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Abstract
SummaryC2, 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.
Highlights
Modern drug discovery still requires tremendous resources and efforts
Developing concise, efficient, and selective synthetic methodologies, somehow, can contribute to solve such a challenge by providing precise and useful molecule-editing tools, which enable medicinal chemists to quickly assemble drug-like small molecule libraries with broader chemical space and accelerate SAR (Structure-Activities Relationship) studies (Dugger et al, 2017; Bostrom et al, 2018; Campos et al, 2019)
Compound 13-1 showed only a moderate inhibition rate in K562 cell. These results showed that our products could serve a good starting point for anticancer drug discovery
Summary
Modern drug discovery still requires tremendous resources and efforts. The chance from target validation to drug approval still remains very low (
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