(2R,8S)-8-(溴甲基)-4-羟基-2-甲基-1-氧代-6-(5,6,7-三甲氧基1h-吲哚-2-羰基)-7,8-二氢-3H-吡咯并[3,2-e]吲哚-2-羧酸甲酯 | 124325-94-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: (2R,8S)-8-(溴甲基)-4-羟基-2-甲基-1-氧代-6-(5,6,7-三甲氧基1h-吲哚-2-羰基)-7,8-二氢-3H-吡咯并[3,2-e]吲哚-2-羧酸甲酯
• 中文别名: 1,1,1-乙三甲腈,2,2,2-三氨基-
• 英文名称: duocarmycin B2
• 英文别名: duocarmycinB2；DUMB2；DC-89B2；methyl (2R,8S)-8-(bromomethyl)-4-hydroxy-2-methyl-1-oxo-6-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-7,8-dihydro-3H-pyrrolo[3,2-e]indole-2-carboxylate
• CAS: 124325-94-6
• 化学式: C₂₆H₂₆BrN₃O₈
• 分子量: 588.412
• InChiKey: UQPQXFUURNIVNJ-MZHQLVBMSA-N

物化性质

• 沸点：
  777.2±60.0 °C(Predicted)
• 密度：
  1.542±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  38
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  139
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (2R,8S)-8-(溴甲基)-4-羟基-2-甲基-1-氧代-6-(5,6,7-三甲氧基1h-吲哚-2-羰基)-7,8-二氢-3H-吡咯并[3,2-e]吲哚-2-羧酸甲酯 在 咪唑 、 sodium tetrahydroborate 、 camphor-10-sulfonic acid 作用下， 以 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 8.0h， 生成 3-methoxycarbonyl-2-methylduocarmycin A
  参考文献：
  名称：

  Wagner-Meerwein Rearrangement of Duocarmycins.

  摘要：

  我们发现，在甲苯中，使用樟脑磺酸（CSA）处理8-O保护的3-羟基衍生物DUMB2（1c）时，有意思的是以良好产率得到了DUMB2（1c）的A环吡咯类似物。它们的结构根据核磁共振（NMR）和质谱明确阐明，并且认为其机制是瓦格纳-迈尔外因重排。另一方面，使用CSA处理9-O保护的3-羟基衍生物DUMB1（1b）则得到了不同的重排产物。在9-O位置有较大的基团，如叔丁基二甲基硅基团的情况下，得到了正常的A环吡咯类似物。然而，在相同条件下，9-O-N,N-二甲基氨基甲酰基-3-羟基化合物1b生成了螺环化合物，这是由甲氧羰基的1,2-移位以及C-8位置与C-2'位置之间的键合得来的。具有中等大小保护基团的化合物得到了正常的重排产物与螺环衍生物的混合物。

  DOI：

  10.1248/cpb.44.933
• 作为产物：
  描述：

  倍癌霉素A 在 potassium bromide 作用下， 以 丙酮 为溶剂， 反应 12.0h， 以17%的产率得到(2R,7R,8S)-8-溴-4-羟基-7-甲基-1-氧代-6-(5,6,7-三甲氧基1h-吲哚-2-羰基)-3,7,8,9-四氢-2H-吡啶并[3,2-e]吲哚-2-羧酸甲酯
  参考文献：
  名称：

  Duocarmycins，链霉菌属（Streptomyces sp。）生产的有效抗肿瘤抗生素。结构和化学。

  摘要：

  从三个独立收集的链霉菌属菌种中分离出七种新型强效抗肿瘤抗生素，杜卡霉素A（1），C1（2），C2（3），D（4），B1（5），B2（6）和SA（7）。 。完整的结构，包括绝对的立体化学，是通过对那些杜卡霉素和几种衍生物的光谱和化学研究确定的。Duocarmycins A（1）和SA（7）具有1,2,7,7a-四氢环丙[1,2-c]吲哚-4-一亚基，这是与链霉菌中CC-1065（10）相同的药效基团zelensis。

  DOI：

  10.1248/cpb.43.378

文献信息

• Synthesis and Antitumor Activity of Duocarmycin Derivatives: Modification of Segment A of Duocarmycin B2.
  作者：Satoru NAGAMURA、Akira ASAI、Yutaka KANDA、Eiji KOBAYASHI、Katsushige GOMI、Hiromitsu SAITO

  DOI：10.1248/cpb.44.1723

  日期：——

  Several A-ring pyrrole derivatives of duocarmycin B2 were synthesized effectively from the 3-hydroxy compounds by utilizing an interesting acid-catalyzed rearrangement, their anticellular activity was preliminarily evaluated by assays of growth inhibition of HeLa S3 cells (in vitro) and antitumor activity against murine sarcoma 180 (in vivo). The 8-O-N, N-dialkylcarbamoyl derivatives of the A-ring pyrrole compound showed remarkably potent in vivo antitumor activity, superior to that of duocarmycin B2. These derivatives were subjected to further biological evaluation. They exhibited potent antitumor activity toward murine solid tumors including M5076 sarcoma, B-16 melanoma and Colon 26 adenocarcinoma. Their most noteworthy feature was their efficacy against various human xenografts including LC-6 (lung), St-4 (stomach), and Co-3 (colon).

