9-Hydroxy-2,3,8-trimethoxy-6-(3-morpholin-4-ylpropyl)indeno[1,2-c]isoquinoline-5,11-dione | 1415806-49-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: 9-Hydroxy-2,3,8-trimethoxy-6-(3-morpholin-4-ylpropyl)indeno[1,2-c]isoquinoline-5,11-dione
• 英文别名: 9-hydroxy-2,3,8-trimethoxy-6-(3-morpholin-4-ylpropyl)indeno[1,2-c]isoquinoline-5,11-dione
• CAS: 1415806-49-3
• 化学式: C₂₆H₂₈N₂O₇
• 分子量: 480.518
• InChiKey: DIZYBTAYMOFSCR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  35
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  97.8
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  1H-benzo[d][1,2,3]triazol-1-yl 2-(pyridin-2-yldisulfanyl)ethyl carbonate 、 9-Hydroxy-2,3,8-trimethoxy-6-(3-morpholin-4-ylpropyl)indeno[1,2-c]isoquinoline-5,11-dione 在 4-二甲氨基吡啶 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 16.0h， 以90%的产率得到2-(pyridin-2-yl disulfanyl)ethyl (2,3,8-trimethoxy-6-(3-morpholinopropyl)-5,11-dioxo-6,11-dihydro-5H-indeno[1,2-c]-isoquinolin-9-yl) carbonate
  参考文献：
  名称：

  用于选择性前列腺癌细胞靶向的细胞毒性茚并异喹啉拓扑异构酶 I 抑制剂的 DUPA 偶联

  摘要：

  前列腺特异性膜抗原 (PSMA) 在大多数前列腺癌细胞中过度表达，而在正常细胞中以低水平或检测不到的水平存在。这种差异提供了一个机会，可以选择性地向前列腺癌细胞递送细胞毒性药物，同时保留缺乏 PSMA 的正常细胞，从而提高效力并降低毒性。PSMA 对 2-[3-(1,3-二羧丙基)脲基]戊二酸 (DUPA) ( K i= 8 纳米）。与 DUPA 药物偶联物结合后，PSMA 内化、卸载偶联物并返回表面。在目前的研究中，茚并异喹啉拓扑异构酶 I 抑制剂通过肽接头和药物释放段与 DUPA 结合，促进细胞内裂解以释放药物。DUPA-茚并异喹啉偶联物在 22RV1 细胞培养物中显示出低纳摩尔范围的 IC 50并诱导肿瘤生长完全停止而没有毒性，这由体重减轻和治疗小鼠的死亡确定。

  DOI：

  10.1021/jm5018384
• 作为产物：
  描述：

  3-甲氧基-4-[(4-甲氧基苯基)甲氧基]苯甲醛 在 氯化亚砜 、 sodium sulfate 、 三乙胺 、 sodium iodide 作用下， 以 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 51.0h， 生成 9-Hydroxy-2,3,8-trimethoxy-6-(3-morpholin-4-ylpropyl)indeno[1,2-c]isoquinoline-5,11-dione
  参考文献：
  名称：

  Identification, Synthesis, and Biological Evaluation of Metabolites of the Experimental Cancer Treatment Drugs Indotecan (LMP400) and Indimitecan (LMP776) and Investigation of Isomerically Hydroxylated Indenoisoquinoline Analogues as Topoisomerase I Poisons

  摘要：

  Hydroxylated analogues of the anticancer topoisomerase I (Top1) inhibitors indotecan (LMP400) and indimitecan (LMP776) have been prepared because (1) a variety of potent Top1 poisons are known that contain strategically placed hydroxyl groups, which provides a clear rationale for incorporating them in the present case, and (2) the hydroxylated compounds could conceivably serve as synthetic standards for the identification of metabolites. Indeed, incubating LMP400 and LMP776 with human liver microsomes resulted in two major metabolites of each drug, which had HPLC retention times and mass fragmentation patterns identical to those of the synthetic standards. The hydroxylated indotecan and indimitecan metabolites and analogues were tested as Top1 poisons and for antiproliferative activity in a variety of human cancer cell cultures and in general were found to be very potent. Differences in activity resulting from the placement of the hydroxyl group are explained by molecular modeling analyses.

