3-methoxycarbonyl-2-methylduocarmycin A | 153925-97-4

• 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: 3-methoxycarbonyl-2-methylduocarmycin A
• 英文别名: DU-86；1,2,4,5,8,8a-hexahydro-6-methyl-4-oxo-2-((5,6,7-trimethoxy-1H-indol-2-yl)carbonyl)-cyclopropa(c)pyrrolo(3,2-e)indole-7-carboxylic acid methyl ester；methyl (1R,12S)-4-methyl-7-oxo-10-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-5,10-diazatetracyclo[7.4.0.01,12.02,6]trideca-2(6),3,8-triene-3-carboxylate
• CAS: 153925-97-4
• 化学式: C₂₆H₂₅N₃O₇
• 分子量: 491.5
• InChiKey: YTGSKSUJQQNWRS-SRGMZFCMSA-N

物化性质

• 沸点：
  815.5±65.0 °C(Predicted)
• 密度：
  1.50±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  36
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  123
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  3-methoxycarbonyl-2-methylduocarmycin A 在 甲醇 、 氢溴酸 、 sodium methylate 、 sodium hydride 作用下， 以 乙腈 为溶剂， 反应 8.0h， 生成 methyl (8S)-8-(bromomethyl)-6-[(E)-3-[3-(dimethylamino)-4-methoxyphenyl]prop-2-enoyl]-4-hydroxy-2-methyl-7,8-dihydro-3H-pyrrolo[3,2-e]indole-1-carboxylate
  参考文献：
  名称：

  Synthesis and Antitumor Activity of Duocarmycin Derivatives:  A-Ring Pyrrole Compounds Bearing Cinnamoyl Groups

  摘要：

  A series of N-cinnamates of the A-ring pyrrole compound of duocarmycin were synthesized and evaluated for in vitro anticellular activity against HeLa S-3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. The 4'-methoxy- and 4'-BocNH-cinnamates exhibited strong in vitro anticellular activity among the synthesized compounds. The ortho substitution of the 4'-methoxycinnamate did not affect the anticellular activity and contributed to an enhancement of water solubility. Most of the 8-O-(N,N-dialkylcarbamoyl) derivatives of the 4'-methoxycinnamates displayed remarkably superior in vivo antitumor activity to duocarmycin A or B2. Moreover, it is noteworthy that these 8-O-(N,N-dialkylcarbamoyl) derivatives exhibited significant antitumor activity at wider range of doses as compared with the A-ring pyrrole derivatives having the trimethoxyindole skeleton in segment B.

  DOI：

  10.1021/jm9606094
• 作为产物：
  描述：

  methyl (8S)-8-(chloromethyl)-4-hydroxy-2-methyl-6-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-7,8-dihydro-3H-pyrrolo[3,2-e]indole-1-carboxylate 在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 乙腈 为溶剂， 以97%的产率得到3-methoxycarbonyl-2-methylduocarmycin A
  参考文献：
  名称：

  Novel Syntheses of Optically Active CC-1065, U-73,975(Adozelesin), U-80,244(Carzelesin), U-77,779 (Bizelesin), KW-2189, and DU-86

  摘要：

  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.

  DOI：

  10.3987/com-97-7920

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
• Synthesis and antitumor activity of duocarmycin derivatives: modification at C-8 position of A-ring pyrrole compounds bearing the simplified DNA-binding groups
  作者：Nobuyoshi Amishiro、Satoru Nagamura、Chikara Murakata、Akihiko Okamoto、Eiji Kobayashi、Masao Asada、Katsushige Gomi、Tatsuya Tamaoki、Masami Okabe、Naoko Yamaguchi、Kazuo Yamaguchi、Hiromitsu Saito

  DOI：10.1016/s0968-0896(99)00293-x

  日期：2000.2

  A series of the 8-O-substituted A-ring pyrrole derivatives of duocarmycin bearing the simplified DNA-binding moieties such as cinnamoyl or heteroarylacryloyl groups were synthesized, and evaluated for in vitro anticellular activity against HeLa S-3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. In addition, the stability of the 8-O-substituted analogues in aqueous solution and the conversion to their active form (cyclopropane compound) from the 8-O-substituted analogues in mice or human serum were examined. The 8-O-substituted A-ring pyrrole derivatives bearing the simplified DNA-binding moieties showed remarkably potent in vivo antitumor activity and low peripheral blood toxicity compared with the 8-O-substituted A-ring pyrrole derivatives having the trimethoxyindole skeleton in segment-B (Seg-B), which were equal to 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates and 4'-methoxy-beta-heteroarylacrylates. Moreover, among 8-O-substituted analogues, several compounds can be chemically or enzymatically converted to their active form in human serum. This result indicated that new 8-O-substituted derivatives were different prodrugs from KW-2189 and 8-O-substituted analogues being the same type of prodrug as KW-21S9. (C) 2000 Elsevier Science Ltd. All rights reserved.
• Synthesis and antitumor activity of duocarmycin derivatives: A-ring pyrrole analogues of duocarmycin B2
  作者：Satoru Nagamura、Eiji Kobayashi、Katsushige Gomi、Hiromitsu Saito

  DOI：10.1016/0968-0896(96)00132-0

  日期：1996.8

  A series of the eight-substituted A-ring pyrrole derivatives of duocarmycin B2 were synthesized, and evaluated for in vitro anticellular activity against HeLa S-3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. In addition, the stability of the analogues in aqueous solution was examined. The 8-H and the 8-CN compounds which cannot structurally release the cyclopropane compound (DU-86), exhibited extremely diminished anticellular activity compared with duocarmycin A (1a) or DU-86. The ethers and the sulfonates which were not converted to DU-86 under usual conditions (35 degrees C, pH 7), showed almost equal in vivo activities to that of 1a. However, their optimal doses were significantly higher than that for 1a. Most of the A-ring pyrrole analogues which can be chemically or enzymatically converted to DU-86, displayed remarkably superior in vivo antitumor activity to 1a. These results suggest that the A-ring pyrrole analogues need to chemically or enzymatically release DU-86 as an active metabolite to exhibit potent in vivo antitumor activity. Copyright (C) 1996 Elsevier Science Ltd