Anticancer Molecule Discovery via C2-Substituentvia C2-Substituent Promoted Oxidative Coupling of Indole and Enolate
Anticancer Molecule Discovery via C2-Substituentvia C2-Substituent Promoted Oxidative Coupling of Indole and Enolate
复制标题
基于二维材料的机械传感器：传感机制、结构设计和可穿戴应用
作者：
Lu Helin;Zhu Guirong;Tang Tiange;Ma Zhuang;Chen Qin;Chen Zhilong
C2，C3-二取代吲哚是生物活性生物碱和药物化学中最常见的基序之一。因此，开发新的，简洁的，有效的访问它是非常需要的药物发现。在此，我们提出了这样一种方法，通过直接氧化偶联C2-取代的吲哚和烯醇化物的这种支架。与不含C2-取代基的吲哚相比，大多数情况下C2-取代吲哚的产率可达96%以上。反应机理研究表明，吲哚上的C2-取代基通过两种途径促进了反应的进行：（1）稳定C2-自由基中间体;（2）减少吲哚的同偶联。该方法为快速构建具有生物活性的C2，C3-二取代吲哚类化合物小分子库提供了一种有效的合成工具，并且有几种化合物显示出很好的抗癌活性。此外，吲哚美辛及其类似物的三步合成方法简便、高效，显示了该方法在药物化学中的潜在应用。
C2, C3-disubstituted indole is one of the most frequently encountered motifs in bioactive alkaloids and medicinal chemistry. Thus, developing novel, concise, and efficient access to it is highly desired in drug discovery. Herein, we present such an approach to this scaffold by direct oxidative coupling of C2-substituted indoles and enolates. Compared with indole bearing no C2-substituent, higher yields (up to 96%) were obtained for C2-substituted indoles in most cases. Mechanistic studies showed the reaction went through a Fe-chelated radical-anion oxidative coupling procedure promoted by C2-substituent on indole by two means: (1) stabilizing C2-radical intermediate during the reaction; (2) reducing indole homocoupling. This approach serves as a synthetic useful tool to quickly build up bioactive small molecule library of C2, C3-disubstituted indoles, and several products showed promising anticancer activities. Besides, indomethacin and its analogs were conveniently prepared in three-step sequence efficiently, indicating the potential application of our approach in medicinal chemistry.