fistularin 3 | 87099-50-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: fistularin 3
• 英文别名: 1-Oxa-2-azaspiro(4.5)deca-2,6,8-triene-3-carboxamide, 7,9-dibromo-N-(3-(2,6-dibromo-4-(2-((((5S,10R)-7,9-dibromo-10-hydroxy-8-methoxy-1-oxa-2-azaspiro(4.5)deca-2,6,8-trien-3-yl)carbonyl)amino)-1-hydroxyethyl)phenoxy)-2-hydroxypropyl)-10-hydroxy-8-methoxy-, (5S,10R)-；(5S,6R)-7,9-dibromo-N-[3-[2,6-dibromo-4-[2-[[(5S,6R)-7,9-dibromo-6-hydroxy-8-methoxy-1-oxa-2-azaspiro[4.5]deca-2,7,9-triene-3-carbonyl]amino]-1-hydroxyethyl]phenoxy]-2-hydroxypropyl]-6-hydroxy-8-methoxy-1-oxa-2-azaspiro[4.5]deca-2,7,9-triene-3-carboxamide
• CAS: 87099-50-1
• 化学式: C₃₁H₃₀Br₆N₄O₁₁
• 分子量: 1114.02
• InChiKey: TURTULDFIIAPTC-CJQKJACMSA-N

物化性质

• 密度：
  2.19±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  52
• 可旋转键数：
  12
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  210
• 氢给体数：
  6
• 氢受体数：
  13

制备方法与用途

生物活性

Isofistularin-3 ((+)-11-epi-Fistularin 3) 是一种直接的 DNA 竞争性 DNMT1 抑制剂，IC50 值为 13.5 μM。作为 DNA 去甲基化剂，Isofistularin-3 可诱导肿瘤细胞周期阻滞和 TRAIL 敏感性，并且可以作为抗体偶联药物 (ADC) 的毒素部分。

靶点

靶点	IC50
DNMT1	13.5 μM

靶点	常规细胞毒性剂

体外研究

Isofistularin-3 (1-50 μM; 24-72 小时) 显著减少了细胞增殖。Isofistularin-3 (5-50 μM; 24 小时) 增加了癌细胞在 G0/G1 细胞周期相的阻滞。Isofistularin-3 (25 μM; 72 小时) 提高了 AHR 表达，并诱导 AHR 甲基化去甲基化。Isofistularin-3 (72 小时) 抑制了一系列癌细胞株的增殖，GI50 值范围为 7.3-14.8 μM。Isofistularin-3 引起 RAJI 细胞形态变化和自噬，并诱导了 caspase-依赖性和 -非依赖性细胞死亡。Isofistularin-3 增强了淋巴瘤细胞对 TRAIL 诱导的凋亡敏感性。

细胞增殖实验

实验项目	RAJI 和 U-937 淋巴瘤细胞
浓度 (μM)	1, 5, 15, 25, 50
孵育时间 (小时)	24 和 72
结果	显著减少细胞增殖

细胞周期分析

实验项目	RAJI 和 U-937 细胞
浓度 (μM)	5, 50
孵育时间 (小时)	24
结果	两个细胞系的 G0/G1 相阻滞

RT-PCR

实验项目	RAJI 细胞
浓度 (μM)	25
孵育时间 (小时)	72 h
结果	AHR mRNA 表达水平提高了 5.1 倍

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反应信息

• 作为反应物：
  描述：

  fistularin 3 在 咪唑 、 marine sponge Aplysina aerophoba 作用下， 以 乙醇 为溶剂， 反应 0.66h， 生成
  参考文献：
  名称：

  Wound Activation of Protoxins in Marine Sponge Aplysina aerophoba

  摘要：

  The marine sponge Aplysina aerophoba accumulates brominated isoxazoline alkaloids, which include aerophobin-2, aplysinamisin-1, and isofistularin-3 as major constituents. Following disruption of compartmentalization, the isoxazoline alkaloids are enzymatically converted to aeroplysinin-1, which in rum gives rise to a dienone. The described bioconversions were demonstrated for the first time in vitro using an enzyme preparation from A. aerophoba. Cell-free extracts of other Aplysina species were capable of performing the same bioconversions, whereas enzyme extracts of sponges from other orders, which lack isoxazoline alkaloids, were inactive with regard to the reactions analyzed. These findings suggest that the enzyme activities studied are linked to the accumulation of suitable substrates and hence represent a specific biochemical property of sponges from the genus Aplysina. Time-course experiments with A. aerophoba, performed in situ, demonstrated that wound-induced bioconversions of isoxazoline alkaloids proceeded rapidly. Within 40 sec after mechanical damage of a tube of A. aerophoba, both aerophobin-2 and aplysinamisin-1 were completely converted to the dienone. The wound activation of protoxins results in a pronounced increase of the fish deterrent activity of A. aerophoba as shown in bioassays employing the common Caribbean wrasse Thalassoma bifasciatum.

  DOI：

  10.1023/b:joec.0000006475.10310.3a

文献信息

• Wound Activation of Protoxins in Marine Sponge Aplysina aerophoba
  作者：Rainer Ebel、Marko Brenzinger、Arno Kunze、Hans J. Gross、Peter Proksch

  DOI：10.1023/b:joec.0000006475.10310.3a

  日期：1997.5

  The marine sponge Aplysina aerophoba accumulates brominated isoxazoline alkaloids, which include aerophobin-2, aplysinamisin-1, and isofistularin-3 as major constituents. Following disruption of compartmentalization, the isoxazoline alkaloids are enzymatically converted to aeroplysinin-1, which in rum gives rise to a dienone. The described bioconversions were demonstrated for the first time in vitro using an enzyme preparation from A. aerophoba. Cell-free extracts of other Aplysina species were capable of performing the same bioconversions, whereas enzyme extracts of sponges from other orders, which lack isoxazoline alkaloids, were inactive with regard to the reactions analyzed. These findings suggest that the enzyme activities studied are linked to the accumulation of suitable substrates and hence represent a specific biochemical property of sponges from the genus Aplysina. Time-course experiments with A. aerophoba, performed in situ, demonstrated that wound-induced bioconversions of isoxazoline alkaloids proceeded rapidly. Within 40 sec after mechanical damage of a tube of A. aerophoba, both aerophobin-2 and aplysinamisin-1 were completely converted to the dienone. The wound activation of protoxins results in a pronounced increase of the fish deterrent activity of A. aerophoba as shown in bioassays employing the common Caribbean wrasse Thalassoma bifasciatum.