9-ethyl-9-hydroxy-2,3,8,9-tetrahydro-5H-6-oxa-3a-azacyclohepta[f]indene-1,4,7-trione | 863217-08-7

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 9-ethyl-9-hydroxy-2,3,8,9-tetrahydro-5H-6-oxa-3a-azacyclohepta[f]indene-1,4,7-trione
• 英文别名: 5-Ethyl-5-hydroxy-1,4,8,9-tetrahydrooxepino[3,4-f]indolizine-3,7,11-trione
• CAS: 863217-08-7
• 化学式: C₁₄H₁₅NO₅
• 分子量: 277.277
• InChiKey: KACPPDOMFFLSTG-UHFFFAOYSA-N

物化性质

• 沸点：
  690.4±55.0 °C(Predicted)
• 密度：
  1.45±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -1.1
• 重原子数：
  20
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  83.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  9-ethyl-9-hydroxy-2,3,8,9-tetrahydro-5H-6-oxa-3a-azacyclohepta[f]indene-1,4,7-trione 在 三甲基氯硅烷 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 10-[4-(diethylamino)butoxy]-5-ethyl-1,4,5,13-tetrahydro-5-hydroxy-12-methyl-3H,15H-oxepino[3',4':6,7]indolizino[1,2-b]quinoline-3,15-dione
  参考文献：
  名称：

  拓扑异构酶 I 介导的 10-取代和 12-取代高喜树碱的抗增殖活性

  摘要：

  Homocamptothecin (hCPT) 是一种 E 环修饰的喜树碱 (CPT) 类似物，对拓扑异构酶 I 显示出显着的抑制活性。 为了寻找新的 hCPT 型抗癌剂，合成了两个系列的 hCPT 衍生物并在体外对三种人类肿瘤进行了评估细胞系。结果表明，10-取代的hCPT衍生物比12-取代的具有更高的细胞毒活性。在 10 个取代的化合物中，8a、8b、9b 和 9i 对肺癌细胞系 A-549 显示出与阳性对照药物拓扑替康相当甚至更强的活性。此外，hCPT 类似物 8a 和 8b 在 100 μM 的浓度下表现出比 CPT 更高的拓扑异构酶 I 抑制活性。

  DOI：

  10.1002/cbdv.201000307
• 作为产物：
  描述：

  在 三氟乙酸 作用下， 反应 10.0h， 生成 9-ethyl-9-hydroxy-2,3,8,9-tetrahydro-5H-6-oxa-3a-azacyclohepta[f]indene-1,4,7-trione
  参考文献：
  名称：

  Phosphate ester derivatives of homocamptothecin: Synthesis, solution stabilities and antitumor activities

  摘要：

  Homocamptothecins (hCPTs) represents a new promising class of topoisomerase I inhibitors with enhanced stability and superior antitumor activity. Some phosphodiesters and phosphotriesters homocamptothecin derivatives were designed and synthesized based on our previous synthetic route. The cytotoxicity in vitro on three cancer cell lines and antitumor activity in vivo, and inhibitory properties of topoisomerase I of these derivatives were evaluated. Among them compounds 24e and 24f exhibited higher cytotoxic activity than IRT and the former exhibited the best antitumor activity in vivo and solution stability both at pH 7.4 and pH 3.0. (c) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.03.039

文献信息

• Trifluoromethyl-promoted homocamptothecins: Synthesis and biological activity
  作者：Lingjian Zhu、Zhenyuan Miao、Chunquan Sheng、Wei Guo、Jianzhong Yao、Wenfeng Liu、Xiaoying Che、Wenya Wang、Pengfei Cheng、Wannian Zhang

  DOI：10.1016/j.ejmech.2010.02.051

  日期：2010.7

  The homocamptothecin (hCPT) represents a new class of topoisomerase inhibitor which combines enhanced plasma stability and strong antitumor activity. Fluorine imparts desirable characteristics to drugs by modulating both the pharmacokinetics and pharmacodynamic properties of a drug. Therefore, in an attempt to improve the antitumor activity of homocamptothecins, seven new 7-trifluoromethylated homocamptothecin

  同型喜树碱（hCPT）代表一类新的拓扑异构酶抑制剂，它具有增强的血浆稳定性和强大的抗肿瘤活性。氟通过调节药物的药代动力学和药效学性质赋予药物所需的特性。因此，为了提高同型喜树碱的抗肿瘤活性，通过脯氨酸催化的弗里德兰德法制备了七个新的7-三氟甲基化的同型喜树碱衍生物。评价了在体内和体外对癌细胞系的抗肿瘤活性，以及拓扑异构酶I介导的化合物6c和8b的DNA切割的抑制特性。这些三氟甲基化的hCPT衍生物中的几种（例如6a，6b和6c）具有比拓扑替康（TPT）更高的体外抗肿瘤活性。特别地，化合物6c显示出与TPT相当的有效体内抗肿瘤活性。
• Synthesis and evaluation of 9-benzylideneamino derivatives of homocamptothecin as potent inhibitors of DNA topoisomerase I
  作者：Wei Guo、Zhenyuan Miao、Chunquan Sheng、Jianzhong Yao、Hao Feng、Wannian Zhang、Lingjian Zhu、Wenfeng Liu、Pengfei Cheng、Jing Zhang、Xiaoying Che、Wenya Wang、Chuan Luo、Yulan Xu

  DOI：10.1016/j.ejmech.2010.01.063

  日期：2010.6

  A series of novel 9-benzylideneamino derivatives of homocamptothecin were synthesized via Friedlaender cyclization from our obtained intermediate 5. All the compounds were evaluated for in vitro cytotoxicity against three cancer cell lines (A549, LOVO and MDA-MB-435). Most of these derivatives possessed potent growth inhibitory effect on all the tested cell lines and four compounds (6d, 6f, 6i, 6k)

  通过我们的中间体5通过Friedlaender环化合成了一系列喜树碱的9-亚苄基氨基衍生物。评估了所有化合物对三种癌细胞系（A549，LOVO和MDA-MB-435）的体外细胞毒性。这些衍生物中的大多数对所有测试细胞系均具有有效的生长抑制作用，四种化合物（6d，6f，6i，6k）对乳腺癌细胞的IC 50值为2.3 nM–9.8 nM，高于拓扑替康。与CPT相比，化合物6f显示更高的拓扑异构酶I抑制活性。
• Synthesis and Biological Assays of 9-(Acylamino)homocamptothecins as DNA Topoisomerase I Inhibitors
  作者：Wei Guo、Guoqiang Dong、Lingjian Zhu、Wenfeng Liu、Chunlin Zhuang、Zizhao Guo、Jianzhong Yao、Chunquan Sheng、Huojun Zhang、Zhenyuan Miao、Wannian Zhang

  DOI：10.1002/cbdv.201200311

  日期：2013.10

  an effort to improve the stability of homocamptothecin and reduce the toxicity, novel homocamptothecin analogs with acylamino groups at C(9) were designed and synthesized. The cytotoxic activities of all the synthetic compounds against three cancer cell lines were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, and irinotecan was used as reference compound

  为了提高高喜树碱的稳定性并降低毒性，设计并合成了在C（9）具有酰基氨基的新高喜树碱类似物。通过3-（4,5-二甲基噻唑-2-基）-2,5-二苯基-2H-溴化四唑（MTT）分析评估所有合成化合物对三种癌细胞的细胞毒活性，并使用伊立替康作为参考化合物。在C（9）处带有哌啶基乙酰酰胺基的化合物7c和带有苯基乙酰酰胺基的化合物10a在体外和体内均显示出强大的活性。此外，他们还发现了显着的拓扑异构酶I抑制作用，这种抑制作用与活性口袋中与氨基酸残基Arg364和Asp533的牢固结合形成。根据生物活性，7c和10a将是进一步研究的潜在候选者。
• Synthesis and biological evaluation of novel 7-acyl homocamptothecins as Topoisomerase I inhibitors
  作者：Wenfeng Liu、Lingjian Zhu、Wei Guo、Chunlin Zhuang、Yongqiang Zhang、Chunquan Sheng、Pengfei Cheng、Jianzhong Yao、Wenya Wang、Guoqiang Dong、Shengzheng Wang、Zhenyuan Miao、Wannian Zhang

  DOI：10.1016/j.ejmech.2011.03.024

  日期：2011.6

  (TPT). Furthermore, compounds 6d, 6e, and 6k showed highly potent inhibitory activities with the IC50 values from less than 1 nM to 2.2 nM. In Topoisomerase I (Topo I)-induced DNA cleavage assay, compounds 6a, 6d, and 6k, as compared to CPT, revealed higher Topo I inhibitory activity.

  设计并合成了一系列新的高喜树碱7-酰基衍生物（hCPT），目的是通过10-甲氧基高喜树碱的Minisci自由基反应来提高hCPT的抗肿瘤活性。评估了所有化合物对三种癌细胞系（A549，MDA-MB-435和HCT116）的体外细胞毒性。对于MDA-MB-435细胞系，化合物6a，6b，6k和所有7-烷基羰基高喜树碱衍生物的体外抑制活性均高于拓扑替康（TPT）。此外，化合物6d，6e和6k对IC 50表现出高度有效的抑制活性值从小于1 nM到2.2 nM。在拓扑异构酶I（Topo I）诱导的DNA裂解测定中，与CPT相比，化合物6a，6d和6k显示出更高的Topo I抑制活性。
• New homocamptothecins: Synthesis, antitumor activity, and molecular modeling
  作者：Zhenyuan Miao、Chunquan Sheng、Wannian Zhang、Haitao Ji、Jing Zhang、Lücheng Shao、Liang You、Min Zhang、Jianzhong Yao、Xiaoyin Che

  DOI：10.1016/j.bmc.2007.10.046

  日期：2008.2.1

  Homocamptothecins (hCPTs) represent a class of new emerging antitumor agents, which contains a seven-membered beta-hydroxylactone in place of the conventional six-membered alpha-hydroxylactone ring (E ring) of camptothecins. Some novel 7-substituted hCPTs were designed and synthesized based on a newly developed synthetic route which couples ring A with ring C, E and D. Most of the synthesized compounds exhibit very high cytotoxic activity on tumor cell line A549. Some compounds, such as 9b, 91, and 9y, show broad in vitro antitumor spectrum and are more potent than topotecan. Three-dimensional quantitative structure-activity relationship (3D-QSAR) methods, CoMFA and CoMSIA, were applied to explain the structure-activity relationship (SAR) of the synthesized compounds. Furthermore, molecular docking was used to clarify the binding mode of the synthesized compounds to human DNA topoisomerase I. The important hydrophobic, base-pair stacking, and hydrogen-bonding interactions were observed between the hCPT derivatives and their receptor. The results from molecular modeling will guide the design of novel hCPTs with higher antitumor activity. (C) 2007 Elsevier Ltd. All rights reserved.