👤 Ramani MV

Title: Terpyridine-based ruthenium complexes containing a 4,5-diazafluoren-9-one ligand with light-driven enhancement of biological activity. Abstract: There has been growing effort in the scientific community to develop new antibiotics to address the major threat of bacterial resistance. One promising approach is the use of metal complexes that provide broader opportunities. Among these systems, polypyridine-ruthenium(II) complexes have received particular attention as drug candidates. Here, we prepared two new ruthenium(II) complexes with the formulation [Ru(DFO)(phtpy-R)Cl](PF6), where phtpy = 4'-phenyl-2,2':6',2''-terpyridine; R = -H(MPD1), -CH3(MPD2); and DFO = 4,5-diazafluoren-9-one, and investigated their chemical, biochemical and antibacterial activities. These compounds exhibit photoreactivity and produce reactive oxygen species (ROSs). Photogeneration of singlet oxygen (1O2) was measured in acetonitrile with significant quantum yields using blue light, Φ = 0.40 and 0.39 for MDP1 and MPD2, respectively. Further studies have shown that MPD1 and MPD2 can generate superoxide radicals. Antibacterial assays demonstrated a significant enhancement in MIC (minimum inhibitory concentration) upon blue light irradiation (>32-fold), with MICs of 15.6 μg mL-1 (S. aureus, ATCC 700698) and 3.9 μg mL-1 (S. epidermidis, ATCC 35984) for both metal complexes. Interestingly, an MIC of 15.6 μg mL-1 for MPD1 and MPD2 was observed against S. epidermidis ATCC 12228 under red light irradiation. The latter results are encouraging, considering that red light penetrates deeper into the skin. In addition, no significant cytotoxicity was observed in some mammalian cells, even upon light irradiation, supporting their potential safety. Altogether, these data show evidence of the potential use of these compounds as antimicrobial photodynamic therapeutic agents, enriching our arsenal to combat this worldwide bacterial threat. Show less

In this work, we studied six Ruthenium(II)-diphosphine compounds containing different mercapto ligands (N-S), with general formula [Ru(N-S)(dppm)₂]Cl (dppm=1,1-bis(diphenylphosphino)methane). These compounds were characterized by several techniques (NMR [¹H, ³¹P(¹H), and ¹³C], HRMS, IR, UV-Vis and XRD) and their purity confirmed by elemental analysis. DLS experiments revealed low diameters and polydispersity indexes, and positive log P values in n-octanol/PBS indicated their preference for the organic phase. In general, these compounds are stable in different media over 48 h. Cytotoxicity experiments revealed promising IC₅₀ values on A549 breast cancer cells, 0.48 μM and 0.80 μM for [Ru(mtz)(dppm)₂]Cl (1) and [Ru(mmi)(dppm)₂]Cl (2), respectively (mtz and mmi are 2-mercapto-2-thiazoline and mercapto-1-methylimidazole in their deprotonated form, respectively). Clonogenic and migration experiments indicated their antiproliferative and anti-migratory capacity. ICP-MS results indicated their cellular accumulation in the nucleus, with little amounts in mitochondria. No covalent DNA binding was observed by ICP-MS. JC-1 and cell Mito Stress test confirmed mitochondrial dysfunction, which was verified by mitochondrial membrane potential uncoupling and drastic alterations in the oxygen consumption rate. Taken together, our results provide crucial insights regarding the anticancer potential of ruthenium(II)-phosphine compounds. Show less

Cancer resistance to chemotherapeutic agents such as cisplatin presents a significant challenge, leading to treatment failure and poor outcomes. Novel metal-based compounds offer a promising strategy to overcome drug resistance and to enhance efficacy. Four Ru(II) complexes with fenamic acid derivatives were synthesized and characterized: [Ru(L)(bipy)(dppp)]PF₆, where L represents fenamic acid (HFen, complex 1), mefenamic acid (HMFen, complex 2), tolfenamic acid (HTFen, complex 3), and flufenamic acid (HFFen, complex 4). Their composition was supported by molar conductivity, elemental analysis, Fourier transform infrared spectroscopy, ultraviolet-visible spectroscopy, mass spectrometry, and ³¹P{¹H}, ¹H, and ¹³C nuclear magnetic resonance, with the crystal structure of complex 1 confirmed via X-ray diffraction. Complexes 1-4 exhibited notable cytotoxicity against tested cell lines, particularly A2780 and A2780cisR (cisplatin-resistant ovarian tumors), compared to MDA-MB-231 (breast) and A549 (lung) lines. Mechanistic studies revealed weak DNA interactions through minor grooves or electrostatic binding. Cellular uptake assays showed effective internalization of complexes 1 (3.6%) and 2 (4.5%), correlating with potent IC₅₀ values. These complexes also altered cell morphology, reduced cell density, and inhibited colony formation in the A2780 cells. Staining assays indicated induced cell death and organelle damage, highlighting their potential as promising antitumor agents. Show less

