Design, Synthesis, and Evaluation of New Sugar-Substituted Imidazole Derivatives as Selective Transcription Repressors Targeting the Promoter G-Quadruplex.

is a key driver of tumorigenesis. Repressing the transcription of by stabilizing the G-quadruplex (G4) structure with small molecules is a potential strategy for cancer therapy. Herein, we designed and synthesized 49 new derivatives by introducing carbohydrates to our previously developed G4 ligand . Among these compounds, coupled with a d-glucose 1,2-orthoester displayed better G4 binding, stabilization, and protein binding disruption abilities than . Our further evaluation indicated that blocked transcription by targeting the promoter G4, leading to -dependent cancer cell death in triple-negative breast cancer cell MDA-MB-231. Also, significantly inhibited tumor growth in the MDA-MB-231 mouse xenograft model accompanied by downregulation. Notably, the safety of was dramatically improved compared to . Our findings indicated that could become a promising anticancer candidate, which suggested that introducing carbohydrates to improve the G4-targeting and antitumor activity is a feasible option.