3,11-dihydroxy-14-(3-hydroxy-4-methoxyphenyl)-2,12-dimethoxy-6H-[1]benzopyrano-[4′,3′:4,5]pyrrolo[2,1-a]isoquinolin-6-one | 149379-26-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: 3,11-dihydroxy-14-(3-hydroxy-4-methoxyphenyl)-2,12-dimethoxy-6H-[1]benzopyrano-[4′,3′:4,5]pyrrolo[2,1-a]isoquinolin-6-one
• 英文别名: 3,11-dihydroxy-14-(3-hydroxy-4-methoxyphenyl)-2,12-dimethoxy-6H-[1]benzopyrano-[4',3':4,5]pyrrolo[2,1-a]-isoquinolin-6-one；3,11-dihydroxy-14-(3-hydroxy-4-methoxyphenyl)-2,12-dimethoxy-6H-[1]benzopyrano[4',3':4,5]pyrrolo[2,1-a]isoquinolin-6-one；14-(3-hydroxy-4-methoxyphenyl)-3,11-dihydroxy-2,12-dimethoxy-6H-chromeno[4',3':4,5]pyrrolo[2,1-a]isoquinolin-6-one；lamellarin N；lmellarin N；Lam N；7,17-dihydroxy-12-(3-hydroxy-4-methoxyphenyl)-8,16-dimethoxy-4-oxa-1-azapentacyclo[11.8.0.02,11.05,10.014,19]henicosa-2(11),5,7,9,12,14,16,18,20-nonaen-3-one
• CAS: 149379-26-0
• 化学式: C₂₈H₂₁NO₈
• 分子量: 499.477
• InChiKey: POCZBHBFCIWCCV-UHFFFAOYSA-N

物化性质

• 熔点：
  280-300 °C (decomp)
• 密度：
  1.49±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  37
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  119
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  乙酸酐 、 3,11-dihydroxy-14-(3-hydroxy-4-methoxyphenyl)-2,12-dimethoxy-6H-[1]benzopyrano-[4′,3′:4,5]pyrrolo[2,1-a]isoquinolin-6-one 在 吡啶 作用下， 以1 mg的产率得到3,11-bis(acetoxy)-14-(3-acetoxy-4-methoxyphenyl)-2,12-dimethoxy-6H-[1]benzopyrano[4′,3′:4,5]pyrrolo[2,1-a]-isoquinolin-6-one
  参考文献：
  名称：

  来自阿拉伯海一位身份不明的海生动物的新层状生物碱

  摘要：

  一名来自阿拉伯海的身份不明的海鞘含有9种新的薄片蛋白生物碱以及薄片蛋白N。薄片蛋白T，U，V和Y（1-4）和薄片蛋白T-X（5的20种硫酸盐衍生物的结构）–9）通过对光谱数据的解释来识别。这是硫酸lamellarin的首次报道。

  DOI：

  10.1016/s0040-4020(97)00073-2
• 作为产物：
  描述：

  异香兰素 在 lithium aluminium tetrahydride 、 噻吩-2-甲酸亚铜(I) 、 茴香硫醚 、 ammonium acetate 、 碳酸氢钠 、 sodium carbonate 、 potassium carbonate 、 sodium amide 、 溶剂黄146 、 三氟乙酸 、 2,3-二氯-5,6-二氰基-1,4-苯醌 、 三氯氧磷 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 150.0 ℃ 、689.49 kPa 条件下， 反应 36.25h， 生成 3,11-dihydroxy-14-(3-hydroxy-4-methoxyphenyl)-2,12-dimethoxy-6H-[1]benzopyrano-[4′,3′:4,5]pyrrolo[2,1-a]isoquinolin-6-one
  参考文献：
  名称：

  片状和含内酰胺衍生物的简便多样的合成，具有改善的药物相似性和生物活性

  摘要：

  为了改善薄层蛋白的水溶性，其骨架中的内酯环被氮杂层蛋白中的内酰胺部分取代。然而，所报道的合成路线以非常低的产率产生了此类衍生物。因此，本研究着重于开发一种有效的简化的全合成方案，该方案可从相同的吡咯酯中间体中同时提供氮杂戊酰胺和母体薄片。随后的比较分析表明，引入的内酯-内酰胺替代使得这些分子的亲脂性降低，而它们的癌细胞毒性仍然与母体化合物相同。有趣的是，它们对多层面GSK-3β酶的抑制活性显着增强。

  DOI：

  10.1002/asia.201500611

文献信息

• Total synthesis of lamellarins D, L, and N
  作者：Naotaka Fujikawa、Takeshi Ohta、Tomohiro Yamaguchi、Tsutomu Fukuda、Fumito Ishibashi、Masatomo Iwao

  DOI：10.1016/j.tet.2005.10.014

  日期：2006.1

  Total synthesis of cytotoxic marine alkaloids, lamellarins D, L, and N, has been achieved by using Hinsberg-type pyrrole synthesis and palladium-catalyzed Suzuki–Miyaura coupling of the 3,4-dihydroxypyrrole bistriflate 6 as the key reactions. The total yields of lamellarins D, L, and N from the common intermediate 6 are 54, 58, and 50%, respectively.