A novel bioorganometallic PNA conjugate (Ir-PNA) was synthesized by covalently bonding a model PNA tetramer to a luminescent bis-cyclometalated Ir(III) complex that acted as a photosensitizer under light irradiation to generate singlet oxygen (¹O₂). The conjugate was prepared using an Ir complex bearing the 1,10-phenanthroline ligand functionalized with either a free primary amine (Ir-NH₂) or a carboxyl group (Ir-COOH) for the conjugation to PNA. The photophysical studies on the Ir-COOH and the Ir-PNA demonstrated that the luminescent properties were maintained after the conjugation of the Ir fragment to PNA. Furthermore, the abilities to produce ¹O₂ of Ir-COOH and Ir-PNA were confirmed in a cuvette under visible light irradiation employing 1,5-dihydroxynaphthalene as a reporter, and the measured singlet oxygen quantum yield (Φ_Δ) supported the Ir-PNA conjugate efficacy as a photosensitizer (Φ_Δ = 0.54). Two-photon absorption microscopy on HeLa cells revealed that Ir-PNA localized in both the cytosol and nucleus, suggesting its potential as an intracellular carrier for PNA. Cytotoxicity assays by MTT tests showed that Ir-PNA was nontoxic in the absence of light, but induced cell death (EC₅₀ = 18 μM) after UV irradiation. Overall, the Ir-PNA conjugate represents a promising system for the intracellular delivery of the PNA and its application in PDT. Show less

Title: Exploring the potential of ruthenium(II)-phosphine-mercapto complexes as new anticancer agents. Abstract: The search for new metal-based anticancer drug candidates is a fundamental task in medicinal inorganic chemistry. In this work, we assessed the potential of two new Ru(II)-phosphine-mercapto complexes as potential anticancer agents. The complexes, with the formula [Ru(bipy)(dppen)(Lx)]PF6 [(1), HL1 = 2-mercapto-pyridine and (2), HL2 = 2-mercapto-pyrimidine, bipy = 2,2'-bipyridine, dppen = cis-1,2-bis(diphenylphosphino)-ethylene] were synthesized and characterized by nuclear magnetic resonance (NMR) [1H, 31P(1H), and 13C], high resolution mass spectrometry (HR-MS), cyclic voltammetry, infrared and UV-Vis spectroscopies. Complex 2 was obtained as a mixture of two isomers, 2a and 2b, respectively. The composition of these metal complexes was confirmed by elemental analysis and liquid chromatography-mass spectrometry (LC-MS). To obtain insights into their lipophilicity, their distribution coefficients between n-octanol/PBS were determined. Both complexes showed affinity mainly for the organic phase, presenting positive log P values. Also, their stability was confirmed over 48 h in different media (i.e., DMSO, PBS and cell culture medium) via HPLC, UV-Vis and 31P{1H} NMR spectroscopies. Since enzymes from the P-450 system play a crucial role in cellular detoxification and metabolism, the microsomal stability of 1, which was found to be the most interesting compound of this study, was investigated using human microsomes to verify its potential oxidation in the liver. The analyses by LC-MS and ESI-MS reveal three main metabolites, obtained by oxidation in the dppen and bipy moieties. Moreover, 1 was able to interact with human serum albumin (HSA). The cytotoxicity of the metal complexes was tested in different cancerous and non-cancerous cell lines. Complex 1 was found to be more selective than cisplatin against MDA-MB-231 breast cancer cells when compared to MCF-10A non-cancerous cells. In addition, complex 1 affects cell morphology and migration, and inhibits colony formation in MDA-MB-231 cells, making it a promising cytotoxic agent against breast cancer. Show less

