罕见的亚比斯类生物的总合成,生物评估和目标鉴定
Dexter C Davis1, Dominic G Hoch2, Li Wu3
1Department of Chemistry, Center for Cancer Research and Institute for Drug Discovery , Purdue University , West Lafayette , Indiana 47907 , United States.
Journal of the American Chemical Society
|November 22, 2018
概括
研究人员从临灭绝的中国树中合成了Abies的化物,验证了弱蛋白质氨酸酸酶1B的抑制,并确定了针对SHP2的新类型. 他们发现DNA聚合酶epsilon子单元3 (POLE3) 是癌症治疗的新目标.
科学领域:
- 自然产品合成
- 医学化学
- 化学生物学
背景情况:
- 贝珊津 C 和 D 是从临灭绝的中国 (Abies beshanzuensis) 中分离出来的Abies .
- 这些化合物对蛋白质氨酸酸酶1B (PTP1B) 的抑制活性较弱.
研究的目的:
- 为了实现第一个AbiespirosideA,贝尚烯C和贝尚烯D的完全合成.
- 探索这些合成化合物及其类型的生物活动.
- 识别这些Abies的新细胞标.
主要方法:
- 使用 (+) - 卡作为基质池的起始材料的总合成.
- 催化碳酸乳化和德雷丁-施密特反应用于构建关键结构图案.
- 用于化学蛋白质目标识别的化物标记探针分子的开发.
主要成果:
- 已经成功地合成了Abies的三基.
- 证实了贝尚烯C的弱PTP1B抑制活性.
- 鉴定具有强大和选择性的SHP2抑制活性的合成类型.
- 发现DNA聚合酶epsilon子单元3 (POLE3) 作为一种新的细胞标.
- 证明POLE3无活化增强了对DNA损伤剂的化学敏感性.
结论:
- 总合成提供了有价值的阿比斯和它们的类似物.
- 用小分子准POLE3代表了癌症治疗的潜在新策略,特别是化学敏感化.
- 这些发现为开发基于POLE3抑制的新型癌症疗法开辟了道路.
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