Rose M. Carlos

Luminescent Ruthenium Complexes for Theranostic Applications

The water-soluble and visible luminescent complexes cis-[Ru(L-L)2(L)2](2+) where L-L = 2,2-bipyridine and 1,10-phenanthroline and L= imidazole, 1-methylimidazole, and histamine have been synthesized and characterized by spectroscopic techniques. Spectroscopic (circular dichroism, saturation transfer difference NMR, and diffusion ordered spectroscopy NMR) and isothermal titration calorimetry studies indicate binding of cis-[Ru(phen)2(ImH)2](2+) and human serum albumin occurs via noncovalent interactions with K(b) = 9.8 × 10(4) mol(-1) L, ΔH = -11.5 ± 0.1 kcal mol(-1), and TΔS = -4.46 ± 0.3 kcal mol(-1). High uptake of the complex into HCT116 cells was detected by luminescent confocal microscopy. Cytotoxicity of cis-[Ru(phen)2(ImH)2](2+) against proliferation of HCT116p53(+/+) and HCT116p53(-/-) shows IC50 values of 0.1 and 0.7 μmol L(-1). Flow cytometry and western blot indicate RuphenImH mediates cell cycle arrest in the G1 phase in both cells and is more prominent in p53(+/+). The complex activates proapoptotic PARP in p53(-/-), but not in p53(+/+). A cytostatic mechanism based on quantification of the number of cells during the time period of incubation is suggested.

Copper (II) and 2,2′-Bipyridine Complexation Improves Chemopreventive Effects of Naringenin against Breast Tumor Cells

Cancer is the second leading cause of death worldwide and there is epidemiological evidence that demonstrates this tendency is emerging. Naringenin (NGEN) is a trihydroxyflavanone that shows various biological effects such as antioxidant, anticancer, anti-inflammatory, and antiviral activities. It belongs to flavanone class, which represents flavonoids with a C6-C3-C6 skeleton. Flavonoids do not exhibit sufficient activity to be used for chemotherapy, however they can be chemically modified by complexation with metals such as copper (Cu) (II) for instance, in order to be applied for adjuvant therapy. This study investigated the effects of Cu(II) and 2,2′-bipyridine complexation with naringenin on MDA-MB-231 cells. We demonstrated that naringenin complexed with Cu(II) and 2,2′-bipyridine (NGENCuB) was more efficient inhibiting colony formation, proliferation and migration of MDA-MB-231 tumor cells, than naringenin (NGEN) itself. Furthermore, we verified that NGENCuB was more effective than NGEN inhibiting pro-MMP9 activity by zymography assays. Finally, through flow cytometry, we showed that NGENCuB is more efficient than NGEN inducing apoptosis in MDA-MB-231 cells. These results were confirmed by gene expression analysis in real time PCR. We observed that NGENCuB upregulated the expression of pro-apoptotic gene caspase-9, but did not change the expression of caspase-8 or anti-apoptotic gene Bcl-2. There are only few works investigating the effects of Cu(II) complexation with naringenin on tumor cells. To the best of our knowledge, this is the first work describing the effects of Cu(II) complexation of a flavonoid on MDA-MB-231 breast tumor cells.

Photochemical reactions of fac-[Mn(CO)3(phen)imidazole]+: evidence for long-lived radical species intermediates.

The electronic absorption spectrum of fac-[Mn(CO)(3)(phen)imH](+), fac-1 in CH(2)Cl(2) is characterized by a strong absorption band at 378 nm (epsilon(max) = 3200 mol(-1) L cm(-1)). On the basis of quantum mechanical calculations, the visible absorption band has been assigned to ligand-to-ligand charge-transfer (LLCT, im-->phen) and metal-to-ligand charge-transfer (MLCT, Mn-->phen) charge transfer transition. When fac-1 in CH(2)Cl(2) is irradiated with 350 nm continuous light, the absorption features are gradually shifted to represent those of the meridional complex mer-[Mn(CO)(3)(phen)imH](+), mer-1 (lambda(max) = 556 nm). The net photoreaction under these conditions is a photoisomerization, although, the presence of the long-lived radical species was also detected by (1)H NMR and FTIR spectroscopy. 355 nm continuous photolysis of fac-1 in CH(3)CN solution also gives the long-lived intermediate which is readily trapped by metylviologen (MV(2+)) giving rise to the formation of the one-electron reduced methyl viologen (MV(*+)). The UV-vis spectra monitored during the slow (45 min) thermal back reaction exhibited isosbestic conversion at 426 nm. On the basis of spectroscopic techniques and quantum mechanical calculations, the role of the radicals produced is analyzed.

