(+)-CBI-TMI | 157922-78-6

• 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: (+)-CBI-TMI
• 英文别名: (1R,13S)-11-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-11-azatetracyclo[8.4.0.01,13.02,7]tetradeca-2,4,6,9-tetraen-8-one
• CAS: 157922-78-6
• 化学式: C₂₅H₂₂N₂O₅
• 分子量: 430.46
• InChiKey: PITJNOYHDJOZBD-DLUDVSRJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  32
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  80.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  甲醇 、 (+)-CBI-TMI 以 水 为溶剂， 生成
  参考文献：
  名称：

  Duocarmycin 和 CC-1065 类似物在亚基连接酰胺中含有修饰的合成和评价。

  摘要：

  描述了双癌霉素和 CC-1065 的类似物 6 和 7 的制备和评估，其中连接酰胺的亚基已被脒和硫代酰胺取代。与硫代酰胺相对于酰胺增加的吸电子特性和共轭相一致，7 在 pH 3 下显示出增加的溶剂分解反应性（t1/2，160 小时与 230 小时），这归因于反应烷基化亚单元的乙烯基酰胺稳定性减弱。尽管吸电子特性减弱，但脒 6 被证明更不稳定（t1/2，12 小时），但经历了优先 N2 脒键水解而不是烷基化亚基的溶剂分解，这归因于优先 N2 乙烯基酰胺与脒共轭。天然异构体 (+)-6 和 (+)-7 表现出与 (+)-CBI-TMI 和 (+)-duocarmycin SA 相同的 DNA 烷基化选择性，但效率较低 (10-100x)。(+)-6 和 (+)-7（分别为 0.75 和 1.1 nM）的生物学研究表明，这些类似物保留了良好的细胞毒活性 (L1210)，但不如 (+)-duocarmycin

  DOI：

  10.1021/jo990452y
• 作为产物：
  描述：

  (S)-1-(chloromethyl)-2,3-dihydro-1H-benzo[e]indol-5-ol hydrochloride 在 sodium hydride 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.0h， 生成 (+)-CBI-TMI
  参考文献：
  名称：

  CBI-TMI: Synthesis and Evaluation of a Key Analog of the Duocarmycins. Validation of a Direct Relationship between Chemical Solvolytic Stability and Cytotoxic Potency and Confirmation of the Structural Features Responsible for the Distinguishing Behavior of Enantiomeric Pairs of Agents

  摘要：

  The synthesis of (+)- and ent-(-)-CBI-TMI (3), a key analog of the naturally occurring potent antitumor antibiotics duocarmycin SA (1) and duocarmycin A (2), is disclosed and was facilitated by the development of a general and direct chromatographic resolution of the advanced synthetic intermediate 13 on a preparative Diacel Chiralcel OD HPLC column. The DNA alkylation properties and the cytotoxic activity of (+)- and (-)-CBI-TMI (3) are detailed in conjunction with a comparative study of a key series of duocarmycin SA and A analogs. (+)-CBI-TMI proved to be an effective DNA alkylating agent which exhibited a selectivity and efficiency of DNA alkylation that are not distinguishable from those of (+)-duocarmycin SA (1), and it was found to be an exceptionally potent cytotoxic agent (IC50 = 30 PM, L1210). The comparative examination of the natural enantiomers of duocarmycin SA (1), duocarmycin A (2), CBI-TMI (3), and CI-TMI (4) revealed that the agents follow a predictable linear relationship between solvolytic chemical stability and cytotoxic activity which spans 3-4 orders of magnitude for the series of agents examined. In contrast, ent-(-)-CBI-TMI, unlike ent-(-)-duocarmycin SA, exhibited less effective DNA alkylation properties (100X) and it proved to be a relatively nonpotent cytotoxic agent (100X). These latter observations are consistent with expectations based on recent models advanced which suggest that the distinguishing behavior of such unnatural enantiomers is the result of destabilizing steric interactions surrounding the duocarmycin C7 center.

  DOI：

  10.1021/ja00097a006

文献信息

• A Unique Class of Duocarmycin and CC-1065 Analogues Subject to Reductive Activation
  作者：Wei Jin、John D. Trzupek、Thomas J. Rayl、Melinda A. Broward、George A. Vielhauer、Scott J. Weir、Inkyu Hwang、Dale L. Boger

  DOI：10.1021/ja075398e

  日期：2007.12.1

  activating such derivatives (tunable N-O bond cleavage) and increasing their sensitivity to the prodrug treatment. Preliminary studies indicate the prodrugs effectively release the free drug in functional cellular assays for cytotoxic activity approaching or matching the activity of the free drug, yet remain essentially stable and unreactive to in vitro DNA alkylation conditions (<0.1-0.01% free drug release)

  据报道，CBI-TMI 和 CBI-indole2 的 N-酰基 O-氨基苯酚衍生物是 Duocarmycin 和 CC-1065 类抗肿瘤剂的一类新的还原活化前药的原型成员。期望低氧肿瘤环境具有更高的还原能力，携带内在更高浓度的“还原性”亲核试剂（例如硫醇），能够激活此类衍生物（可调节的 NO 键裂解）并增加它们对前药治疗的敏感性。初步研究表明，前药在功能细胞试验中有效释放游离药物，细胞毒活性接近或匹配游离药物的活性，但仍保持基本稳定，对体外 DNA 烷基化条件无反应（<0.1-0.01% 游离药物释放）和pH 7.0 磷酸盐缓冲液，并在人血浆中表现出稳定的半衰期 (t1/2 = 3 h)。体内代表性 O-（酰氨基）前药的表征表明它们接近效力并超过游离药物本身（CBI-吲哚2）的功效，表明游离药物不仅能从无活性的前药中有效释放，而且它们提供了与体内受控或靶向释放相关的额外优势。
• Preparation of Benzene, Furan, and Thiophene Analogs of Duocarmycin SA Employing a Newly-Devised Phenol-Forming Reaction.
  作者：Hideaki MURATAKE、Aki HAYAKAWA、Mitsutaka NATSUME

