methyl (1S)-1-(bromomethyl)-7-methyl-5-[(4-methylpiperazinyl)carbonyloxy]-3-[(5,6,7-trimethoxy-2-indolyl)-carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-8-carboxylate | 154889-68-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: methyl (1S)-1-(bromomethyl)-7-methyl-5-[(4-methylpiperazinyl)carbonyloxy]-3-[(5,6,7-trimethoxy-2-indolyl)-carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-8-carboxylate
• 英文别名: 3-methoxycarbonyl-2-methyl-8-O-(4-methyl-1-piperazinylcarbonyl)duocarmycin B2；KW-2189；Pibrozelesin；methyl (8S)-8-(bromomethyl)-2-methyl-4-(4-methylpiperazine-1-carbonyl)oxy-6-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-7,8-dihydro-3H-pyrrolo[3,2-e]indole-1-carboxylate
• CAS: 154889-68-6
• 化学式: C₃₂H₃₆BrN₅O₈
• 分子量: 698.571
• InChiKey: QRMNENFZDDYDEF-GOSISDBHSA-N

物化性质

• 沸点：
  829.9±65.0 °C(Predicted)
• 密度：
  1.473±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  46
• 可旋转键数：
  9
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  139
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  methyl (1S)-1-(bromomethyl)-7-methyl-5-[(4-methylpiperazinyl)carbonyloxy]-3-[(5,6,7-trimethoxy-2-indolyl)-carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-8-carboxylate 在 氢溴酸 作用下， 以 甲醇 、 丙酮 为溶剂， 反应 16.0h， 以84%的产率得到methyl (1S)-1-(bromomethyl)-7-methyl-5-[(4-methylpiperazinyl)carbonyloxy]-3-[(5,6,7-trimethoxy-2-indolyl)-carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-8-carboxylatehydrobromide
  参考文献：
  名称：

  Practical Synthesis of the High-Quality Antitumor Agent KW-2189 from Duocarmycin B2 Using a Facile One-Pot Synthesis of an Intermediate

  摘要：

  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.

  DOI：

  10.1021/op980038k
• 作为产物：
  描述：

  methyl (1S,7R)-1-(bromomethyl)-8-hydroxy-7-methyl-5-[(4-methylpiperazinyl)carbonyloxy]-3-[(5,6,7-tri-methoxy-2-indolyl)carbonyl]-1,2,7,8-tetrahydro-3H-pyrrolo[3,2-e]indole-7-carboxylate 在 甲烷磺酸 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 5.0h， 以86%的产率得到methyl (1S)-1-(bromomethyl)-7-methyl-5-[(4-methylpiperazinyl)carbonyloxy]-3-[(5,6,7-trimethoxy-2-indolyl)-carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-8-carboxylate
  参考文献：
  名称：

  Practical Synthesis of the High-Quality Antitumor Agent KW-2189 from Duocarmycin B2 Using a Facile One-Pot Synthesis of an Intermediate

  摘要：

  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.

  DOI：

  10.1021/op980038k

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。
• Wagner-Meerwein Rearrangement of Duocarmycins.
  作者：Satoru NAGAMURA、Yutaka KANDA、Akira ASAI、Eiji KOBAYASHI、Katsushige GOMI、Hiromitsu SAITO

  DOI：10.1248/cpb.44.933

  日期：——

  We found that treatment of the 8-O-protected-3-hydroxy derivatives of duocarmycin B2 (DUMB2, 1c) with camphorsulfonic acid (CSA) in toluene interestingly gave A-ring pyrrole analogs of DUMB2 (1c) in good yields. Their structures were unambiguously elucidated on the basis of NMR and mass spectrometry, and the mechanism was considered to be a Wagner-Meerwein type rearrangement. On the other hand, treatment of the 9-O-protected-3-hydroxy derivatives of duocarmycin B1 (1b) with CSA afforded different rearrangement products. In the case of bulky groups at the 9-O position, such as a tert-butyldimethylsilyl group, normal A-ring pyrrole analogs were obtained. Under the same condition, however, the 9-O-N, N-dimethylcarbamoyl-3-hydroxy compound of 1b gave a spiro compound, which was derived from a 1, 2-shift of the methoxycarbonyl group and a bonding between the C-8 position and the C-2' position. Compounds having a protective group of medium size gave a mixture of the normal rearrangement and the spiro derivative.

  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。
• Antitumor antibiotics: Duocarmycins
  作者：Satoru Nagamura、Hiromitsu Saito

  DOI：10.1007/bf02317808

  日期：1998.12
• A Novel Property of Duocarmycin and Its Analogs for Covalent Reaction with DNA
  作者：Akira Asai、Satoru Nagamura、HIromitsu Saito

  DOI：10.1021/ja00089a004

  日期：1994.5

  For understanding the mechanism of action of antitumor agents and designing new drugs, the DNA alkylating property of duocarmycin (DUM) and its analogues was examined. The thermal depurination products of calf thymus DNA covalently bonded to DUMA were revealed to be not only the DUMA-N3 adenine adduct but also unexpectedly the DUMA-N3 guanine adduct. In addition DUMSA and synthetic analogues, 1 and 2 with higher solvolytic stability, reacted more selectively with N3 adenine than DUMA did. The correlation between electrophilicity of the cyclopropane subunit in the molecule and selectivity to adenine was observed. KW-2189, the synthetic derivative of 1 which has improved in vivo antitumor activity, was designed as a prodrug requiring enzymatic hydrolysis of the carbamoyl moiety, followed by regeneration of 1. Surprisingly we discovered that KW-2189 itself alkylated DNA covalently without release of the carbamoyl moiety. For the mechanism of DNA alkylation by KW-2189, a novel alkylating reaction via the formation of an iminium intermediate 18 without loss of the carbamoyl moiety was proposed.
• Novel Syntheses of Optically Active CC-1065, U-73,975(Adozelesin), U-80,244(Carzelesin), U-77,779 (Bizelesin), KW-2189, and DU-86
  作者：Yasumichi Fukuda、Hirosuke Furuta、Futoshi Shiga、Yoshikazu Asahina、Shiro Terashima

  DOI：10.3987/com-97-7920

  日期：——

  The title syntheses were achieved by the method featuring oxidative cyclization of the enamino esters [(S)-13 and (S)-24] derived from the 5-aminoindoline [(S)-12], acylation with various structural types of indole-2-carboxylic acids, and formation of cyclopropapyrroloindole moieties.