1. Constructing triazole-modified quinazoline derivatives as selective c-MYC G-quadruplex ligands and potent anticancer agents through click chemistry.
- Author
-
Cai, Jiong-Heng, Yang, Dan-Yan, Zhang, Jun-Jie, Tan, Jia-Heng, Huang, Zhi-Shu, and Chen, Shuo-Bin
- Subjects
- *
CLICK chemistry , *QUINAZOLINE , *QUADRUPLEX nucleic acids , *ANTINEOPLASTIC agents , *LIGANDS (Chemistry) , *PROMOTERS (Genetics) - Abstract
[Display omitted] • A new triazole-modified quinazoline derivatives were developed as c-MYC G4 ligands through Click Chemistry. • Compound A6 exhibited high selectivity in stabilizing c-MYC G4 and in suppressing G4-related c-MYC transcription. • Our findings identify a potent anticancer agent and provide new insights for optimizing c-MYC G4-targeting ligands. c-MYC is a hallmark of various cancers, playing a critical role in promoting tumorigenesis. The formation of G-quadruplex (G4) in the c-MYC promoter region significantly suppresses its expression. Therefore, developing small-molecule ligands to stabilize c-MYC G4 formation and subsequentially suppress c-MYC expression is an attractive topic for c-MYC -driven cancer therapy. However, achieving selective ligands for c-MYC G4 poses challenges. In this study, we developed a series of triazole-modified quinazoline (TMQ) derivatives as potential c-MYC G4 ligands and c-MYC transcription inhibitors from 4-anilinoquinazoline lead 7a using click chemistry. Importantly, the c-MYC G4 stabilizing ability and antiproliferation activity were well correlated among these new derivatives, particularly in the c-MYC highly expressed colorectal cancer cell line HCT116. Among them, compound A6 exhibited good selectivity in stabilizing c-MYC G4 and in suppressing c-MYC transcription better than 7a. This compound induced G4 formation, selectively inhibited G4-related c-MYC transcription and suppressed the progression of HCT116 cells. These findings identify a new c-MYC transcription inhibitor and provide new insights for optimizing c-MYC G4-targeting ligands. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF