Journal
BIOORGANIC CHEMISTRY
Volume 106, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2020.104433
Keywords
Tanshinone IIA derivatives; G-quadruplex DNA; DNA damage; Intermolecular interaction; Molecular docking
Funding
- National Natural Science Foundation of China [81572926, 81703349]
- China Postdoctoral Science Foundation [2017M610576]
- Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center [IP-2019-016, 4001013-04, 5001-4001008, 5001-4001007]
- Provincial Major Scientific Research Projects in Universities of Guangdong Province [2014KZDXM053]
- Science and Technology Project of Guangdong Province [2014A020212312]
- Innovation Team Projects in Universities of Guangdong Province [2016KCXTD018]
- Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems [201805010006]
- Key Laboratory of New Drug Discovery and Evaluation of ordinary universities of Guangdong province [2017KSYS002]
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The study shows that tanshinone IIA derivative 4 can induce DNA damage by stabilizing multiple G4 DNAs, inhibiting the growth, metastasis, and angiogenesis of triple-negative breast cancer cells.
The G-quadruplex (G4) DNA, which has been developed as a potential anticancer target in drug screening and design, plays a crucial role in the oncogene transcription and translation. Tanshinone IIA derivatives with a planar heterocycle structure may function as G4 stabilizers. We present an innovative case of imidazole-based tanshinone IIA derivatives (1-8) especially compound 4 that improve the selectivity and the binding affinity with G4 DNA and enhance the target tumor inhibition. Cellular and in vivo experiments indicate that the tanshinone IIA derivative 4 inhibits the growth, metastasis, and angiogenesis of triple-negative breast cancer cells possibly through the stabilization of multiple G4 DNAs (e.g., c-myc, K-ras, and VEGF) to induce DNA damage. Further investigation of the intermolecular interaction and the molecular docking indicates that tanshinone IIA derivatives have better selective binding capability to various G4 DNAs than to double-stranded DNA. These findings provide guidance in modifying the molecular structures of tanshinone IIA derivatives and reveal their potential to function as specific G4 stabilizers.
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