一个关键系列C5替代维布拉斯衍生物的总合成和评估
Porino Va1, Erica L Campbell, William M Robertson
1Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Journal of the American Chemical Society
|June 4, 2010
概括
芬布拉斯衍生物的总合成显示,C5乙基对氨酸结合至关重要. 这种替代剂的修改显著影响模拟活性,一些C5甲基类似物显示出相似的疗效.
科学领域:
- 有机化学 有机化学
- 药用化学 医学化学
- 化学生物学 化学生物学
背景情况:
- 维布拉斯是一种重要的抗癌药物,来自自然来源.
- 了解结构-活动关系是开发改进治疗方法的关键.
- 乙基C5替代剂在维布拉斯疗效中的作用需要详细的研究.
研究的目的:
- 为了合成一系列在C5位置有系统修改的温布拉斯类型.
- 探究C5乙基组的大小,形状和极性对氨酸结合和生物活性的重要性.
主要方法:
- 采用了一个简洁的七到八步总合成策略.
- 关键中间体的组装使用了1,3,4-oxadiazoles的分子内 [4 + 2]/[3 + 2] 循环添加级联.
- 维布拉斯类型通过单步生物模拟合与卡萨兰丁形成.
主要成果:
- 蛋白结合部位对C5位置的修改非常敏感.
- 在C5处的乙基是最佳的活性,性能优于,甲基和替代剂.
- 替代品的形状和极性也极大地影响了活性,与乙基相比,基和基基基团的有效性降低了.
结论:
- C5乙基的存在,大小,形状和极性是维布拉斯类似物活性的关键决定因素.
- 战略性修改,如C5甲基组,可以产生类似物,其活性接近天然产品的活性.
- 这种合成方法为合理设计新型抗癌剂提供了宝贵的见解.
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