PR-104H | 952144-65-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: PR-104H
• 英文别名: PR-104 metabolite M22；2-[N-(2-bromoethyl)-4-(hydroxyamino)-2-(2-hydroxyethylcarbamoyl)-6-nitroanilino]ethyl methanesulfonate
• CAS: 952144-65-9
• 化学式: C₁₄H₂₁BrN₄O₈S
• 分子量: 485.313
• InChiKey: GGQLBTNLBIONTJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  28
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  182
• 氢给体数：
  4
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  PR-104A 在 锌 作用下， 生成 PR-104H
  参考文献：
  名称：

  Identification of human reductases that activate the dinitrobenzamide mustard prodrug PR-104A: A role for NADPH:cytochrome P450 oxidoreductase under hypoxia

  摘要：

  Hypoxia is a common trait found in many solid tumours and thus represents a therapeutic target with considerable potential. PR-104, a hypoxia-activated prodrug currently in clinical trial, is a water-soluble phosphate ester which is converted in vivo to the corresponding alcohol, PR-104A. This 3,5-dinitrobenzamide-2-nitrogen mustard is activated by reduction to the corresponding 5-hydroxylamine (PR-104H) and 5-amine (PR-104M) in hypoxic cells. The clinical effectiveness of PR-104 will depend in part on the expression of reductases within tumours that can effect this reduction. Here, we evaluate the roles of NADPH:cytochrome P450 oxidoreductase (CYPOR; E.C.1.6.2.4) and NAD(P)H:quinone oxidoreductase (NQ01; E.C.1.6.99.2) as candidate PR-104A reductases. A weak correlation was observed between NQ01 activity and aerobic cytotoxicity in a panel of eight tumour cell lines. However, overexpression of human NQ01 did not increase cytotoxicity of PR-104A or the formation of PR-104H/M, showing that PR-104A is not a substrate for NQ01. Overexpression of human CYPOR did, however, increase the hypoxic cytotoxicity of PR-104A, and its metabolism to PR-104H and PR-104M, demonstrating it to be a PR-104A reductase. To assess the contribution of CYPOR to overall activation of PR-104A in hypoxic SiHa cells, a combination of siRNA transfection and antisense expression were used to suppress CYPOR protein by 91% ( +/- 3%), a phenotype which conferred 45% ( +/- 7%) decrease in cytotoxic potency of PR-104A. Regression analysis of all CYPOR depletion data was found to correlate with cytoprotection and metabolism (p < 0.001). Residual PR-104A reductase activity could be inhibited by the flavoprotein inhibitor diphenyhodonium. We conclude that CYPOR is an important PR-104A reductase, but that other flavoenzymes also contribute to its activation in hypoxic SiHa cells. (C) 2007 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2007.06.014

文献信息

• Novel Prodrugs And Methods Of Use Thereof
  申请人：Smaill Jeffrey Bruce

  公开号：US20150299230A1

  公开（公告）日：2015-10-22

  The invention relates to compounds of use as targeted cytotoxic agents and methods of use thereof. In particular, the invention relates to prodrugs that are substantially resistant to human AKR1C3 enzyme metabolism, methods of cell ablation using said compounds and methods of treatment of cancer and other hyperproliferative disorders using said compounds.

  该发明涉及用作靶向细胞毒性剂的化合物及其使用方法。特别是，该发明涉及对人类AKR1C3酶代谢具有相当抵抗力的前药、使用该化合物进行细胞消融的方法，以及使用该化合物治疗癌症和其他过度增殖性疾病的方法。
• US9505791B2
  申请人：——

  公开号：US9505791B2

  公开（公告）日：2016-11-29
• Identification of human reductases that activate the dinitrobenzamide mustard prodrug PR-104A: A role for NADPH:cytochrome P450 oxidoreductase under hypoxia
  作者：Chris P. Guise、Anderson T. Wang、Anke Theil、David J. Bridewell、William R. Wilson、Adam V. Patterson

  DOI：10.1016/j.bcp.2007.06.014

  日期：2007.9

  Hypoxia is a common trait found in many solid tumours and thus represents a therapeutic target with considerable potential. PR-104, a hypoxia-activated prodrug currently in clinical trial, is a water-soluble phosphate ester which is converted in vivo to the corresponding alcohol, PR-104A. This 3,5-dinitrobenzamide-2-nitrogen mustard is activated by reduction to the corresponding 5-hydroxylamine (PR-104H) and 5-amine (PR-104M) in hypoxic cells. The clinical effectiveness of PR-104 will depend in part on the expression of reductases within tumours that can effect this reduction. Here, we evaluate the roles of NADPH:cytochrome P450 oxidoreductase (CYPOR; E.C.1.6.2.4) and NAD(P)H:quinone oxidoreductase (NQ01; E.C.1.6.99.2) as candidate PR-104A reductases. A weak correlation was observed between NQ01 activity and aerobic cytotoxicity in a panel of eight tumour cell lines. However, overexpression of human NQ01 did not increase cytotoxicity of PR-104A or the formation of PR-104H/M, showing that PR-104A is not a substrate for NQ01. Overexpression of human CYPOR did, however, increase the hypoxic cytotoxicity of PR-104A, and its metabolism to PR-104H and PR-104M, demonstrating it to be a PR-104A reductase. To assess the contribution of CYPOR to overall activation of PR-104A in hypoxic SiHa cells, a combination of siRNA transfection and antisense expression were used to suppress CYPOR protein by 91% ( +/- 3%), a phenotype which conferred 45% ( +/- 7%) decrease in cytotoxic potency of PR-104A. Regression analysis of all CYPOR depletion data was found to correlate with cytoprotection and metabolism (p < 0.001). Residual PR-104A reductase activity could be inhibited by the flavoprotein inhibitor diphenyhodonium. We conclude that CYPOR is an important PR-104A reductase, but that other flavoenzymes also contribute to its activation in hypoxic SiHa cells. (C) 2007 Elsevier Inc. All rights reserved.