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- Title
5-Hydroxyindole-Based EZH2 Inhibitors Assembled via TCCA-Catalyzed Condensation and Nenitzescu Reactions.
- Authors
Du, Fangyu; Zhou, Qifan; Sun, Wenjiao; Yang, Cheng; Wu, Chunfu; Wang, Lihui; Chen, Guoliang
- Abstract
5-Hydroxyindole derivatives have various demonstrated biological activities. Herein, we used 5-hydroxyindole as a synthetic starting point for structural alterations in a combinatorial process to synthesize 22 different compounds with EZH2 inhibitor pharmacophores. A series of 5-hydroxyindole-derived compounds were screened inhibitory activities against K562 cells. According to molecular modeling and in vitro biological activity assays, the preliminary structure-activity relationship was summarized. Compound L–04 improved both the H3K27Me3 reduction and antiproliferation parameters (IC50 = 52.6 μM). These findings revealed that compound L–04 is worthy of consideration as a lead compound to design more potent EZH2 inhibitors. During the preparation of compounds, we discovered that trichloroisocyanuric acid (TCCA) is a novel catalyst which demonstrates condensation-promoting effects. To gain insight into the reaction, in situ React IR technology was used to confirm the reactivity. Different amines were condensed in high yields with β-diketones or β-ketoesters in the presence of TCCA to afford the corresponding products in a short time (10~20 min), which displayed some advantages and provided an alternative condensation strategy.
- Subjects
CONDENSATION reactions; BIOLOGICAL assay; STRUCTURE-activity relationships; MOLECULAR models; LEAD compounds
- Publication
Molecules, 2020, Vol 25, Issue 9, p2059
- ISSN
1420-3049
- Publication type
Article
- DOI
10.3390/molecules25092059