7-demethoxy-6-demethyl-7,7-(ethylenedioxy)-6-methylene-6,7-dihydromitomycin B | 141936-28-9

• 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: 7-demethoxy-6-demethyl-7,7-(ethylenedioxy)-6-methylene-6,7-dihydromitomycin B
• 英文别名: [(4'S,6'S,7'R,8'R)-7'-hydroxy-5'-methyl-12'-methylidene-10',13'-dioxospiro[1,3-dioxolane-2,11'-2,5-diazatetracyclo[7.4.0.02,7.04,6]tridec-1(9)-ene]-8'-yl]methyl carbamate
• CAS: 141936-28-9
• 化学式: C₁₇H₁₉N₃O₇
• 分子量: 377.354
• InChiKey: FOFFWVSUIGJWST-QOMVODDISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.6
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  131
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  7-demethoxy-6-demethyl-7,7-(ethylenedioxy)-6-methylene-6,7-dihydromitomycin B 在 copper(l) iodide 、 potassium carbonate 作用下， 以 四氢呋喃 、 乙醚 为溶剂， 反应 3.5h， 生成 (4S,6S,7R,8R)-7-hydroxy-8-(hydroxymethyl)-11-methoxy-5-methyl-12-(2-methylpropyl)-2,5-diazatetracyclo[7.4.0.02,7.04,6]trideca-1(9),11-diene-10,13-dione
  参考文献：
  名称：

  Synthesis and Antitumor Activity of Novel 6-Alkyl-6-demethylmitomycins

  摘要：

  A series of 6-alkyl-6-demethylmitomycins (1-5) was synthesized and evaluated for anticellular and antitumor activities. These novel compounds were prepared by Michael addition of various carbanion species to 6-demethyl-7,7-(ethylenedioxy)-6,7-dihydro-6-methylidenemitosane (6 and 9) followed by treatment with NH3 or MeOH/K2CO3. Alkylation at the C-6 position of 6-demethyl-6-selenide (7) was also useful for the alternative synthesis of 6-alkyl-6-demethylmitomycins. The antitumor activity of these derivatives was evalulated, and 6-demethyl-6-ethylmitomycin A (2a) was found to exhibit excellent activity against S-180 solid tumor in mice. The structure-activity relationship is also discussed.

  DOI：

  10.1021/jm00038a009
• 作为产物：
  描述：

  [(4'S,6'S,7'R,8'R)-7'-hydroxy-5',12'-dimethyl-10',13'-dioxo-12'-phenylselanylspiro[1,3-dioxolane-2,11'-2,5-diazatetracyclo[7.4.0.02,7.04,6]tridec-1(9)-ene]-8'-yl]methyl carbamate 在 吡啶 、 间氯过氧苯甲酸 作用下， 以 氯仿 为溶剂， 反应 0.5h， 生成 7-demethoxy-6-demethyl-7,7-(ethylenedioxy)-6-methylene-6,7-dihydromitomycin B
  参考文献：
  名称：

  新型的丝裂霉素衍生物的合成及其抗肿瘤活性，所述丝裂霉素衍生物在C-6-甲基位置含有官能团。

  摘要：

  合成了一系列C-6取代的甲基丝裂霉素，并评估了其抗细胞和抗肿瘤活性。这些新颖的化合物是通过将各种醇或硫醇迈克尔加成至6-去甲基-7,7-（乙二氧基）-6,7-二氢-6-亚甲基亚神经松脂中，然后用NH3或MeOH / K2CO3处理而制备的。大多数化合物对HeLa S3均有效，其中一些化合物对小鼠的P388白血病和肉瘤180显示出优于丝裂霉素C（MMC）的活性。此外，某些化合物对小鼠的MMM耐药P388表现出显着活性。这些丝裂霉素衍生物的FAB-MS光谱表明，从丝裂霉素骨架上消除了C-6-甲基取代基，从而形成了醌甲基化物。有趣的是 用二乙胺处理6-去甲基-6-[[[（2-嘧啶基）硫代]甲基]丝裂霉素C（12v）得到6-脱甲基-6-[[（二乙氨基）甲基]丝裂霉素C（31），收率高。这些结果表明，C-6取代的甲基丝裂霉素将具有与MMC不同的生物学特性。

  DOI：

  10.1021/jm00038a008

文献信息

• Synthesis and Antitumor Activity of Novel Mitomycin Derivatives Containing Functional Groups at the C-6-Methyl Position
  作者：Hitoshi Arai、Yutaka Kanda、Tadashi Ashizawa、Makoto Morimoto、Katsushige Gomi、Motomichi Kono、Masaji Kasai

  DOI：10.1021/jm00038a008

  日期：1994.6

  compounds exhibited remarkable activity against MMC-resistant P388 in mice. FAB-MS spectra of these mitomycin derivatives showed the elimination of the C-6-methyl substituents from the mitomycin skeletons to form quinonemethides. Interestingly, treatment of 6-demethyl-6-[[(2-pyrimidinyl)thio]methyl ]mitomycin C (12v) with diethylamine afforded 6-demethyl-6-[(diethylamino)methyl]mitomycin C (31) in good

