(4S)-N,3-bis(2-chloroethyl)-4-methoxy-2-oxo-1,3,2lambda5-oxazaphosphinan-2-amine | 64858-51-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氧氮杂膦
• 英文名称: (4S)-N,3-bis(2-chloroethyl)-4-methoxy-2-oxo-1,3,2lambda5-oxazaphosphinan-2-amine
• 英文别名: (4S)-N,3-bis(2-chloroethyl)-4-methoxy-2-oxo-1,3,2λ5-oxazaphosphinan-2-amine
• CAS: 64858-51-1；64858-52-2
• 化学式: C₈H₁₇Cl₂N₂O₃P
• 分子量: 291.114
• InChiKey: RWTBNEHVKWJYTK-UOCSPZAXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  16
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  50.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  甲醇 、 异环磷酰胺 在 氟硼酸钠 作用下， 生成 (4S)-N,3-bis(2-chloroethyl)-4-methoxy-2-oxo-1,3,2lambda5-oxazaphosphinan-2-amine 、 (4R)-N,3-bis(2-chloroethyl)-4-methoxy-2-oxo-1,3,2lambda5-oxazaphosphinan-2-amine
  参考文献：
  名称：

  Preactivated Oxazaphosphorines Designed for Isophosphoramide Mustard Delivery as Bulk Form or Nanoassemblies: Synthesis and Proof of Concept

  摘要：

  Oxazaphosphorines are alkylating agents used in routine clinical practices for treatment of cancer for many years. They are antitumor prodrugs that require cytochrome P450 bioactivation leading to 4-hydroxy derivatives. In the case of ifosfamide (IFO), the bioactivation produces two toxic metabolites: acrolein, a urotoxic compound, concomitantly generated with the isophosphoramide mustard; and chloroacetaldehyde, a neurotoxic and nephrotoxic compound, arising from the oxidation of the side chains. To improve the therapeutic index of IFO, we have designed preactivated IFO derivatives with the covalent binding of several O- and S-alkyl moieties including polyisoprenoid groups at the C-4 position of the oxazaphosphorine ring to avoid cytochrome bioactivation favoring the release of the active entity and limiting the chloroacetaldehyde release. Thanks to the grafted terpene moieties, some of these new conjugates demonstrated spontaneous self-assembling properties into nanoassemblies when dispersed in water. The cytotoxic activities on a panel of human tumor cell lines of these novel oxazaphosphorines, in bulk form or as nanoassemblies, and the release of 4-hydroxy-IFO from these preactivated IFO analogues in plasma are reported.

  DOI：

  10.1021/jm501224x

文献信息

• Preactivated Oxazaphosphorines Designed for Isophosphoramide Mustard Delivery as Bulk Form or Nanoassemblies: Synthesis and Proof of Concept
  作者：Charles Skarbek、Lea L. Lesueur、Hubert Chapuis、Alain Deroussent、Catherine Pioche−Durieu、Aurore Daville、Joachim Caron、Michael Rivard、Thierry Martens、Jean-Rémi Bertrand、Eric Le Cam、Gilles Vassal、Patrick Couvreur、Didier Desmaele、Angelo Paci

  DOI：10.1021/jm501224x

  日期：2015.1.22

  Oxazaphosphorines are alkylating agents used in routine clinical practices for treatment of cancer for many years. They are antitumor prodrugs that require cytochrome P450 bioactivation leading to 4-hydroxy derivatives. In the case of ifosfamide (IFO), the bioactivation produces two toxic metabolites: acrolein, a urotoxic compound, concomitantly generated with the isophosphoramide mustard; and chloroacetaldehyde, a neurotoxic and nephrotoxic compound, arising from the oxidation of the side chains. To improve the therapeutic index of IFO, we have designed preactivated IFO derivatives with the covalent binding of several O- and S-alkyl moieties including polyisoprenoid groups at the C-4 position of the oxazaphosphorine ring to avoid cytochrome bioactivation favoring the release of the active entity and limiting the chloroacetaldehyde release. Thanks to the grafted terpene moieties, some of these new conjugates demonstrated spontaneous self-assembling properties into nanoassemblies when dispersed in water. The cytotoxic activities on a panel of human tumor cell lines of these novel oxazaphosphorines, in bulk form or as nanoassemblies, and the release of 4-hydroxy-IFO from these preactivated IFO analogues in plasma are reported.