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

c-Myc is a key driver of tumorigenesis. Repressing the transcription of c-Myc 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 c-Myc G4 ligand 1. Among these compounds, 19a coupled with a d-glucose 1,2-orthoester displayed better c-Myc G4 binding, stabilization, and protein binding disruption abilities than 1. Our further evaluation indicated that 19a blocked c-Myc transcription by targeting the promoter G4, leading to c-Myc-dependent Cancer cell death in triple-negative breast Cancer cell MDA-MB-231. Also, 19a significantly inhibited tumor growth in the MDA-MB-231 mouse xenograft model accompanied by c-Myc downregulation. Notably, the safety of 19a was dramatically improved compared to 1. Our findings indicated that 19a could become a promising Anticancer candidate, which suggested that introducing carbohydrates to improve the G4-targeting and antitumor activity is a feasible option.