3-fluoro-10-methoxy-14-methyl-8,13,13b,14-tetrahydroindolo[2',3':3,4]pyrido[2,1-b]quinazolin-5(7H)-one | 1355077-67-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 3-fluoro-10-methoxy-14-methyl-8,13,13b,14-tetrahydroindolo[2',3':3,4]pyrido[2,1-b]quinazolin-5(7H)-one
• 英文别名: 17-Fluoro-7-methoxy-21-methyl-3,13,21-triazapentacyclo[11.8.0.02,10.04,9.015,20]henicosa-2(10),4(9),5,7,15(20),16,18-heptaen-14-one
• CAS: 1355077-67-6
• 化学式: C₂₀H₁₈FN₃O₂
• 分子量: 351.38
• InChiKey: IIBBDHJWIQMYIZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  26
• 可旋转键数：
  1
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  48.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-fluoro-10-methoxy-14-methyl-8,13,13b,14-tetrahydroindolo[2',3':3,4]pyrido[2,1-b]quinazolin-5(7H)-one 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 反应 2.5h， 以60%的产率得到3-fluoro-10-hydroxylevodiamine
  参考文献：
  名称：

  发现具有有效抗肿瘤活性的新型双吴茱萸碱衍生物

  摘要：

  受抗肿瘤天然产物吴茱萸碱的启发，设计合成了一系列新型双吴茱萸碱衍生物，具有较强的抗肿瘤活性。特别是化合物13b有效地抑制了HCT116细胞的增殖和迁移。进一步的机制研究表明，化合物13b的作用是诱导 HCT116 细胞凋亡并将细胞周期阻滞在 G2/M 期。因此，化合物13b代表了用于发现新型抗肿瘤药物的有希望的先导化合物。

  DOI：

  10.1016/j.bmc.2022.116793
• 作为产物：
  描述：

  N-formyl-5-methoxytryptamine 在 三氯氧磷 作用下， 以 二氯甲烷 为溶剂， 反应 12.0h， 生成 3-fluoro-10-methoxy-14-methyl-8,13,13b,14-tetrahydroindolo[2',3':3,4]pyrido[2,1-b]quinazolin-5(7H)-one
  参考文献：
  名称：

  New Tricks for an Old Natural Product: Discovery of Highly Potent Evodiamine Derivatives as Novel Antitumor Agents by Systemic Structure–Activity Relationship Analysis and Biological Evaluations

  摘要：

  Evodiamine is a quinazolinocarboline alkaloid isolated from the fruits of traditional Chinese herb Evodiae fructus. Previously, we identified N13-substituted evodiamine derivatives as potent topoisomerase I inhibitors by structure-based virtual screening and lead optimization. Herein, a library of novel evodiamine derivatives bearing various substitutions or modified scaffold were synthesized. Among them, a number of evodiamine derivatives showed substantial increase of the antitumor activity, with GI(50) values lower than 3 nM. Moreover, these highly potent compounds can effectively induce the apoptosis of A549 cells. Interestingly, further computational target prediction calculations in combination with biological assays confirmed that the evodiamine derivatives acted by dual inhibition of topoisomerases I and II. Moreover, several hydroxyl derivatives, such as 10-hydroxyl evodiamine (10j) and 3-amino-10-hydroxyl evodiamine (18g), also showed good in vivo antitumor efficacy and low toxicity at the dose of 1 mg/kg or 2 mg/kg. They represent promising candidates for the development of novel antitumor agents.

  DOI：

  10.1021/jm300605m

文献信息

• 10.1016/j.bmc.2024.117759
  作者：Bai, Haohao、Huang, Wenjing、Li, Jinqiu、Ji, Yajing、He, Shipeng、Hu, Honggang

  DOI：10.1016/j.bmc.2024.117759

  日期：——

  3-fluoro-10-hydroxy-Evodiamine (F-OH-Evo), a potent derivative of Evodiamine, whose development is curtailed due to suboptimal tumor selectivity and heightened cytotoxicity. By harnessing the remarkable stability, specificity, and αβ integrin affinity of c(RGDFK), a novel prodrug by conjugating F-OH-Evo with cRGD was synthesized. This innovative prodrug substantially enhanced the tumor-specific targeting