Ruthenium complex exerts antineoplastic effects that are mediated by oxidative stress without inducing toxicity in Walker-256 tumor-bearing rats

Abstract The present study evaluated the in vivo antitumor effects and toxicity of a new Ru(II) compound, cis‐(Ru[phen]2[ImH]2)2+ (also called RuphenImH [RuC]), against Walker‐256 carcinosarcoma in rats. After subcutaneous inoculation of Walker‐256 cells in the right pelvic limb, male Wistar rats received 5 or 10 mg kg−1 RuC orally or intraperitoneally (i.p.) every 3 days for 13 days. A positive control group (2 mg kg−1 cisplatin) and negative control group (vehicle) were also used. Tumor progression was checked daily. After treatment, tumor weight, plasma biochemistry, hematology, oxidative stress, histology, and tumor cell respiration were evaluated. RuC was effective against tumors when administered i.p. but not orally. The highest i.p. dose of RuC (10 mg kg−1) significantly reduced tumor volume and weight, induced oxidative stress in tumor tissue, reduced the respiration of tumor cells, and induced necrosis but did not induce apoptosis in the tumor. No clinical signs of toxicity or death were observed in tumor‐bearing or healthy rats that were treated with RuC. These results suggest that RuC has antitumor activity through the modulation of oxidative stress and impairment of oxidative phosphorylation, thus promoting Walker‐256 cell death without causing systemic toxicity. These effects make RuC a promising anticancer drug for clinical evaluation. Graphical abstract Figure. No caption available. HighlightsThe compound RuphenImH (RuC) presented antitumor effect against the Walker‐256 tumor in rats.RuC induced oxidative stress and reduced the respiration of tumor cells.RuC presented antitumor effect by i.p. but not by p.o. administration.RuC has antitumor effect without causing systemic toxicity.

Luminescent Ru(II) Phenanthroline Complexes as a Probe for Real-Time Imaging of Aβ Self-Aggregation and Therapeutic Applications in Alzheimer’s Disease

The complexes cis-[Ru(phen)2(Apy)2]2+, Apy = 4-aminopyridine and 3,4-aminopyridine, are stable in aqueous solution with strong visible absorption. They present emission in the visible region with long lifetime that accumulates in the cytoplasm of Neuro2A cell line without appreciable cytotoxicity. The complexes also serve as mixed-type reversible inhibitors of human AChE and BuChE with high active site contact. cis-[Ru(phen)2(3,4Apy)2]2+ competes efficiently with DMPO by the OH• radical. Luminescence using fluorescence lifetime imaging (FLIM) enables real-time imaging of the conformational changes of the self-aggregation of Aβ with incubation of complexes (0-24 h) in phosphate buffer at micromolar concentrations. By this technique, we identified protofibrills in the self-assembly of Aβ1-40 and globular structures in the short fragment Aβ15-21 in aqueous solution.

A novel ruthenium complex with xanthoxylin induces S-phase arrest and causes ERK1/2-mediated apoptosis in HepG2 cells through a p53-independent pathway

Ruthenium-based compounds have gained great interest due to their potent cytotoxicity in cancer cells; however, much of their potential applications remain unexplored. In this paper, we report the synthesis of a novel ruthenium complex with xanthoxylin (RCX) and the investigation of its cellular and molecular action in human hepatocellular carcinoma HepG2 cells. We found that RCX exhibited a potent cytotoxic effect in a panel of cancer cell lines in monolayer cultures and in a 3D model of multicellular cancer spheroids formed from HepG2 cells. This compound is detected at a high concentration in the cell nuclei, induces DNA intercalation and inhibits DNA synthesis, arresting the cell cycle in the S-phase, which is followed by the activation of the caspase-mediated apoptosis pathway in HepG2 cells. Gene expression analysis revealed changes in the expression of genes related to cell cycle control, apoptosis and the MAPK pathway. In addition, RCX induced the phosphorylation of ERK1/2, and pretreatment with U-0126, an MEK inhibitor known to inhibit the activation of ERK1/2, prevented RCX-induced apoptosis. In contrast, pretreatment with a p53 inhibitor (cyclic pifithrin-α) did not prevent RCX-induced apoptosis, indicating the activation of a p53-independent apoptosis pathway. RCX also presented a potent in vivo antitumor effect in C.B-17 SCID mice engrafted with HepG2 cells. Altogether, these results indicate that RCX is a novel anticancer drug candidate.