  合成了一系列C-6取代的甲基丝裂霉素，并评估了其抗细胞和抗肿瘤活性。这些新颖的化合物是通过将各种醇或硫醇迈克尔加成至6-去甲基-7,7-（乙二氧基）-6,7-二氢-6-亚甲基亚神经松脂中，然后用NH3或MeOH / K2CO3处理而制备的。大多数化合物对HeLa S3均有效，其中一些化合物对小鼠的P388白血病和肉瘤180显示出优于丝裂霉素C（MMC）的活性。此外，某些化合物对小鼠的MMM耐药P388表现出显着活性。这些丝裂霉素衍生物的FAB-MS光谱表明，从丝裂霉素骨架上消除了C-6-甲基取代基，从而形成了醌甲基化物。有趣的是 用二乙胺处理6-去甲基-6-[[[（2-嘧啶基）硫代]甲基]丝裂霉素C（12v）得到6-脱甲基-6-[[（二乙氨基）甲基]丝裂霉素C（31），收率高。这些结果表明，C-6取代的甲基丝裂霉素将具有与MMC不同的生物学特性。
• Mitomycin derivatives having unique condensed-ring structures. Their synthesis and antitumor activity.
  作者：HITOSHI ARAI、YUTAKA KANDA、TADASHI ASHIZAWA、MAKOTO MORIMOTO、KATSUSHIGE GOMI、MOTOMICHI KONO、MASAJI KASAI

  DOI：10.7164/antibiotics.47.1312

  日期：——

  A series of mitomycin derivatives 1-3 having unique condensed-ring structures was synthesized and evaluated for their anticellular and antitumor activity. These compounds were synthesized by the Michael addition of 1.3-dicarbonyl compounds to 6-demethyl-7,7-(ethylenedioxy)-6,7-dihydro-6-methylenemitosanes (4-6, and 14) and the subsequent cyclization. For the preparation of 1. the allyloxycarbonyl (Aloc)

  合成了一系列具有独特的稠环结构的丝裂霉素衍生物1-3，并评估了它们的抗细胞和抗肿瘤活性。这些化合物是通过将1.3-二羰基化合物迈克尔加成至6-去甲基-7,7-（亚乙二氧基）-6,7-二氢-6-亚甲基二氢呋喃酮（4-6和14）并随后环化而合成的。为了制备1.烯丙氧基羰基（Aloc）基团可用于保护氮丙啶（1a-NH），因为在温和的条件下用Pd（0）和HCO 2 H-NEt 3进行脱保护时，底物没有分解。在这些结构独特的衍生物中，化合物1a，1b，1d和1e对小鼠的HeLa S3人肿瘤细胞和肉瘤180实体瘤非常有效。
• Synthesis and Antitumor Activity of Novel 6-Alkyl-6-demethylmitomycins
  作者：Hitoshi Arai、Yutaka Kanda、Tadashi Ashizawa、Makoto Morimoto、Katsushige Gomi、Motomichi Kono、Masaji Kasai

  DOI：10.1021/jm00038a009

  日期：1994.6

  A series of 6-alkyl-6-demethylmitomycins (1-5) was synthesized and evaluated for anticellular and antitumor activities. These novel compounds were prepared by Michael addition of various carbanion species to 6-demethyl-7,7-(ethylenedioxy)-6,7-dihydro-6-methylidenemitosane (6 and 9) followed by treatment with NH3 or MeOH/K2CO3. Alkylation at the C-6 position of 6-demethyl-6-selenide (7) was also useful for the alternative synthesis of 6-alkyl-6-demethylmitomycins. The antitumor activity of these derivatives was evalulated, and 6-demethyl-6-ethylmitomycin A (2a) was found to exhibit excellent activity against S-180 solid tumor in mice. The structure-activity relationship is also discussed.
• Synthesis and Antitumor Activity of Various 6-Demethylmitomycins and 6-Demethyl-6-halomitomycins
  作者：Hitoshi Arai、Tadashi Ashizawa、Katsushige Gomi、Motomichi Kono、Hiromitsu Saito、Masaji Kasai

  DOI：10.1021/jm00016a005

  日期：1995.8

  A series of 6-demethylmitomycins and 6-demethyl-6-halomitomycins having various mitomycin skeletons were synthesized, taking into account the electronic effect toward the quinone moiety and the partition coefficients. Treatment of enones 15 and 16 with selenenamide or N-halosuccinimide-Et(2)NH afforded the 6-demethyl intermediates 17, 18, and 21-24 via the tandem Michael addition/retro-Mannich reaction sequence. Subsequent conversions into the mitomycin skeletons resulted in the formation of the desired derivatives 7a-c, 8a-c, 11a-c, and 12a,b. These mitomycin derivatives including 3a-c and 4a-c were evaluated for their anticellular activity against HeLa S-3 cells and antitumor activity against Sarcoma 180 in mice. The anticellular activity of 1 and 3a-c depends on the substituent at the C-6 position and the order of increasing activity is H < CH3 < Br < Cl. A similar tendency was observed in their antitumor potency (ED(50)) The activities of 9 and 11a-c also follow a pattern similar to that of 1 and 3a-c. Compounds 4b,c, 8b,c, and 12b having both a halogen at the C-6 position and a methoxy group at the C-7 position did not show the activities because of the instability of the compounds. Interestingly, a correlation between the anticellular activity (IC50) and the partition coefficients (log k') determined by HPLC was observed within the compounds studied except the unstable compounds, while their antitumor activity (ED(50) or T/C) did not correlate with the quinone reduction potential (E(1/2)). These results would indicate the importance of the C-6 substituents and the mitomycin skeletons for exhibiting both anticellular and antitumor activities.