Wen-Jie Mei

DNA binding and photocleavage specificities of a group of tricationic metalloporphyrins

The interactions of 5,10,15-tris(1-methylpyridinium-4-yl)-20-(4-hydroxyphenyl)porphyrinatozinc(II) Zn[TMPyHP](3+) (2) along with Cu[TMPyHP](3+) (3), Co[TMPyHP](4+) (4), Mn[TMPyHP](4+) (5) and the free base porphyrin H(2)[TMPyHP](3+) (1) with duplex DNA have been studied by using a combination of absorption, fluorescence titration, surface-enhanced Raman spectroscopy (SERS), induced circular dichroism (ICD) spectroscopy, thermal DNA denaturation, viscosity measurements as well as gel electrophoresis experiment. Their binding modes and intrinsic binding constants (K(b)) to calf DNA (CT DNA) were comparatively studied and were found significantly influenced by different metals coordinated with the porphyrin plane. Except 3, which has four-coordination structure at the metal, all the metal derivatives showed non-intercalative DNA-binding mode and lower K(b) than the free base porphyrin 1, most probably due to the steric hindrance results from the axial ligands of the inserted metals which are five or six-coordination structures. Meanwhile, the insertion of metals into cationic porphyrin greatly removed the self-aggregation of the metal-free porphyrins, and thus fully enhanced the singlet oxygen ((1)O(2)) productivities in the DNA photocleavage experiments. Therefore, these metalloporphyrins have comparable DNA cleavage ability with the free base porphyrin.

Ruthenium(II) complexes as apoptosis inducers by stabilizing c-myc G-quadruplex DNA

Two ruthenium(II) complexes, [Ru(L)2(p-tFMPIP)](ClO4)2 (L = bpy, 1; phen, 2; p-tFMPIP = 2-(4-(trifluoromethyphenyl)-1H-imidazo[4,5f][1,10] phenanthroline)), were prepared by microwave-assisted synthesis technology. The inhibitory activity evaluated by MTT assay shown that 2 can inhibit the growth of MDA-MB-231 cells with inhibitory activity (IC50) of 16.3 μM, which was related to the induction of apoptosis. Besides, 2 exhibit low toxicity against normal HAcat cells. The inhibitory growth activity of both complexes related to the induction of apoptosis was also confirmed. Furthermore, the studies on the interaction of both complexes with c-myc G4 DNA shown that 1 and 2 can stabilize the conformation of c-myc G4 DNA in groove binding mode, which has been rational explained by using DFT theoretical calculation methods. In a word, this type of ruthenium(II) complexes can act as potential apoptosis inducers with low toxicity in clinic by stabilizing c-myc G4 DNA.

Ruthenium(II) complexes of 2-(2′-pyridyl)naphthoimidazole: synthesis, characterization and DNA-binding studies

The perchlorate salts of two new ruthenium(II) complexes incorporating 2-(2′-pyridyl)naphthoimidazole are synthesized in good yield. Complexes [Ru(phen)2(PYNI)]2+ (phen = 1,10-phenanthroline) 1 and [Ru(dmp)2(PYNI)]2+ (dmp = 2,9-dimethyl-1,10-phenanthroline, PYNI = 2-(2′-pyridyl)naphthoimidazole) 2 are fully characterized by elemental analysis, FAB-MS, ES-MS, 1H NMR and cyclic voltammetric methods. The DNA-binding behavior of the complexes have been studied by spectroscopic titration, viscosity measurements and thermal denaturation. Absorption titration and thermal denaturation studies reveal that these complexes are moderately strong binders of calf-thymus DNA (CT-DNA), with their binding constants spanning the range (2.73–5.35) × 104 M−1. The experimental results show that 1 interacts with calf thymus DNA (CT-DNA) by intercalative mode, while 2 binds to CT-DNA by partial intercalation.

Effect of the ancillary ligands on the binding of ruthenium(II) complexes [Ru(dmp)2(MCMIP)]2+ and [Ru(dmb)2(MCMIP)]2+ with DNA

Two polypyridine ruthenium(II) complexes, [Ru(dmp)2(MCMIP)]2+ (1) (MCMIP = 2-(6-methyl-3-chromonyl)imidazo[4,5-f][1,10]-phenanthroline, dmp = 2,9-dimethyl-1,10-phenanthroline) and [Ru(dmb)2(MCMIP)]2+ (2) (dmb = 4,4′-dimethyl-2,2′-bipyridine), have been synthesized and characterized by elemental analysis, ES-MS and 1H NMR. The DNA-binding behaviors of these complexes were investigated by electronic absorption titration, fluorescence spectroscopy, viscosity measurements and thermal denaturation. The results show that 1 and 2 effectively bind to CT-DNA; the DNA-binding affinities are closely related to the ancillary ligand.

Synthesis, characterization and DNA-binding properties of Ru(II) complexes coordinated by ofloxacin as potential antitumor agents

Three Ru complexes coordinated by oxfloxacin, [Ru(L)2(OFX)]Cl·2H2O (L = bpy, 1; dmbpy, 2; phen, 3; and OFX = ofloxacin), were synthesized and characterized. These complexes can inhibit the growth of cervical cancer HeLa cells efficiently. Furthermore, these three complexes exhibited excellent binding affinities with DNA, as confirmed by spectroscopy methods and viscosity experiments. Therefore, the synthesized Ru(II) complexes have excellent DNA-binding abilities with potential applications in cancer chemotherapy.

