1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one | 128571-50-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one
• 英文别名: (+)-CBI；(1R,13S)-11-azatetracyclo[8.4.0.01,13.02,7]tetradeca-2,4,6,9-tetraen-8-one
• CAS: 128571-50-6
• 化学式: C₁₃H₁₁NO
• 分子量: 197.236
• InChiKey: GSCDDRVFRLSQHN-AMIZOPFISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  15
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  29.1
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one 在 盐酸 作用下， 以 乙酸乙酯 为溶剂， 反应 0.5h， 生成 (+)-seco-CBI
  参考文献：
  名称：

  Novel tumor-selective chemotherapeutic agents

  摘要：

  本发明涉及新型CC-1065衍生物，其在体外和体内与白蛋白结合形成白蛋白-药物结合物，并且它们的制备方法和用作抗肿瘤剂的方法。

  公开号：

  US20050239864A1
• 作为产物：
  描述：

  (-)-(1R)-5-(benzyloxy)-3-(tert-butyloxycarbonyl)-1-(hydroxymethyl)-1,2-dihydro-3H-benzindole 在 palladium on activated charcoal 四氯化碳 、 甲酸铵 、 sodium hydride 、 三苯基膦 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one
  参考文献：
  名称：

  Synthesis of N-(tert-butyloxycarbonyl)-CBI, CBI, CBI-CDPI1, and CBI-CDPI2: enhanced functional analogs of CC-1065 incorporating the 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) left-hand subunit

  摘要：

  DOI：

  10.1021/jo00310a013

文献信息

• [EN] SELF-IMMOLATIVE LINKERS CONTAINING MANDELIC ACID DERIVATIVES, DRUG-LIGAND CONJUGATES FOR TARGETED THERAPIES AND USES THEREOF<br/>[FR] LIEURS AUTO-IMMOLABLES CONTENANT DES DÉRIVÉS D'ACIDE MANDÉLIQUE, CONJUGUÉS MÉDICAMENT-LIGAND POUR THÉRAPIES CIBLÉES, ET LEURS UTILISATIONS
  申请人：ASANA BIOSCIENCES LLC

  公开号：WO2015038426A1

  公开（公告）日：2015-03-19

  The invention provides a therapeutic drug and targeting conjugate, pharmaceutical compositions containing these conjugates in pharmaceutical composition, and uses of these conjugates in anti-neoplastic and other therapeutic regimens. Also provided are novel intermediates thereof. The conjugates provide a therapeutic drug fragment or prodrug fragment bound to a targeting moiety via a linker which comprises a substrate cleavable by a protease such as Cathepsin B. The targeting moiety is a ligand which targets a cell surface molecule, such as a cell surface receptor on an anti-neoplastic cell. The ligand may function solely as a targeting moiety or may itself have a therapeutic effect. Following administration of the therapeutic drug and targeting conjugate of formula I and exposure of the conjugate to the protease specific for the substrate, the linker is cleaved and the targeting moiety is separated from the conjugate, which causes the drug fragment or prodrug fragment to convert to the drug or prodrug. The recited conjugates are useful in anti-neoplastic therapies. Also provided are methods of making the therapeutic drug and targeting conjugates and intermediates thereof, and kits comprising the therapeutic drug and targeting conjugates.

  该发明提供了一种治疗药物和靶向共轭物，包含这些共轭物的药物组合物，以及这些共轭物在抗肿瘤和其他治疗方案中的用途。还提供了其新颖的中间体。这些共轭物通过一个由蛋白酶如半胱氨酸蛋白酶B可切割的底物组成的连接物将治疗药物片段或前药片段与靶向基团结合。靶向基团是一个以细胞表面分子为靶点的配体，例如抗肿瘤细胞上的细胞表面受体。该配体可能仅作为靶向基团，也可能本身具有治疗效果。在给药公式I的治疗药物和靶向共轭物并使共轭物暴露于特异于底物的蛋白酶的情况下，连接物被切割，靶向基团与共轭物分离，导致药物片段或前药片段转化为药物或前药。所述的共轭物在抗肿瘤疗法中很有用。还提供了制备治疗药物和靶向共轭物及其中间体的方法，以及包含治疗药物和靶向共轭物的试剂盒。
• CROSS-LINKERS AND THEIR USES
  申请人：ImmunoGen, Inc.