A aplicação da fotoquímica inorgânica nas diversas áreas da ciência

This article provides an overview of the current status of research involving the photochemical behavior of transition metal complexes in the following important areas: medicine, biology and materials science including some of the experiences of the writer. Coverage is selective, generally focusing on highlights and the most recent developments, with the broad aim of showing the interdisciplinary field of inorganic photochemistry.

Synthesis, Characterization, and Photochemical Properties of a New Square Mn(I)-Ru(II) Complex Using Pyrazine as Bridge Ligand

e photochemical properties of the complexes cis,fac-[Ru(phen)2(pz)2-Mn(CO)3Br]2 4+ (I), cis-[Ru(phen)2(pz)2] 2+ (II), and fac-Mn(CO)3(pz)2Br (III) where phen is phenanthroline and pz is pyrazine in acetonitrile solution are reported. e three complexes were characterized using H NMR, UV-vis and FTIR spectroscopy and electrochemical (cyclic voltammetry and spectroelectrochemical) techniques. e complexes show intense absorption in the visible region assigned to the population of MLCT excited states. e absorption spectrum of I is the sum of the spectra of the mononuclear species II and III, and the two oxidation potentials at +1.10 and +1.56V versus Ag/AGCl observed in I are ascribed to the different coordination environments of metal centers. e photolysis in the acetonitrile solution resulted in the pz dissociation to give the monoacetonitrile complexes for I, II, and III, respectively.

cis-Bis(1,10-phenanthroline-κ2N,N′)bis­(pyridin-4-amine-κN1)ruthenium(II) bis­(hexa­fluoridophosphate)

In the title complex, [Ru(C12H8N2)2(C5H6N2)2](PF6)2, the RuII atom is bonded to two α-diimine ligands, viz. 1,10-phenanthroline (phen), in a cis configuration, in addition with with two 4-aminopyridine (4Apy) ligands, resulting in a distorted octahedral coordination geometry. N—H⋯F hydrogen-bonding interactions play an important role in the crystal assembly: 21-screw-axis-related complex molecules and PF6 − counter-ions alternate in helical chains formed along the a axis by means of these contacts. N—H⋯π contacts (H⋯centroid = 3.45 Å) are responsible for cross-linking between the helical chains along [001].

cis-Bis(2,2′-bipyridine-κ2N,N′)bis­(pyridin-4-amine-κN1)ruthenium(II) bis­(hexa­fluoridophosphate) acetonitrile monosolvate

In the title complex, [Ru(C10H8N2)2(C5H6N2)2](PF6)2·CH3CN, the RuII atom is bonded to two α-diimine ligands, viz. 2,2′-bipyridine, in a cis configuration and to two 4-aminopyridine (4Apy) ligands in the expected distorted octahedral configuration. The compound is isostructural with [Ru(C10H8N2)2(C5H6N2)2](ClO4)2·CH3CN [Duan et al. (1999 ▶). J. Coord. Chem. 46, 301–312] and both structures are stabilized by classical hydrogen bonds between 4Apy ligands as donors and counter-ions and acetonitrile solvent molecules as acceptors. Indeed, N—H⋯F interactions give rise to an intermolecularly locked assembly of two centrosymmetric complex molecules and two PF6 − counter-ions, which can be considered as the building units of both crystal architectures. The building blocks are connected to one another through hydrogen bonds between 4Apy and the connecting pieces made up of two centrosymmetric motifs with PF6 − ions and acetonitrile molecules, giving rise to ribbons running parallel to [011]. 21-Screw-axis-related complex molecules and PF6 − counter-ions alternate in helical chains formed along the a axis by means of these contacts.