Phenanthroimidazole derivatives act as potentinducer of autophagy by activating DNA damage pathway.

A series of imidazo[4,5f][1,10]phenanthroline derivatives (1-6) have been synthesized in this study, and their inhibitory activity was evaluated by MTT assay. Results showed that all of these compounds demonstrate a promising inhibitory activity against a panel of human cancer cell lines. The 6, the most effective compound with IC50 of approximately 2.3 ±â€¯0.1 µM, was against the growth and could induce autophagy of HepG2 cells. This condition was confirmed by abundant autophagic vacuoles appearing in cells and evident ultrastructural changes observed under transmission electron microscopy. The autophage induced by 6 has also been demonstrated by up-regulating LC3-II and Beclin1. The apoptosis and G2/M phase cell cycle arrest through DSB damage have also been confirmed after the HepG2 cells were treated by 6. These multiple effects, especially induction apoptosis and autophagy, indicate the potential of 6 for development as a novel anticancer drug.

A Bis(methylpiperazinylstyryl)phenanthroline as a Fluorescent Ligand for G-Quadruplexes.

G-quadruplex (G4)-forming sequences are prevalent in the genome and are considered to play important roles in gene regulation, and hence have been viewed as potential therapeutic targets in oncology. However, the structures and functions of most G4s in the genome are poorly understood. Therefore, the development of fluorescent probes and ligands for G4s is important for G4 research and drug discovery. Herein, we report a new G4 ligand, 2,9-bis[4-(4-methylpiperazin-1-yl)styryl]-1,10-phenanthroline (BMSP), which was synthesized by a simple process. BMSP exhibits almost no fluorescence in aqueous buffer. The interaction of BMSP with G4s greatly enhances its fluorescence with a large Stokes' shift of 160 nm. Antiparallel human telomeric G4s exhibit the strongest binding affinity (Kd ≈0.13 µm) to BMSP and induce a fluorescence enhancement of up to 150-fold. BMSP binds to G4s through π-π stacking on the terminal G-quartets. BMSP can enter live cells, and it strongly inhibits the growth of cancer cells rather than causing cell death. Our results suggest that BMSP has the potential to serve both as a fluorescent probe for some G4s and as a chemotherapeutic agent for cancer treatment.

Synthesis and biological activity of 1H-imidazo[4,5-f][1,10]phenanthroline as a potential antitumor agent with PI3K/AKT/mTOR signaling.

1H-imidazo[4,5-f][1,10]phenanthroline (IPM713) is a type of tricyclic conjugated rigid planar structure with potential medical applications, but its anticancer activity has not yet been fully studied. In the present research, cells from seven different cancer types were used to study the anticancer effect, and IPM713 was found to inhibit the colorectal cancer cell line HCT116 most significantly, with a half maximal inhibitory concentration (IC50) of 1.7 µM. The mechanisms by which IPM713 exerts anti-colorectal cancer activity were studied. IPM713 blocked the cell cycle in G0/G1 phase and induced apoptosis by suppressing the PI3K/AKT/mTOR axis. In addition, an acute toxicity test showed that the median lethal dose (LD50) was above 5000 mg/kg. The findings of this research suggest that IPM713 can interfere with the PI3K/AKT/mTOR signaling pathway and might be a potential therapeutic candidate for the treatment of colorectal cancer.

A phenanthroline derivative enhances radiosensitivity of hepatocellular carcinoma cells by inducing mitochondria-dependent apoptosis.

Combining radiosensitizers with ionizing radiation (IR) is an effective strategy to increase the radiation therapeutic effect for hepatocellular carcinoma (HCC) patients. A phenanthroline derivative, 2-phenyl-imidazo [4, 5 f] [1, 10] phenanthroline (L02), had been synthesized. This study investigated the radiosensitization and mechanisms of L02 combined with IR against HCC. The radiosensitization of L02 combined with IR was evaluated by the sensitivity enhancement ratio (SER) and the isobolographic analysis. The toxicity of L02 and cisplatin were compared by the zebrafish model. The cell cycle and apoptosis were examined by flow cytometry. DNA damage was measured by comet assay and the expressions of apoptosis related proteins were analyzed by western blotting. L02 was effective in sensitizing HCC to IR. The SERs in HepG2 and BEL7402 were 1.41 and 1.28, respectively. The sensitization of L02 was comparable with cisplatin. L02 treatment with IR had synergistic anti-tumor effect. L02 enhanced the percentage of IR induced apoptosis cells. L02 increased comet tail in comet assay when combined with IR. L02 sensitized HCC to IR by the activation of P53 signaling, the decrease in Bcl-2, up-regulation of cytochrome c and the subsequent activation of caspase-3. L02 sensitizes HCC to IR, mostly likely by inhibiting cell proliferation, inducing DNA damage and mitochondria-dependent apoptosis. L02 may be a novel radiosensitizer for HCC.

Supramolecular Iron Complex Formed Between Nitrogen Riched Phenanthroline Derivative and Iron With Improved Oxygen Reduction Activity in Alkaline Electrolyte.

