Selective stabilization of multiple promoter G-quadruplex DNA by using 2-phenyl-1H-imidazole-based tanshinone IIA derivatives and their potential suppressing function in the metastatic breast cancer
This study demonstrated that Tanshinone IIA based imidazole derivatives could selectively recognize and stabilize various of G-quadruplex DNA, especially for k-ras G-quadruplex DNA, to inhibit the growth of MDA-MB-231 triple negative breast cancer cells in vitro and in vivo through DNA damage mediat...
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Veröffentlicht in: | Bioorganic chemistry 2021-01, Vol.106, p.104433-104433, Article 104433 |
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Sprache: | eng |
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Zusammenfassung: | This study demonstrated that Tanshinone IIA based imidazole derivatives could selectively recognize and stabilize various of G-quadruplex DNA, especially for k-ras G-quadruplex DNA, to inhibit the growth of MDA-MB-231 triple negative breast cancer cells in vitro and in vivo through DNA damage mediated S phase arrest.
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•Designed and synthesized a series of tanshinone IIA derivates containing imidazole ring.•Obtained two single crystal structure of tanshinone IIA derivates.•Selectively recognize and stabilize various G-quadruplex DNA.•Inhibit the metastasis and angiogenesis of TNBC cells in vitro and in vivo.
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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ISSN: | 0045-2068 1090-2120 |
DOI: | 10.1016/j.bioorg.2020.104433 |