  通过使用Hinsberg型吡咯合成法和钯催化的3,4-二羟基吡咯二酚6的Suzuki-Miyaura偶联，已经完成了细胞毒性海洋生物碱，薄片蛋白D，L和N的总合成。普通中间体6的层状蛋白D，L和N的总产率分别为54％，58％和50％。
• Design, synthesis, and evaluation of A-ring-modified lamellarin N analogues as noncovalent inhibitors of the EGFR T790M/L858R mutant
  作者：Tsutomu Fukuda、Teppei Umeki、Keiji Tokushima、Gao Xiang、Yuki Yoshida、Fumito Ishibashi、Yusuke Oku、Naoyuki Nishiya、Yoshimasa Uehara、Masatomo Iwao

  DOI：10.1016/j.bmc.2017.10.030

  日期：2017.12

  series of A-ring-modified lamellarin N analogues were designed, synthesized, and evaluated as potential noncovalent inhibitors of the EGFR T790M/L858R mutant, a causal factor in the drug-resistant non-small cell lung cancer. Several water-soluble ammonium- or guanidinium-tethered analogues exhibited good kinase inhibitory activities. The most promising analogue, 14f, displayed an excellent inhibitory

  设计，合成和评估了一系列A环修饰的lamellarin N类似物，作为EGFR T790M / L858R突变体的潜在非共价抑制剂，EGFR T790M / L858R突变体是耐药性非小细胞肺癌的致病因素。几种水溶性铵盐或胍盐系的类似物表现出良好的激酶抑制活性。最有前途的类似物14f对T790M / L858R突变体表现出优异的抑制作用[IC 50（WT）= 31.8 nM; IC 50（T790M / L858R）= 8.9 nM]。通过对接研究合理化了A环取代基对活性的影响。
• FOURTH-GENERATION EGFR TYROSINE KINASE INHIBITOR
  申请人：NAGASAKI UNIVERSITY

  公开号：US20210122759A1

  公开（公告）日：2021-04-29

  Provided is a compound having a tyrosine kinase inhibitory activity specific to C797S resistant mutant EGFR (particularly C797S tertiary-resistant mutant EGFR) and is useful as a C797S resistant mutant EGFR (particularly C797S mutant tertiary-resistant EGFR) specific tyrosine kinase inhibitor, an agent for preventing and/or treating non-small cell lung cancer with resistance mutant EGFR and the like, and the like. A compound represented by the formula (I): wherein X is O or NH, R 1 and R 2 are each independently a hydrogen atom or an optionally substituted hydrocarbon group; R 3 and R 4 are each independently a hydrogen atom, a halogen atom or an optionally substituted hydrocarbon group, and R 5 and R 6 are each independently an optionally substituted hydrocarbon group, excluding the following compounds: or a salt thereof.

  提供一种具有特异性抑制C797S耐药突变EGFR的酪氨酸激酶抑制活性的化合物（特别是C797S三级耐药突变EGFR），并且可用作C797S耐药突变EGFR（特别是C797S突变三级耐药EGFR）特异性酪氨酸激酶抑制剂，用于预防和/或治疗具有耐药突变EGFR的非小细胞肺癌等药剂等。一种由以下式（I）表示的化合物：其中X为O或NH，R1和R2分别为氢原子或可选择取代的碳氢基团；R3和R4分别为氢原子、卤素原子或可选择取代的碳氢基团，而R5和R6分别为可选择取代的碳氢基团，但不包括以下化合物：或其盐。
• Modular Synthesis of Lamellarins via Regioselective Assembly of 3,4,5-Differentially Arylated Pyrrole-2-carboxylates
  作者：Masashi Komatsubara、Teppei Umeki、Tsutomu Fukuda、Masatomo Iwao

  DOI：10.1021/jo402181w

  日期：2014.1.17

  A modular synthesis of lamellarins via 3,4,5-differentially arylated pyrrole-2-carboxylate intermediates has been developed. The key reactions employed are Br-Li exchange-methoxycarbonylation of 2,5-dibromo-1-(tert-butoxycarbonyl)-1H-pyrrole (1) followed by palladium-catalyzed iterative Suzuki-Miyaura coupling of the pyrrole core. The 3,4,5-triarylpyrrole 4 thus synthesized was readily converted to 5,6-saturated lamellarin L (2) and 5,6-unsaturated lamellarin N (3) via lactonization followed by annulation of the pyrrole nitrogen and lateral aromatic ring at C5 using 2-bromoethyl phenyl sulfide or bromoacetaldehyde dimethyl acetal as two-carbon homologation agents. In principle, this strategy allows the production of diverse lamellarins in short steps with high yields using readily accessible arylboronic acids as aromatic modules.
• Total Synthesis of Natural and Unnatural Lamellarins with Saturated and Unsaturated D-Rings
  作者：Poonsakdi Ploypradith、Thaninee Petchmanee、Poolsak Sahakitpichan、Nichole D. Litvinas、Somsak Ruchirawat

  DOI：10.1021/jo061810h

  日期：2006.12.1

  Twenty-eight natural and unnatural lamellarins with either a saturated or an unsaturated D-ring were synthesized according to our developed synthetic route. The key step involved the Michael addition/ring closure (Mi-RC) of the benzyldihydroisoquinoline and alpha-nitrocinnamate derivatives, which provided the 2-carboethoxypyrrole intermediates in moderate to good yields (up to 78% yield). Subsequent hydrogenolysis/lactonization furnished lamellarins with a saturated D-ring in excellent yields (up to 93% yield). DDQ oxidation of the saturated lamellarin acetates led directly to the corresponding unsaturated analogues in 54-95% yield. In addition, only two steps in our developed strategy require column chromatography.