  DOI：10.1248/cpb.48.1558

  日期：——

  route toward duocarmycin SA. The problem encountered at the crucial phenol forming step to secure 17a, b from 16a, b under the conventionally used Kuwajima conditions was overcome by devising a more convenient method: simple heating of 16a-c in benzene in the presence of bis(triphenylphosphine)palladium(II) chloride (10 mol%), cesium carbonate (3 eq), and triphenylphosphine (0.3 eq) gave 17a-c in high

  以消旋形式合成了五种杜卡霉素SA 9a-e的A环类似物，从而改变了我们向杜卡霉素SA的第二条合成路线。通过设计更方便的方法克服了在关键的苯酚形成步骤中从传统的Kuwajima条件下将16a，b中的17a，b固定下来的问题：在双（三苯基膦）钯存在下，简单地在苯中加热16a-c （II）氯化物（10摩尔％），碳酸铯（3当量）和三苯基膦（0.3当量）以高产率86-91％得到17a-c。几乎根据所报道的途径，容易将中间体17a-e引入A环类似物（+/-）-9a-e。
• Synthesis and Evaluation of Duocarmycin and CC-1065 Analogues Containing Modifications in the Subunit Linking Amide
  作者：Dale L. Boger、Alejandro Santillán、Mark Searcey、Qing Jin

  DOI：10.1021/jo990452y

  日期：1999.7.1

  duocarmycins and CC-1065 in which the subunit linking amide has been replaced with an amidine and thioamide, are described. Consistent with the increased electron-withdrawing properties and conjugation of thioamides relative to amides, 7 showed increased solvolysis reactivity (t1/2, 160 h versus 230 h) at pH 3, attributable to a diminished vinylogous amide stabilization of the reacting alkylation subunit. Amidine

  描述了双癌霉素和 CC-1065 的类似物 6 和 7 的制备和评估，其中连接酰胺的亚基已被脒和硫代酰胺取代。与硫代酰胺相对于酰胺增加的吸电子特性和共轭相一致，7 在 pH 3 下显示出增加的溶剂分解反应性（t1/2，160 小时与 230 小时），这归因于反应烷基化亚单元的乙烯基酰胺稳定性减弱。尽管吸电子特性减弱，但脒 6 被证明更不稳定（t1/2，12 小时），但经历了优先 N2 脒键水解而不是烷基化亚基的溶剂分解，这归因于优先 N2 乙烯基酰胺与脒共轭。天然异构体 (+)-6 和 (+)-7 表现出与 (+)-CBI-TMI 和 (+)-duocarmycin SA 相同的 DNA 烷基化选择性，但效率较低 (10-100x)。(+)-6 和 (+)-7（分别为 0.75 和 1.1 nM）的生物学研究表明，这些类似物保留了良好的细胞毒活性 (L1210)，但不如 (+)-duocarmycin
• CBI-TMI: Synthesis and Evaluation of a Key Analog of the Duocarmycins. Validation of a Direct Relationship between Chemical Solvolytic Stability and Cytotoxic Potency and Confirmation of the Structural Features Responsible for the Distinguishing Behavior of Enantiomeric Pairs of Agents
  作者：Dale L. Boger、Weiya Yun

  DOI：10.1021/ja00097a006

  日期：1994.9

  The synthesis of (+)- and ent-(-)-CBI-TMI (3), a key analog of the naturally occurring potent antitumor antibiotics duocarmycin SA (1) and duocarmycin A (2), is disclosed and was facilitated by the development of a general and direct chromatographic resolution of the advanced synthetic intermediate 13 on a preparative Diacel Chiralcel OD HPLC column. The DNA alkylation properties and the cytotoxic activity of (+)- and (-)-CBI-TMI (3) are detailed in conjunction with a comparative study of a key series of duocarmycin SA and A analogs. (+)-CBI-TMI proved to be an effective DNA alkylating agent which exhibited a selectivity and efficiency of DNA alkylation that are not distinguishable from those of (+)-duocarmycin SA (1), and it was found to be an exceptionally potent cytotoxic agent (IC50 = 30 PM, L1210). The comparative examination of the natural enantiomers of duocarmycin SA (1), duocarmycin A (2), CBI-TMI (3), and CI-TMI (4) revealed that the agents follow a predictable linear relationship between solvolytic chemical stability and cytotoxic activity which spans 3-4 orders of magnitude for the series of agents examined. In contrast, ent-(-)-CBI-TMI, unlike ent-(-)-duocarmycin SA, exhibited less effective DNA alkylation properties (100X) and it proved to be a relatively nonpotent cytotoxic agent (100X). These latter observations are consistent with expectations based on recent models advanced which suggest that the distinguishing behavior of such unnatural enantiomers is the result of destabilizing steric interactions surrounding the duocarmycin C7 center.