Metallocompounds have emerged as promising new anticancer agents, which can also exhibit properties to be used in photodynamic therapy. Here, we prepared two ruthenium-based compounds with a 2,2'-bipyridine ligand conjugated to an anthracenyl moiety. These compounds coded GRBA and GRPA contain 2,2'-bipyridine or 1,10-phenathroline as auxiliary ligands, respectively, which provide quite a distinct behavior. Notably, compound GRPA exhibited remarkably high photoproduction of singlet oxygen even in water (ϕ_Δ = 0.96), almost twice that of GRBA (ϕ_Δ = 0.52). On the other hand, this latter produced twice more superoxide and hydroxyl radical species than GRPA, which may be due to the modulation of their excited state. Interestingly, GRPA exhibited a modest binding to DNA (K_b = 4.51 × 10⁴), while GRBA did not show a measurable interaction only noticed by circular dichroism measurements. Studies with bacteria showed a great antimicrobial effect, including a synergistic effect in combination with commercial antibiotics. Besides that, GRBA showed very low or no cytotoxicity against four mammalian cells, including a hard-to-treat MDA-MB-231, triple-negative human breast cancer. Potent activities were measured for GRBA upon blue light irradiation, where IC₅₀ of 43 and 13 nmol L^-1 were seen against hard-to-treat triple-negative human breast cancer (MDA-MB-231) and ovarian cancer cells (A2780), respectively. These promising results are an interesting case of a simple modification with expressive enhancement of biological activity that deserves further biological studies. Show less

Ovarian cancer represents a leading cause of cancer-related deaths in women worldwide. Chemotherapeutic agents are usually employed to treat the patients, and Ruthenium(II)-based compounds have been investigated as possible substitutes for platinum drugs. In this work, we studied three different Ru(II)-phosphine-mercapto complexes (1-3) as potential cytotoxic agents against A2780 and A2780-cisR ovarian cancer cells. A time-dependent cytotoxicity was observed for 2, which also exhibited better selectivity than cisplatin control. A similar cytotoxic behavior was observed on 3D tumor spheroids. Although no changes were observed in cell cycle distribution, compound 2 affected the mitochondrial membrane potential on A2780 cells, and caused cell death via apoptotic pathway, which was confirmed by flow cytometry assay. Western blotting experiments revealed that 2 affected the expression of p53, PCNA, γH2AX and cleaved caspase-3, making it a promising anticancer agent for ovarian cancer. Show less

Title: Neutral rhenium(I) tricarbonyl complexes with sulfur-donor ligands: anti-proliferative activity and cellular localization. Abstract: Rhenium(I) tricarbonyl complexes are widely studied for their cell imaging properties and anti-cancer and anti-microbial activities, but the complexes with S-donor ligands remain relatively unexplored. A series of six fac-[Re(NN)(CO)3(SR)] complexes, where (NN) is 2,2'-bipyridyl (bipy) or 1,10-phenanthroline (phen), and RSH is a series of thiocarboxylic acid methyl esters, have been synthesized and characterized. Cellular uptake and anti-proliferative activities of these complexes in human breast cancer cell lines (MDA-MB-231 and MCF-7) were generally lower than those of the previously described fac-[Re(NN)(CO)3(OH2)]+ complexes; however, one of the complexes, fac-[Re(CO)3(phen)(SC(Ph)CH2C(O)OMe)] (3b), was active (IC50 ∼ 10 μM at 72 h treatment) in thiol-depleted MDA-MB-231 cells. Moreover, unlike fac-[Re(CO)3(phen)(OH2)]+, this complex did not lose activity in the presence of extracellular glutathione. Taken together these properties show promise for further development of 3b and its analogues as potential anti-cancer drugs for co-treatment with thiol-depleting agents. Conversely, the stable and non-toxic complex, fac-[Re(bipy)(CO)3(SC(Me)C(O)OMe)] (1a), predominantly localized in the lysosomes of MDA-MB-231 cells, as shown by live cell confocal microscopy (λex = 405 nm, λem = 470-570 nm). It is strongly localized in a subset of lysosomes (25 μM Re, 4 h treatment), as shown by co-localization with a Lysotracker dye. Longer treatment times with 1a (25 μM Re for 48 h) resulted in partial migration of the probe into the mitochondria, as shown by co-localization with a Mitotracker dye. These properties make complex 1a an attractive target for further development as an organelle probe for multimodal imaging, including phosphorescence, carbonyl tag for vibrational spectroscopy, and Re tag for X-ray fluorescence microscopy. Show less

