(2,5-Dioxopyrrolidin-1-yl) 2-(4-phosphonooxyphenyl)acetate | 1027945-78-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机磷酸及其衍生物
• 英文名称: (2,5-Dioxopyrrolidin-1-yl) 2-(4-phosphonooxyphenyl)acetate
• CAS: 1027945-78-3
• 化学式: C₁₂H₁₂NO₈P
• 分子量: 329.203
• InChiKey: DDOKQIQNKYLNED-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.8
• 重原子数：
  22
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  130
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  盐酸多柔比星 、 三乙胺 、 (2,5-Dioxopyrrolidin-1-yl) 2-(4-phosphonooxyphenyl)acetate 以 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 N-(4-(phosphonooxy)phenylacetyl)doxorubicin
  参考文献：
  名称：

  Prodrugs of doxorubicin and melphalan and their activation by a monoclonal antibody-penicillin-G amidase conjugate

  摘要：

  The syntheses and cytotoxic activities of substituted N-phenylacetamido derivatives of doxorubicin and melphalan are described. The derivatives were designed as prodrugs which could be activated in a site-specific manner by monoclonal antibody-penicillin-G amidase (mAb-PGA) conjugates. N-(Phenylacetamido)doxorubicin (2) and N-(phenylacetyl)melphalan (6) were found to be 10- and 20-fold less cytotoxic against H2981 lung adenocarcinoma cells than doxorubicin and melphalan, respectively. When incubated with PGA, the cytotoxicity of 2 and 6 increased and became equivalent to that of the corresponding drugs from which they were made. The poor solubility characteristics of 2 in aqueous solutions provided the basis for the development of the more soluble doxorubicin derivatives, N-(4-aminophenylacetyl)doxorubicin (3) and N-(4-phosphonooxy)phenylacetyl)-doxorubicin (4). In vitro cytotoxicity assays indicated that 3 and 4 were at least 1000-fold less toxic than doxorubicin against H2981 cells. PGA and the mAb conjugate L6-PGA were able to effect the activation of 3 and 6 on H2981 cells (L6-antigen positive). Hydrolysis of the phosphate group of 4 was required prior to activation with PGA or L6-PGA. This was achieved using alkaline phosphatase, or by exposing 4 to phosphatases present in cell culture medium. The activation of 3, 4, and 6 on H2981 cells by L6-PGA occurred in an immunologically specific manner, since activation could be blocked by saturating cell surface antigens with L6 prior to treatment with L6-PGA. These results demonstrate that 3, 4, and 6 are prodrugs that can be specifically activated to release clinically approved anticancer agents by a mAb-PGA conjugate.

  DOI：

  10.1021/jm00059a018
• 作为产物：
  描述：

  [4-(Diphenoxy-phosphoryloxy)-phenyl]-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester 在 platinum(IV) oxide 氢气 作用下， 以 四氢呋喃 、 异丙醇 为溶剂， 反应 6.0h， 生成 (2,5-Dioxopyrrolidin-1-yl) 2-(4-phosphonooxyphenyl)acetate
  参考文献：
  名称：

  Prodrugs of doxorubicin and melphalan and their activation by a monoclonal antibody-penicillin-G amidase conjugate

  摘要：

  The syntheses and cytotoxic activities of substituted N-phenylacetamido derivatives of doxorubicin and melphalan are described. The derivatives were designed as prodrugs which could be activated in a site-specific manner by monoclonal antibody-penicillin-G amidase (mAb-PGA) conjugates. N-(Phenylacetamido)doxorubicin (2) and N-(phenylacetyl)melphalan (6) were found to be 10- and 20-fold less cytotoxic against H2981 lung adenocarcinoma cells than doxorubicin and melphalan, respectively. When incubated with PGA, the cytotoxicity of 2 and 6 increased and became equivalent to that of the corresponding drugs from which they were made. The poor solubility characteristics of 2 in aqueous solutions provided the basis for the development of the more soluble doxorubicin derivatives, N-(4-aminophenylacetyl)doxorubicin (3) and N-(4-phosphonooxy)phenylacetyl)-doxorubicin (4). In vitro cytotoxicity assays indicated that 3 and 4 were at least 1000-fold less toxic than doxorubicin against H2981 cells. PGA and the mAb conjugate L6-PGA were able to effect the activation of 3 and 6 on H2981 cells (L6-antigen positive). Hydrolysis of the phosphate group of 4 was required prior to activation with PGA or L6-PGA. This was achieved using alkaline phosphatase, or by exposing 4 to phosphatases present in cell culture medium. The activation of 3, 4, and 6 on H2981 cells by L6-PGA occurred in an immunologically specific manner, since activation could be blocked by saturating cell surface antigens with L6 prior to treatment with L6-PGA. These results demonstrate that 3, 4, and 6 are prodrugs that can be specifically activated to release clinically approved anticancer agents by a mAb-PGA conjugate.

  DOI：

  10.1021/jm00059a018

文献信息

• Prodrugs of doxorubicin and melphalan and their activation by a monoclonal antibody-penicillin-G amidase conjugate
  作者：Vivekananda M. Vrudhula、Peter D. Senter、Keith J. Fischer、Philip M. Wallace

  DOI：10.1021/jm00059a018

  日期：1993.4

  The syntheses and cytotoxic activities of substituted N-phenylacetamido derivatives of doxorubicin and melphalan are described. The derivatives were designed as prodrugs which could be activated in a site-specific manner by monoclonal antibody-penicillin-G amidase (mAb-PGA) conjugates. N-(Phenylacetamido)doxorubicin (2) and N-(phenylacetyl)melphalan (6) were found to be 10- and 20-fold less cytotoxic against H2981 lung adenocarcinoma cells than doxorubicin and melphalan, respectively. When incubated with PGA, the cytotoxicity of 2 and 6 increased and became equivalent to that of the corresponding drugs from which they were made. The poor solubility characteristics of 2 in aqueous solutions provided the basis for the development of the more soluble doxorubicin derivatives, N-(4-aminophenylacetyl)doxorubicin (3) and N-(4-phosphonooxy)phenylacetyl)-doxorubicin (4). In vitro cytotoxicity assays indicated that 3 and 4 were at least 1000-fold less toxic than doxorubicin against H2981 cells. PGA and the mAb conjugate L6-PGA were able to effect the activation of 3 and 6 on H2981 cells (L6-antigen positive). Hydrolysis of the phosphate group of 4 was required prior to activation with PGA or L6-PGA. This was achieved using alkaline phosphatase, or by exposing 4 to phosphatases present in cell culture medium. The activation of 3, 4, and 6 on H2981 cells by L6-PGA occurred in an immunologically specific manner, since activation could be blocked by saturating cell surface antigens with L6 prior to treatment with L6-PGA. These results demonstrate that 3, 4, and 6 are prodrugs that can be specifically activated to release clinically approved anticancer agents by a mAb-PGA conjugate.