  公开号：US20150352223A1

  公开（公告）日：2015-12-10

  Charged or pro-charged cross-linking moieties and conjugates of cell binding agents and drugs comprising the charged or pro-charged cross-linking moieties and method of making the same.

  带电或前充电的交联基团和细胞结合剂和药物的共轭物，包括带电或前充电的交联基团，以及制备方法。
• Resolution of a CBI precursor and incorporation into the synthesis of (+)-cbi, (+)-CBI-CDPI1, (+)-CBI-CDPI2: enhanced functional analogs of (+)-CC-1065. A critical appraisal of a proposed relationship between electrophile reactivity, DNA binding properties, and cytotoxic potency.
  作者：Dale L Boger、Takayoshi Ishizaki

  DOI：10.1016/s0040-4039(00)94629-x

  日期：1990.1

  and its subsequent incorporation into (+)− and (−)-CBI-CDPIn, optically-active enhanced functional analogs of (+)-CC-1065, are described. In marked contrast to a previously detailed direct relationship between electrophile reactivity and cytotoxic potency, an inverse relationship between the properties is detailed.

  直接CBI前体（+）-和（-）- 8的拆分及其随后并入（+）-和（-）-CBI-CDPI n的旋光增强功能类似物的详细信息描述了-CC-1065。与先前详细描述的亲电试剂反应性和细胞毒性潜能之间的直接关系形成鲜明对比的是，特性之间的逆向关系得到了详细描述。
• Establishing the Parabolic Relationship between Reactivity and Activity for Derivatives and Analogues of the Duocarmycin and CC-1065 Alkylation Subunits
  作者：Jay P. Parrish、Terry V. Hughes、Inkyu Hwang、Dale L. Boger

  DOI：10.1021/ja038162t

  日期：2004.1.1

  modulate the reactivity of the resulting CC-1065/duocarmycin alkylation subunit analogue (rho = 0.17). The derivatives were found to be exceptionally stable and to exhibit a well-defined relationship between reactivity and cytotoxic potency. When combined with the results of an extensive series of N-acyl CBI analogues and derivatives assembled over the past 15 years, the studies define a fundamental parabolic

  详细介绍了一系列新型 N-芳基 CBI 衍生物的制备，其中芳基对位取代基可用于可预测地调节所得 CC-1065/duocarmycin 烷基化亚基类似物 (rho = 0.17) 的反应性。发现这些衍生物异常稳定并且在反应性和细胞毒性效力之间表现出明确的关系。结合过去 15 年收集的大量 N-酰基 CBI 类似物和衍生物的结果，这些研究定义了反应性和细胞毒性效力之间的基本抛物线关系。
• Synthesis, X-ray Structure, and Properties of Fluorocyclopropane Analogs of the Duocarmycins Incorporating the 9,9-Difluoro-1,2,9,9a-tetrahydrocyclopropa[<i>c</i>]benzo[<i>e</i>]indol-4-one (F₂CBI) Alkylation Subunit
  作者：Dale L. Boger、Tracy J. Jenkins

  DOI：10.1021/ja961888n

  日期：1996.1.1

  (24) provided a key analog of the duocarmycins. A study of the solvolysis of N-BOC-F2CBI (19) revealed that introduction of the difluorocyclopropane substitution increased the reactivity 500× without altering the inherent regioselectivity which occurred with nucleophilic addition to the difluoro substituted C9 cyclopropane carbon. A single-crystal X-ray structure analysis of 17 and its comparison with

  9,9-difluoro-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (F2CBI) 的合成，CC-1065 的二氟环丙烷类似物和 duocarmycin 烷基化亚基，代表第一个此类试剂含有取代天然产物中的反应中心，详述。F2CBI 的核心结构是通过使用对醌二叠氮将分子内金属类卡宾插入 1,1-二氟烯烃 (74%) 的反应制备的，并将其掺入 F2CBI-TMI (24) 中提供了双癌霉素的关键类似物。对 N-BOC-F2CBI (19) 的溶剂分解的研究表明，二氟环丙烷取代的引入将反应性提高了 500 倍，而不会改变与二氟取代的 C9 环丙烷碳进行亲核加成时发生的固有区域选择性。