8-O-tert-butyldimethylsilyl-2-methylduocarmycin B2 | 183240-29-1

• 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: 8-O-tert-butyldimethylsilyl-2-methylduocarmycin B2
• 英文别名: 8-O-(tert-butyldimethylsilyl)-2-methyl-A-ring-pyrrole-duocarmyicin B2；[(8S)-8-(bromomethyl)-4-[tert-butyl(dimethyl)silyl]oxy-2-methyl-7,8-dihydro-3H-pyrrolo[3,2-e]indol-6-yl]-(5,6,7-trimethoxy-1H-indol-2-yl)methanone
• CAS: 183240-29-1
• 化学式: C₃₀H₃₈BrN₃O₅Si
• 分子量: 628.638
• InChiKey: UXQQBRATMCYWBP-GOSISDBHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.51
• 重原子数：
  40.0
• 可旋转键数：
  7.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  88.81
• 氢给体数：
  2.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  8-O-tert-butyldimethylsilyl-2-methylduocarmycin B2 在 N-氯代丁二酰亚胺 、 四丁基氟化铵 、 sodium methylate 、 silica gel 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.58h， 生成 (1R,12S)-3-chloro-10-[(E)-3-(4-methoxyphenyl)prop-2-enoyl]-4-methyl-5,10-diazatetracyclo[7.4.0.01,12.02,6]trideca-2(6),3,8-trien-7-one
  参考文献：
  名称：

  Synthesis and Antitumor Activity of Duocarmycin Derivatives:  Modification of Segment-A of A-Ring Pyrrole Compounds

  摘要：

  A series of S-substituted A-ring pyrrole compounds 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. These compounds were evaluated on the peripheral blood toxicity and delayed lethal toxicity. Further, to expand our investigation of their peripheral blood toxicity, the toxicity to bone marrow cells (CFU-GM, CFU-Meg) was investigated. Among S-substituted A-ring pyrrole compounds of duocarmycin bearing a 5',6',7'-trimethoxy-2'-indolecarboxyl group as segment-B (Seg-B), several analogues showed remarkably potent antitumor activity with low peripheral blood toxicity. The 3-formyl compound 12h, one of such analogues, showed stronger antitumor activity with lower toxicity to bone marrow cells compared to DU-86 (2a), an active metabolite of KW-2189 (2b). However, compound 12h caused delayed death. On the other hand, the 3-bromo compound 15f, one of the 3-substituted A-ring pyrrole derivatives bearing a 4'-methoxycinnamoyl group as Seg-B, showed the most potent antitumor activity among the 4'-methoxycinnamate analogues with low toxicity to bone marrow cells. Furthermore, compound 15f did not cause delayed death similarly to 2d. These results would indicate the importance of the C-3 substituents of A-ring pyrrole duocarmycin derivatives for exhibiting antitumor activity and decreasing toxicity.

  DOI：

  10.1021/jm990094r
• 作为产物：
  描述：

  8-O-(tert-butyldimethylsilyl)-2-methyl-3-carboxy-A-ring-pyrrole-duocarmicyn B2 在 溴苯 作用下， 反应 10.0h， 以60%的产率得到8-O-tert-butyldimethylsilyl-2-methylduocarmycin B2
  参考文献：
  名称：

  Synthesis and Antitumor Activity of Duocarmycin Derivatives:  Modification of Segment-A of A-Ring Pyrrole Compounds

  摘要：

  A series of S-substituted A-ring pyrrole compounds 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. These compounds were evaluated on the peripheral blood toxicity and delayed lethal toxicity. Further, to expand our investigation of their peripheral blood toxicity, the toxicity to bone marrow cells (CFU-GM, CFU-Meg) was investigated. Among S-substituted A-ring pyrrole compounds of duocarmycin bearing a 5',6',7'-trimethoxy-2'-indolecarboxyl group as segment-B (Seg-B), several analogues showed remarkably potent antitumor activity with low peripheral blood toxicity. The 3-formyl compound 12h, one of such analogues, showed stronger antitumor activity with lower toxicity to bone marrow cells compared to DU-86 (2a), an active metabolite of KW-2189 (2b). However, compound 12h caused delayed death. On the other hand, the 3-bromo compound 15f, one of the 3-substituted A-ring pyrrole derivatives bearing a 4'-methoxycinnamoyl group as Seg-B, showed the most potent antitumor activity among the 4'-methoxycinnamate analogues with low toxicity to bone marrow cells. Furthermore, compound 15f did not cause delayed death similarly to 2d. These results would indicate the importance of the C-3 substituents of A-ring pyrrole duocarmycin derivatives for exhibiting antitumor activity and decreasing toxicity.

  DOI：

  10.1021/jm990094r

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

  DOI：10.1007/bf02317808

  日期：1998.12