Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 65, Issue 19, Pages 12675-12700Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c00467
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Funding
- National Natural Science Foundation of China [81872732, 81973184, 81930098]
- Outstanding Talents of Guangdong Special Plan [2019JC05Y456]
- Guangdong Basic and Applied Basic Research Foundation [2019B151502015, 2021A1515010059]
- Fundamental Research Funds for the Central Universities [20ykzd16]
- 111 Project [B16047]
- Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program [2017BT01Y093]
- Ministry of Education of China [IRT-17R111]
- Guangdong Provincial Key Laboratory of Construction Foundation [2020B1212060034]
- Natural Science Foundation of Guangdong Province [2017A030308003]
- China Postdoctoral Science Foundation [2020 M683143]
- Fundamental Research Funds for the Central Universities, Sun Yat-sen University [22qntd4512]
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Research suggests that drugs targeting G4 structures and improving anti-tumor activity through the introduction of carbohydrates could be a promising option for cancer treatment.
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.
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