A series of arene Ru(II) complexes, [(η6-MeC6H5)Ru(L)Cl]Cl, (L=o-ClPIP, 1; m-ClPIP, 2 and p-ClPIP, 3) (o-ClPIP=2-(2-chlorophenyl)imidazo[4,5-f][1,10]phenanthroline; m-ClPIP=2-(3-chlorophenyl)imidazo[4,5-f][1,10]phenanthroline; p-ClPIP=2-(4-chlorophenyl)imidazo[4,5-f][1,10]phenanthroline) was synthesized and investigated as a potential apoptosis inducer in chemotherapy. Spectroscopy and molecular docking simulations show that 1 exhibits moderated binding affinity to KRAS G-quadruplex DNA by groove mode. Further, in vitro studies reveal that 1 displays inhibitory activity against MCF-7 growth with IC50 = 3.7 ± 0.2 μM. Flow cytometric analysis, comet assay, and immunofluorescence confirm that 1 can induce the apoptosis of MCF-7 cells and G0/G1 phase arrest through DNA damage. In summary, the prepared arene Ru(II) complexes can be developed as a promising candidate for targeting G-quadruplex structure to induce the apoptosis of breast cancer cells via binding and stabilizing KRAS G-quadruplex conformation on oncogene promoter.
This study showed that levofloxacin-based ruthenium(ii) complex 2 effectively inhibited the growth of A549 cells by inducing G2/M phase arrest through triggering DNA damage.
Here, a series of half-sandwich arene Ru(II) complexes with difluorinated ligands [Ru(η6-arene)(L)Cl] (L1 = 2-(2,3-difluorophenyl)imidazole[4,5f][1,10]-phenanthroline; L2 = 2-(2,4-difluorophenyl)imidazole[4,5f][1,10]-phenanthroline; arene = benzene, toluene, and p-cymene) were synthesized and characterized. Molecular docking analysis showed that these complexes bind to c-myc G-quadruplex DNA through either groove binding or π–π 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 c-myc 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 1 exhibited a better affinity and stability in relation to c-myc G-quadruplex DNA with a DC50 of 6.6 μM and ΔTm 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 3 and 6, 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 3 and 6 had favorable lipid-water partition coefficients of −0.6615 and −0.8077, respectively. Moreover, it was found that complex 6 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 c-myc G-quadruplex DNA to block the transcription and expression of c-myc. 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 c-myc G-quadruplex DNA, and could be used in clinical applications in the future.
Background
Breast cancer targeting diagnostic agent with effective imaging ability is important in guiding plan formulation, prediction, and curative effect evaluation of tumors in clinic. A tumor-targeting nanoprobe based on the functional and programmable Liquid–Liquid phase separation of AS1411 promoted by Ru(II) complex RuPEP may develop into a potential phosphorescence probe to detect breast cancer cells, where AS1411 act as a tumor-targeting guidance moiety to distinguish tumor cells from normal cells and RuPEP act as a light-emitting element to highlight breast cancer cells.
Methods
Here we designed and constructed a nanoprobe AS1411@RuPEP, and the physicochemical and biochemical properties were characterized by TEM, AFM and EDS. The breast cancer targeting diagnostic capacity was evaluated by normal/tumor cell co-culture assay, tumor cells targeting tracking in xenograft model and cancerous area selectively distinguishing in human patient tissue.
Results
Further studies indicated that the nanoprobe exhibits excellent tumor-targeting imaging ability in vitro and in vivo by effectively recognize the over-expressed nucleolin (NCL) on the breast cancer cells membrane. Intriguingly, we discovered that the selectively enrichment of nanoprobe particles in tumor cells is related to ATP-dependent NCL transport processes that rely on the AS1411 component of nanoprobe to recognize NCL. Furthermore, preferential accumulation of nanoprobe is clearly differentiating the human breast cancer tissue surrounding non-cancerous tissue in histological analysis.
Conclusion
This study produce a potent nanoprobe can be used as a convenient tool to highlight and distinguish tumor cells in vivo, and indicate the tumorous grading and staging in human breast cancer patient pathological section, which provides an effective way for breast cancer diagnostic imaging by targeting recognize NCL.
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