  DOI：

  10.1021/jm300519w

文献信息

• [EN] DUPA-INDENOISOQUINOLINE CONJUGATES<br/>[FR] CONJUGUÉS DUPA-INDÉNOISOQUINOLINE
  申请人：PURDUE RESEARCH FOUNDATION

  公开号：WO2015069766A1

  公开（公告）日：2015-05-14

  A targeting ligand-cytotoxic drug conjugate, for example, a DUPA-Indenoisoquinoline conjugate, is useful for treating cancers, e.g., prostate cancer.

  一种靶向配体-细胞毒性药物结合物，例如DUPA-Indenoisoquinoline结合物，可用于治疗癌症，例如前列腺癌。
• DUPA-INDENOISOQUINOLINE CONJUGATES
  申请人：PURDUE RESEARCH FOUNDATION

  公开号：US20160367685A1

  公开（公告）日：2016-12-22

  A targeting ligand-cytotoxic drug conjugate, for example, a DUPA-Indenoisoquinoline conjugate, is useful for treating cancers, e.g., prostate cancer.
• Identification, Synthesis, and Biological Evaluation of Metabolites of the Experimental Cancer Treatment Drugs Indotecan (LMP400) and Indimitecan (LMP776) and Investigation of Isomerically Hydroxylated Indenoisoquinoline Analogues as Topoisomerase I Poisons
  作者：Maris A. Cinelli、P. V. Narasimha Reddy、Peng-Cheng Lv、Jian-Hua Liang、Lian Chen、Keli Agama、Yves Pommier、Richard B. van Breemen、Mark Cushman

  DOI：10.1021/jm300519w

  日期：2012.12.27

  Hydroxylated analogues of the anticancer topoisomerase I (Top1) inhibitors indotecan (LMP400) and indimitecan (LMP776) have been prepared because (1) a variety of potent Top1 poisons are known that contain strategically placed hydroxyl groups, which provides a clear rationale for incorporating them in the present case, and (2) the hydroxylated compounds could conceivably serve as synthetic standards for the identification of metabolites. Indeed, incubating LMP400 and LMP776 with human liver microsomes resulted in two major metabolites of each drug, which had HPLC retention times and mass fragmentation patterns identical to those of the synthetic standards. The hydroxylated indotecan and indimitecan metabolites and analogues were tested as Top1 poisons and for antiproliferative activity in a variety of human cancer cell cultures and in general were found to be very potent. Differences in activity resulting from the placement of the hydroxyl group are explained by molecular modeling analyses.
• DUPA Conjugation of a Cytotoxic Indenoisoquinoline Topoisomerase I Inhibitor for Selective Prostate Cancer Cell Targeting
  作者：Jyoti Roy、Trung Xuan Nguyen、Ananda Kumar Kanduluru、Chelvam Venkatesh、Wei Lv、P. V. Narasimha Reddy、Philip S. Low、Mark Cushman

  DOI：10.1021/jm5018384

  日期：2015.4.9

  Prostate-specific membrane antigen (PSMA) is overexpressed in most prostate cancer cells while being present at low or undetectable levels in normal cells. This difference provides an opportunity to selectively deliver cytotoxic drugs to prostate cancer cells while sparing normal cells that lack PSMA, thus improving potencies and reducing toxicities. PSMA has high affinity for 2-[3-(1,3-dicarboxyp

  前列腺特异性膜抗原 (PSMA) 在大多数前列腺癌细胞中过度表达，而在正常细胞中以低水平或检测不到的水平存在。这种差异提供了一个机会，可以选择性地向前列腺癌细胞递送细胞毒性药物，同时保留缺乏 PSMA 的正常细胞，从而提高效力并降低毒性。PSMA 对 2-[3-(1,3-二羧丙基)脲基]戊二酸 (DUPA) ( K i= 8 纳米）。与 DUPA 药物偶联物结合后，PSMA 内化、卸载偶联物并返回表面。在目前的研究中，茚并异喹啉拓扑异构酶 I 抑制剂通过肽接头和药物释放段与 DUPA 结合，促进细胞内裂解以释放药物。DUPA-茚并异喹啉偶联物在 22RV1 细胞培养物中显示出低纳摩尔范围的 IC 50并诱导肿瘤生长完全停止而没有毒性，这由体重减轻和治疗小鼠的死亡确定。