Arene Ru(II) Complexes with Difluorinated Ligands Act as Potential Inducers of S-Phase Arrest via the Stabilization of <i>c-myc</i> G-Quadruplex DNA
Here, a series of half-sandwich arene Ru(II) complexes with difluorinated ligands [Ru(<i>η</i><sup>6</sup>-arene)(L)Cl] (<b>L</b><b><sub>1</sub></b> = 2-(2,3-difluorophenyl)imidazole[4,5<i>f</i>][1,10]-phenanthroline; <b>L...
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MDPI AG
2022-03-01
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| Online Access: | https://www.mdpi.com/1420-3049/27/6/1897 |
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| author | Liang Zeng Chanling Yuan Jing Shu Jiayi Qian Qiong Wu Yanhua Chen Ruzhen Wu Xiaoming Ouyang Yuan Li Wenjie Mei |
| author_facet | Liang Zeng Chanling Yuan Jing Shu Jiayi Qian Qiong Wu Yanhua Chen Ruzhen Wu Xiaoming Ouyang Yuan Li Wenjie Mei |
| author_sort | Liang Zeng |
| collection | DOAJ |
| description | Here, a series of half-sandwich arene Ru(II) complexes with difluorinated ligands [Ru(<i>η</i><sup>6</sup>-arene)(L)Cl] (<b>L</b><b><sub>1</sub></b> = 2-(2,3-difluorophenyl)imidazole[4,5<i>f</i>][1,10]-phenanthroline; <b>L</b><b><sub>2</sub></b> = 2-(2,4-difluorophenyl)imidazole[4,5<i>f</i>][1,10]-phenanthroline; arene = benzene, toluene, and <i>p</i>-cymene) were synthesized and characterized. Molecular docking analysis showed that these complexes bind to <i>c-myc</i> G-quadruplex DNA through either groove binding or <i>π</i>–<i>π</i> stacking, and the relative difluorinated site in the main ligand plays a role in regulating the binding mode. The binding behavior of these complexes with <i>c-myc</i> G-quadruplex DNA was evaluated using ultraviolet–visible spectroscopy, fluorescence intercalator displacement assay, fluorescence resonance energy transfer melting assay, and polymerase chain reaction. The comprehensive analysis indicated that complex <b>1</b> exhibited a better affinity and stability in relation to <i>c-myc</i> G-quadruplex DNA with a DC<sub>50</sub> of 6.6 μM and Δ<i>T<sub>m</sub></i> values of 13.09 °C, than other molecules. Further activity evaluation results displayed that this class of complexes can also inhibit the growth of various tumor cells, especially complexes <b>3</b> and <b>6</b>, which exhibited a better inhibitory effect against human U87 glioblastoma cells (51.61 and 23.75 μM) than other complexes, even superior to cisplatin (32.59 μM). Owing to a befitting lipophilicity associated with the high intake of drugs by tumor cells, complexes <b>3</b> and <b>6</b> had favorable lipid-water partition coefficients of −0.6615 and −0.8077, respectively. Moreover, it was found that complex <b>6</b> suppressed the proliferation of U87 cells mainly through an induced obvious S phase arrest and slight apoptosis, which may have resulted from the stabilization of <i>c-myc</i> G-quadruplex DNA to block the transcription and expression of <i>c-myc</i>. In brief, these types of arene Ru(II) complexes with difluorinated ligands can be developed as potential inducers of S-phase arrest and apoptosis through the binding and stabilization of <i>c-myc</i> G-quadruplex DNA, and could be used in clinical applications in the future. |
| first_indexed | 2024-03-09T13:10:56Z |
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| last_indexed | 2024-03-09T13:10:56Z |
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| spelling | doaj.art-c395d4946edb47d28f66b1fe9892f9de2023-11-30T21:42:55ZengMDPI AGMolecules1420-30492022-03-01276189710.3390/molecules27061897Arene Ru(II) Complexes with Difluorinated Ligands Act as Potential Inducers of S-Phase Arrest via the Stabilization of <i>c-myc</i> G-Quadruplex DNALiang Zeng0Chanling Yuan1Jing Shu2Jiayi Qian3Qiong Wu4Yanhua Chen5Ruzhen Wu6Xiaoming Ouyang7Yuan Li8Wenjie Mei9Department of Pathology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, ChinaSchool of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, ChinaSchool of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, ChinaSchool of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, ChinaGuangdong Province Engineering and Technology Centre for Molecular Probe and Biomedicine Imaging, Guangzhou 510006, ChinaSchool of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, ChinaSchool