库库森二烯的总合成和目标鉴定
Chengsen Cui1, Brendan G Dwyer2, Chang Liu1
1Department of Chemistry and Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States.
Journal of the American Chemical Society
|March 11, 2021
概括
研究人员首次实现了曲二烯的全合成,并确定了与BRCA1相关的ATM激活剂1 (BRAT1) 作为关键的抗癌点. 库库松D抑制BRAT1,影响DNA损伤反应和癌细胞迁移.
科学领域:
- 自然产品合成
- 医学化学
- 化学生物学
背景情况:
- 库库松二烯具有独特的 [6-7-5] 三环骨架,并表现出强大的抗癌活性.
- 在本研究之前,库库森的总合成和抗癌机制仍未被探索.
研究的目的:
- 为了实现第一个全合成的curcusone天然产品.
- 为了阐明抗癌作用模式,并确定curcusones的细胞点.
主要方法:
- 采用热[3,3]-信号转移和FeCl3-促进级联反应的融合合成.
- 化学蛋白质组使用基标记探针来识别蛋白质目标.
- 在体外测试以评估素D对BRAT1活性和癌细胞表型的功能影响.
主要成果:
- 在9-12个步骤中实现了curcusone A,B,C,D和dimericursone A的第一次总合成.
- 鉴定BRCA1相关的ATM激活剂1 (BRAT1) 作为curcusone D的直接细胞标.
- 库库松D抑制了BRAT1,导致DNA损伤反应受损,癌细胞迁移减少,并增强了埃托的疗效.
结论:
- 该研究提供了复杂的素二烯的高效合成途径,并验证了它们的拟议生物合成途径.
- BRAT1被确定为一种新的,可用药物治疗的基于curcusone的抗癌疗法.
- 库库松D对BRAT1的抑制为癌症治疗提供了新的策略,特别是在组合疗法中.
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