  源自天然产物的小分子药物对于新的治疗发现至关重要。然而，它们的临床部署常常受到非特异性活性和严重不良反应的阻碍。这项研究的重点是 3-氟-10-羟基-吴茱萸碱 (F-OH-Evo)，它是吴茱萸碱的一种有效衍生物，但由于肿瘤选择性不佳和细胞毒性增强，其开发受到限制。利用 c(RGDFK) 卓越的稳定性、特异性和 αβ 整合素亲和力，通过将 F-OH-Evo 与 cRGD 结合，合成了一种新型前药。这种创新的前药大大增强了 F-OH-Evo 的肿瘤特异性靶向性，提高了抗肿瘤活性。其中，化合物在体外对U87癌细胞表现出最佳的选择性抑制活性。它通过与αβ整合素结合选择性地进入U87细胞，在ROS和GSH的双重响应下释放母体分子，对topo I发挥抑制活性。结果凸显了cRGD缀合的前药在靶向癌症治疗中的潜力。这种方法标志着在开发更安全、更有效的化疗药物方面取得了重大进展，强调了前药策略在克服传统癌症治疗局限性方面的作用。
• Discovery of novel triple targeting G‑quadruplex and topoisomerase 1/2 ligands from natural products evodiamine and rutaecarpine
  作者：Haibo Wang、Xuexin Bai、Yahui Huang、Yueru Chen、Guoqiang Dong、Tianmiao Ou、Shanchao Wu、Defeng Xu、Chunquan Sheng

  DOI：10.1016/j.cclet.2022.07.014

  日期：2023.4
• New Tricks for an Old Natural Product: Discovery of Highly Potent Evodiamine Derivatives as Novel Antitumor Agents by Systemic Structure–Activity Relationship Analysis and Biological Evaluations
  作者：Guoqiang Dong、Shengzheng Wang、Zhenyuan Miao、Jianzhong Yao、Yongqiang Zhang、Zizhao Guo、Wannian Zhang、Chunquan Sheng

  DOI：10.1021/jm300605m

  日期：2012.9.13

  Evodiamine is a quinazolinocarboline alkaloid isolated from the fruits of traditional Chinese herb Evodiae fructus. Previously, we identified N13-substituted evodiamine derivatives as potent topoisomerase I inhibitors by structure-based virtual screening and lead optimization. Herein, a library of novel evodiamine derivatives bearing various substitutions or modified scaffold were synthesized. Among them, a number of evodiamine derivatives showed substantial increase of the antitumor activity, with GI(50) values lower than 3 nM. Moreover, these highly potent compounds can effectively induce the apoptosis of A549 cells. Interestingly, further computational target prediction calculations in combination with biological assays confirmed that the evodiamine derivatives acted by dual inhibition of topoisomerases I and II. Moreover, several hydroxyl derivatives, such as 10-hydroxyl evodiamine (10j) and 3-amino-10-hydroxyl evodiamine (18g), also showed good in vivo antitumor efficacy and low toxicity at the dose of 1 mg/kg or 2 mg/kg. They represent promising candidates for the development of novel antitumor agents.
• Discovery of novel bis-evodiamine derivatives with potent antitumor activity
  作者：Huixin Liang、Wei Wang、Fugui Zhu、Shuqiang Chen、Dan Liu、Chunquan Sheng

  DOI：10.1016/j.bmc.2022.116793

  日期：2022.7

  Inspired by antitumor natural product evodiamine, a series of novel bis-evodiamine derivatives were designed and synthesized, which showed potent antitumor activity. In particular, compound 13b effectively inhibited the proliferation and migration of HCT116 cells. Further mechanism studies revealed that compound 13b acted by inducing HCT116 cell apoptosis and arresting the cell cycle at the G2/M phase

  受抗肿瘤天然产物吴茱萸碱的启发，设计合成了一系列新型双吴茱萸碱衍生物，具有较强的抗肿瘤活性。特别是化合物13b有效地抑制了HCT116细胞的增殖和迁移。进一步的机制研究表明，化合物13b的作用是诱导 HCT116 细胞凋亡并将细胞周期阻滞在 G2/M 期。因此，化合物13b代表了用于发现新型抗肿瘤药物的有希望的先导化合物。