  通过利用一种有趣的酸催化重排方法，从3-羟基化合物有效地合成了几种A环吡咯衍生的duocarmycin B2类似物，并初步通过HeLa S3细胞（体外）的生长抑制试验和对抗小鼠肉瘤180的抗肿瘤活性（体内）评估了它们的抗细胞活性。A环吡咯化合物的8-O-N,N-二烷基氨基甲酰基衍生物表现出显著的体内抗肿瘤活性，优于duocarmycin B2。这些衍生物接受了进一步的生物学评估。它们对包括M5076肉瘤、B-16黑色素瘤和结肠26腺癌在内的多种小鼠实体瘤显示出强大的抗肿瘤活性。它们最显著的特点是对多种人类异种移植瘤包括LC-6（肺）、St-4（胃）和Co-3（结肠）具有疗效。
• Synthesis and Antitumor Activity of Duocarmycin Derivatives.
  作者：Satoru NAGAMURA、Yutaka KANDA、Eiji KOBAYASHI、Katsushige GOMI、Hiromitsu SAITO

  DOI：10.1248/cpb.43.1530

  日期：——

  A series of duocarmycin B2 dirivatives, modified at the phenolic hydroxyl group to ester, carbonate and carbamate, was synthesized. Antitumor activity of these analogs was preliminarily evaluated by assays of growth inhibition of HeLa S3 cells (in vitro) and antitumor activity against murine sarcoma 180 (in vivo). The stability of the compounds under aqueous conditions was examined, and we found a correlation between antitumor activity in vivo and stability in aqueous solution, that is, the more stable derivatives exhibited higher antitumor activity. Among these derivatives, the N, N-dialkylcarbamoyl analogs exhibited both improved antitumor activity and higher stability compared with duocarmycin B2. These analogs were subjected to further biological evaluation and they expressed broad-spectrum activity toward murine solid tumors M5076, Colon 26 and Colon 38, and human xenografted carcinoma MX-1.

  合成了一系列在酚羟基位置改造为酯、碳酸酯和氨基甲酸酯的双卡霉素B2衍生物。通过对HeLa S3细胞的生长抑制实验（体外）和小鼠肉瘤180的抗肿瘤活性（体内）对这些类似物的抗肿瘤活性进行了初步评估。研究了化合物在水相条件下的稳定性，并发现体内抗肿瘤活性与水溶液中的稳定性之间存在相关性，即稳定性越高的衍生物表现出更强的抗肿瘤活性。在这些衍生物中，N,N-二烷基氨基甲酰基类似物相较于双卡霉素B2展现了更强的抗肿瘤活性和更高的稳定性。对这些类似物进行了进一步的生物评估，结果表明它们对小鼠实性肿瘤M5076、结肠26和结肠38以及人类异种移植癌MX-1均表现出广谱活性。
• Antitumor antibiotics: Duocarmycins
  作者：Satoru Nagamura、Hiromitsu Saito

  DOI：10.1007/bf02317808

  日期：1998.12
• Practical Synthesis of the High-Quality Antitumor Agent KW-2189 from Duocarmycin B2 Using a Facile One-Pot Synthesis of an Intermediate
  作者：Masahiko Kinugawa、Satoru Nagamura、Akihiko Sakaguchi、Yoshiaki Masuda、Hiromitsu Saito、Takehiro Ogasa、Masaji Kasai

  DOI：10.1021/op980038k

  日期：1998.11.1

  A facile and large-scale preparation process of a potent antitumor agent KW-2189 (2), derived from the antitumor antibiotic duocarmycin B2 (1), has been developed, This new synthetic route required three steps: (i) one pot carbamoylation and subsequent reduction, (ii) Wagner-Meerwein rearrangement of the methoxycarbonyl group For the production of the pyrrole compound 6, and (iii) formation of the hydrobromide salt 2. The key strategic improvement was to obtain goad quality hydroxy compound 4 in a reasonable yield without isolation of the unstable keto intermediate 3a, During commercial-scale production at a scale of about 50 g, this strategy provided high-quality KW-2189 (2) in a 55% overall yield from 1. Potential degradation compounds 7-9 were also synthesized and shown to be absent in the KW-2189 (2) prepared.
• Synthesis and antitumor activity of novel duocarmycin derivatives
  作者：Akira Asai、Satoru Nagamura、Eiji Kobayashi、Katushige Gomi、Hiromitsu Saito

  DOI：10.1016/0960-894x(96)00203-x

  日期：1996.6

  A series of Duocarmycin B-2 analogs bearing simplified right hand segments (Seg-Bs) with the protected phenolic hydroxyl group in left hand segment (Seg-A) was synthesized. Among them, the cinnamoyl derivatives 6c and 6d exhibited potent antitumor activity against in vivo murine tumor models in the wider range of doses without detectable toxic effects than DUMB(2). Copyright (C) 1996 Elsevier Science Ltd