Syntheses and Evaluation of New Bisacridine Derivatives for Dual Binding of G-Quadruplex and i-Motif in Regulating Oncogene <i>c-myc</i> Expression

Abstract

The <i>c-myc</i> oncogene is an important regulator for cell growth and differentiation, and its aberrant overexpression is closely related to the occurrence and development of various cancers. Thus, the suppression of <i>c-myc</i> transcription and expression has been investigated for cancer treatment. In this study, various new bisacridine derivatives were synthesized and evaluated for their binding with <i>c-myc</i> promoter G-quadruplex and i-motif. We found that <b>a9</b> could bind to and stabilize both G-quadruplex and i-motif, resulting in the downregulation of <i>c-myc</i> gene transcription. <b>a9</b> could inhibit cancer cell proliferation and induce SiHa cell apoptosis and cycle arrest. <b>a9</b> exhibited tumor growth inhibition activity in a SiHa xenograft tumor model, which might be related to its binding with <i>c-myc</i> promoter G-quadruplex and i-motif. Our results suggested that <b>a9</b> as a dual G-quadruplex/i-motif binder could be effective in both oncogene replication and transcription and become a promising lead compound for further development with improved potency and selectivity.