In this work, the synthesis and evaluation of a new type non-noble metal oxygen reduction reaction (ORR) catalyst is reported. The catalyst is a complex containing iron ions and multiple N active sites, which displayed excellent oxygen reduction activity in alkaline medium. 2-(2-(4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)pyridin-2-yl)pyridin-4-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (PIPhen) was synthesized and used as a ligand to form a rich nitrogen iron coordination complex (Fe-PIPhen), and the complex was then loaded onto the carbon powder to form the target catalyst of Fe-PIPhen/C. The physical characterization of the catalyst was conducted by using Scanning Electron Microscopy (SEM), nitrogen adsorption-desorption and X-ray photoelectron spectroscopy (XPS), Brunauer-Emmett-Teller analysis etc. Electrochemical characterizations were realized by taking cyclic voltammetry (CV), linear sweep voltammetry (LSV) and rotating ring disk electrode (RRDE). The results show that Fe-PIPhen/C possesses the good performance; it exhibits a high electrocatalytic activity, which is mainly via a four electron ORR pathway, with a low hydrogen peroxide yield of 2.58%. And, the average electron transfer number of 3.93 was obtained in alkaline electrolyte. In summary, Fe-PIPhen/C will likely become a promising alternative to Pt catalyst in fuel cell.

Anticancer, antibacterial and antifungal activity of new ni (ii) and cu (ii) complexes of imidazole-phenanthroline derivatives.

Two new nickel(II) and copper(II) complexes of 2-(Furan-2-yl)-1H-Imidazo[4,5-f][1,10]Phenanthroline (FIP) and 2-(thiophen-2-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (TIP), imidazophen derivatives were synthesized. The structures of the compounds were determined by UV-visible and FT-IR spectroscopic methods and elemental analysis. The biological activities of Ni and Cu complexes, as anticancer agents, were tested against chronic myelogenous leukemia cell line, K562, at micromolar concentration. The MTT studies showed Cc50 values are 21 and 160 µM for Cu and Ni(II) complexes, respectively; suggesting that Ni (II) complex has Cc50 almost seven times of that obtained for cisplatin. Biological activity of the Ni(II) and Cu(II) complexes were also assayed against selective microorganisms by disc diffusion method. These results showed that the Cu(II) complex is antifungal agent but Ni(II) complex has antibacterial activity.

Fluorescent detection and imaging of Hg(2+) using a novel phenanthroline derivative based single- and two-photon excitation.

A novel phenanthroline derivative, 4-[4-(N-methyl)styrene]-imidazo[4,5-f][1,10]phenanthroline-benzene iodated salt (MSIPBI), was synthesized, and the linear absorption and fluorescent spectra of MSIPBI in different solvents were investigated. The photophysical properties in unbound and in ligand-metal complexes were evaluated by UV absorption and one- and two-photon fluorescent spectra, and the quantum yields, two-photon active cross-sections and the binding constant of dye-metal were calculated. The results indicated that MSIPBI has a large Stokes shift (more than 167nm), and the dye was selective and sensitive for the detection of Hg(2+) with a two-photon active cross-section of 55.5GM in tris-HCl buffer solution at 800nm. Furthermore, the results of the fluorescence microscopy imaging indicated that MSIPBI is an efficient fluorescent probe for the detection of Hg(2+) in living cells by one- and two-photon excitation. Moreover, the experiments of determination Hg(2+) in river water and tap water were finished.

A novelly synthesized phenanthroline derivative is a promising DNA-damaging anticancer agent inhibiting G1/S checkpoint transition and inducing cell apoptosis in cancer cells.

PURPOSE: The study mainly aimed to determine the biological function of a novelly synthesized phenanthroimidazole derivative, named L233, and to explore its potential mechanisms. METHODS: Cell survival was examined using the MTT assays, and the DNA-damaging role of L233 was explored using the comet assay. Moreover, the western blotting assays and immunofluorescence assays were used to detect DNA damage biomarkers. Afterward, the flow cytometry was used to assess the effects of L233 on cell cycle distribution. As for the detection of cell apoptosis upon L233 treatment, the Hoechst 33342 staining, flow cytometry, and western blotting assays were all put into practice. RESULTS: We find that L233 inhibits tumor cell growth more efficiently and safely than cisplatin. Moreover, it is a DNA-damaging agent, interrupting the cell cycle G1/S checkpoint transition and inducing cell apoptosis by not only activating ATM/CHK1 signaling pathway, but also targeting CHK1 to reduce the expression of RAP80 and PARP-1 to compromise the DNA damage repair in tumor cells. CONCLUSIONS: In summary, L233 is a promising anticancer drug for the development of novel chemotherapies in the future.

Selective recognition of specific G-quadruplex vs. duplex DNA by a phenanthroline derivative.

A key problem in designing G-quadruplex ligand is how to discriminate quadruplex DNA specifically from other DNAs, searching ligands targeted at special G-quadruplex structure with high selectivity is a major challenge. Herein, a phenanthrolin-dicarboxylate ester (PD) is proved to exhibit selectivity toward parallel and hybrid G-quadruplex structures with propeller and edge-wise loops, over duplex DNA and antiparallel quadruplex structure with diagonal loop. Such preferred binding of PD to these special G-quadruplex structures is possibly resulted from steric hindrance of: (1) the four substituent groups in PD molecule which prevent close interaction with duplex DNA and (2) the diagonal loop above the G-tetrads in antiparallel G-quadruplex which hinder face-to-face stacking of planar phenanthrolin ring to G-tetrads. In line with its stabilizing ability of G-quadruplex, PD molecule exhibit a inhibitory ability telomerase activity, as well as the potent cytotoxic activity against several human cancer cell lines, which makes it an interesting anti-tumor drug lead.