of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, ChinaDepartment of Pathology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, ChinaDepartment of Pathology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, ChinaSchool of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, ChinaHere, a series of half-sandwich arene Ru(II) complexes with difluorinated ligands [Ru(<i>η</i><sup>6</sup>-arene)(L)Cl] (<b>L</b><b><sub>1</sub></b> = 2-(2,3-difluorophenyl)imidazole[4,5<i>f</i>][1,10]-phenanthroline; <b>L</b><b><sub>2</sub></b> = 2-(2,4-difluorophenyl)imidazole[4,5<i>f</i>][1,10]-phenanthroline; arene = benzene, toluene, and <i>p</i>-cymene) were synthesized and characterized. Molecular docking analysis showed that these complexes bind to <i>c-myc</i> G-quadruplex DNA through either groove binding or <i>π</i>–<i>π</i> stacking, and the relative difluorinated site in the main ligand plays a role in regulating the binding mode. The binding behavior of these complexes with <i>c-myc</i> G-quadruplex DNA was evaluated using ultraviolet–visible spectroscopy, fluorescence intercalator displacement assay, fluorescence resonance energy transfer melting assay, and polymerase chain reaction. The comprehensive analysis indicated that complex <b>1</b> exhibited a better affinity and stability in relation to <i>c-myc</i> G-quadruplex DNA with a DC<sub>50</sub> of 6.6 μM and Δ<i>T<sub>m</sub></i> values of 13.09 °C, than other molecules. Further activity evaluation results displayed that this class of complexes can also inhibit the growth of various tumor cells, especially complexes <b>3</b> and <b>6</b>, which exhibited a better inhibitory effect against human U87 glioblastoma cells (51.61 and 23.75 μM) than other complexes, even superior to cisplatin (32.59 μM). Owing to a befitting lipophilicity associated with the high intake of drugs by tumor cells, complexes <b>3</b> and <b>6</b> had favorable lipid-water partition coefficients of −0.6615 and −0.8077, respectively. Moreover, it was found that complex <b>6</b> suppressed the proliferation of U87 cells mainly through an induced obvious S phase arrest and slight apoptosis, which may have resulted from the stabilization of <i>c-myc</i> G-quadruplex DNA to block the transcription and expression of <i>c-myc</i>. In brief, these types of arene Ru(II) complexes with difluorinated ligands can be developed as potential inducers of S-phase arrest and apoptosis through the binding and stabilization of <i>c-myc</i> G-quadruplex DNA, and could be used in clinical applications in the future.https://www.mdpi.com/1420-3049/27/6/1897difluorinated ligandsarene Ru(II) complexes<i>c-myc</i> G-quadruplex DNA |
| spellingShingle | Liang Zeng Chanling Yuan Jing Shu Jiayi Qian Qiong Wu Yanhua Chen Ruzhen Wu Xiaoming Ouyang Yuan Li Wenjie Mei Arene Ru(II) Complexes with Difluorinated Ligands Act as Potential Inducers of S-Phase Arrest via the Stabilization of <i>c-myc</i> G-Quadruplex DNA Molecules difluorinated ligands arene Ru(II) complexes <i>c-myc</i> G-quadruplex DNA |
| title | Arene Ru(II) Complexes with Difluorinated Ligands Act as Potential Inducers of S-Phase Arrest via the Stabilization of <i>c-myc</i> G-Quadruplex DNA |
| title_full | Arene Ru(II) Complexes with Difluorinated Ligands Act as Potential Inducers of S-Phase Arrest via the Stabilization of <i>c-myc</i> G-Quadruplex DNA |
| title_fullStr | Arene Ru(II) Complexes with Difluorinated Ligands Act as Potential Inducers of S-Phase Arrest via the Stabilization of <i>c-myc</i> G-Quadruplex DNA |
| title_full_unstemmed | Arene Ru(II) Complexes with Difluorinated Ligands Act as Potential Inducers of S-Phase Arrest via the Stabilization of <i>c-myc</i> G-Quadruplex DNA |
| title_short | Arene Ru(II) Complexes with Difluorinated Ligands Act as Potential Inducers of S-Phase Arrest via the Stabilization of <i>c-myc</i> G-Quadruplex DNA |
| title_sort | arene ru ii complexes with difluorinated ligands act as potential inducers of s phase arrest via the stabilization of i c myc i g quadruplex dna |
| topic | difluorinated ligands arene Ru(II) complexes <i>c-myc</i> G-quadruplex DNA |
| url | https://www.mdpi.com/1420-3049/27/6/1897 |
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