant, TS-overexpressing colorectal tumor cells than to normal cells. This finding demonstrates that the ECTA approach to the design of novel chemotherapeutics results in compounds that are selectively cytotoxic to tumor cell lines that overexpress the target enzyme, TS, and therefore may be useful in the treatment of fluoropyrimidine-resistant cancer. (C) 2001 Elsevier Science Inc. All rights reserved.