Arene ruthenium(II) complexes induce S-phase arrest in MG-63 cells through stabilization of c-Myc G-quadruplex DNA

A series of arene ruthenium(II) complexes coordinated by phenanthroimidazole derivatives have been synthesized and evaluated for their in vitro anticancer activities. It has been found that these types of arene Ru(II) complexes, especially [(C6H6)Ru(o-ClPIP)Cl]Cl·2H2O (2a), exhibited acceptable antiproliferative activity against several human cancer cell lines but with low toxicity towards normal HK-2 human cells. Mechanistic studies revealed that 2a-induced growth inhibition against osteosarcoma MG-63 cells was mainly caused by S-phase cell cycle arrest, which was confirmed by the down-regulation of cyclin A and CDK2 using western blot analysis of protein levels. Furthermore, studies using comet assay at single cell level indicated that 2a triggered DNA damage in MG-63 cells, and subsequently initiated S-phase arrest, as shown by the up-regulation of phosphorylated p53 and histone. Moreover, exposure of MG-63 cells to 2a resulted in the down-regulation of c-Myc protein expression. The in vitro DNA-binding behaviors also indicated that 2a could stabilize c-Myc G-quadruplex DNA (G4-DNA) by affecting its conformation. In conclusion, these results suggest that arene Ru(II) complexes coordinated by phenanthroimidazole derivatives serve as c-Myc G4-DNA stabilizers that could induce S-phase arrest in cancer cells by triggering DNA damage, which suggest that these complexes may act as potential candidates for the treatment of human malignant osteosarcoma.

In vitro and in vivo investigations on the antiviral activity of a series of mixed-valence rare earth borotungstate heteropoly blues.

A series of mixed-valence rare earth borotungsto-heteropoly blues, K15H2[Ln(BW9W2O39)2].28H2O (Ln2, Ln=La, Ce, Pr, Nd, Sm, Eu, Gd), have been prepared and characterized by IR, UV, XPS, ESR and electrochemistry. The cytotoxicity and antiviral activity of these rare earth borotungstate heteropoly blues were investigated against influenza A(FluVA) strain (A/H1N1/Jingfang/1/91 and A/H3N2/Jingfang/30/95) and influenza virus B(FluVB) (B/Hufang/1/87) in MDCK cells. The results show that K15H2[Pr(BW9W2O39)2].28H2O (Pr2) exhibits the highest antiviral activity against FluVA with EC50 of less than 4.0 microg/ml (A/H1N1/Jingfang/1/91) and 6.0 microg/ml (A/H3N2/Jingfang/30/95), respectively, and has the lowest toxicity with CC50 of more than 480 microg/ml against MDCK cells. Additionally, both K15H2[Pr(BW9W2O39)2].28H2O (Pr2) and K15H2[Eu(BW9W2O39)2].28H2O (Eu2) showed excellent antiviral activities against FluVB by inhibiting FluVB replication at an EC50 of less than 8.0 microg/ml. Furthermore, investigation on in vivo antiviral activity of Pr2 against FluVA(FM1) in mice by giving the dosage either orally (p.o.) or intraperitoneally (i.p.), indicates that Pr2 exhibits higher inhibitory activity than that of positive control, virazole, and that its more effective when administered by i.p.

Synthesis and characterization of chiral ruthenium(II) complexes Λ/Δ-[Ru(bpy)2(H2iip)](ClO4)2 as stabilizers of c-myc G-quadruplex DNA

In this article, two chiral ruthenium(II) complexes, Λ/Δ-[Ru(bpy)2(H2iip)](ClO4)2 (Λ-1 and Δ-1, bpy = 2,2-bipyridine; H2iip = 2-(indol-3-yl)-imidazo[4,5f][1, 10]phenanthroline), were synthesized and investigated as c-myc G4 DNA stabilizers. The interaction of both complexes with c-myc G4 DNA has been studied using UV–vis spectra, CD spectra, and ITC experiments, and the results show that both isomers strongly bind with c-myc G4 DNA. Furthermore, the FRET melting point experiments give a ΔTm for Λ-1 and Δ-1, which is about 9.5 and 8.3 °C, respectively, indicating that both isomers can stabilize the G-quadruplex conformation of c-myc oncogene in vitro. As a result, the replication ability of c-myc DNA, as evaluated by using PCR-stop assay, by both isomers. Besides, the inhibitory activity evaluated by MTT assay showed that Λ-1 and Δ-1 can inhibit the growth of MDA-MB-231 cells, suggesting their potential utility as inhibitors targeting to c-myc G-quadruplexe in chemotherapy. Graphical Abstract A pair of chiral ruthenium(II) complexes, Λ/Δ-[Ru(bpy)2(H2iip)](ClO4)2, have been synthesized and demonstrated to bind and stabilize c-myc G-quadruplex DNA with moderate affinity.

Effect of substituents on DNA-binding behaviors of ruthenium(II) complexes: [Ru(dmb)2(dtmi)]2+ and [Ru(dmb)2(dtni)]2+

Two Ru(II) complexes [Ru(dmb)2(dtmi)](ClO4)2 (1) (dmb = 4, 4′-dimethyl-2, 2′-bipyridine, dtmi = 3-(pyrazin-2-yl)-as-triazino[5, 6-f]-5-methoxylisatin) and [Ru(dmb)2(dtni)](ClO4)2 (2) (dtni = 3-(pyrazin-2-yl)-as-triazino[5, 6-f]-5-nitroisatin) have been synthesized and characterized by elemental analysis, ES-MS, and 1H NMR. DNA-binding behaviors of these complexes have been investigated by spectroscopic titration, viscosity measurements, and thermal denaturation. The results indicate that the two complexes interact with calf thymus DNA by intercalation.

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

PurposeThe study mainly aimed to determine the biological function of a novelly synthesized phenanthroimidazole derivative, named L233, and to explore its potential mechanisms.MethodsCell 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.ResultsWe 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.ConclusionsIn summary, L233 is a promising anticancer drug for the development of novel chemotherapies in the future.