Mechanisms of defense against ferroptosis (an iron-dependent form of cell death induced by lipid peroxidation) in cellular organelles remain poorly understood, hindering our ability to target ferroptosis in disease treatment. In this study, metabolomic analyses revealed that treatment of cancer cells with glutathione peroxidase 4 (GPX4) inhibitors results in intracellular glycerol-3-phosphate (G3P) depletion. We further showed that supplementation of cancer cells with G3P attenuates ferroptosis induced by GPX4 inhibitors in a G3P dehydrogenase 2 (GPD2)-dependent manner; GPD2 deletion sensitizes cancer cells to GPX4 inhibition-induced mitochondrial lipid peroxidation and ferroptosis, and combined deletion of GPX4 and GPD2 synergistically suppresses tumor growth by inducing ferroptosis in vivo. Mechanistically, inner mitochondrial membrane-localized GPD2 couples G3P oxidation with ubiquinone reduction to ubiquinol, which acts as a radical-trapping antioxidant to suppress ferroptosis in mitochondria. Taken together, these results reveal that GPD2 participates in ferroptosis defense in mitochondria by generating ubiquinol. Show less

With the aim of enhancing the biological activity of ruthenium-nitrosyl complexes, new compounds with four equatorially bound indazole ligands, namely, trans-[RuCl(Hind)₄(NO)]Cl₂·H₂O ([3]Cl₂·H₂O) and trans-[RuOH(Hind)₄(NO)]Cl₂·H₂O ([4]Cl₂·H₂O), have been prepared from trans-[Ru(NO₂)₂(Hind)₄] ([2]). When the pH-dependent solution behavior of [3]Cl₂·H₂O and [4]Cl₂·H₂O was studied, two new complexes with two deprotonated indazole ligands were isolated, namely [RuCl(ind)₂(Hind)₂(NO)] ([5]) and [RuOH(ind)₂(Hind)₂(NO)] ([6]). All prepared compounds were comprehensively characterized by spectroscopic (IR, UV-vis, ¹H NMR) techniques. Compound [2], as well as [3]Cl₂·2(CH₃)₂CO, [4]Cl₂·2(CH₃)₂CO, and [5]·0.8CH₂Cl₂, the latter three obtained by recrystallization of the first isolated compounds (hydrates or anhydrous species) from acetone and dichloromethane, respectively, were studied by X-ray diffraction methods. The photoinduced release of NO in [3]Cl₂ and [4]Cl₂ was investigated by cyclic voltammetry and resulting paramagnetic NO species were detected by EPR spectroscopy. The quantum yields of NO release were calculated and found to be low (3-6%), which could be explained by NO dissociation and recombination dynamics, assessed by femtosecond pump-probe spectroscopy. The geometry and electronic parameters of Ru species formed upon NO release were identified by DFT calculations. The complexes [3]Cl₂ and [4]Cl₂ showed considerable antiproliferative activity in human cancer cell lines with IC₅₀ values in low micromolar or submicromolar concentration range and are suitable for further development as potential anticancer drugs. p53-dependence of Ru-NO complexes [3]Cl₂ and [4]Cl₂ was studied and p53-independent mode of action was confirmed. The effects of NO release on the cytotoxicity of the complexes with or without light irradiation were investigated using NO scavenger carboxy-PTIO. Show less

Current anticancer drug discovery efforts focus on the identification of first-in-class compounds with a mode-of-action distinct from conventional DNA-targeting agents for chemotherapy. An emerging trend is the identification of endoplasmic reticulum (ER) targeting compounds that induce ER stress in cancer cells, leading to cell death. However, a limited pool of such compounds has been identified to date, and there are limited studies done on such compounds to allow for the rational design of ER stress-inducing agents. In our present study, we present a series of highly cytotoxic, ER stress-inducing Ru(II)-arene Schiff-Base (RAS) complexes, bearing iminoquinoline chelate ligands. We demonstrate that by structural modification to the iminoquinoline ligand, we could tune its π-acidity and influence reactive oxygen species (ROS) induction, switching between a ROS-mediated ER stress pathway activation and one that is not mediated by ROS induction. Our current study adds to the available ER stress inducers and shows how structural tuning could be used as a means to modulate the mode-of-action of such compounds. Show less

The promise of the metal(arene) structure as an anticancer pharmacophore has prompted intensive exploration of this chemical space. While N-heterocyclic carbene (NHC) ligands are widely used in catalysis, they have only recently been considered in metal complexes for medicinal applications. Surprisingly, a comparatively small number of studies have been reported in which the NHC ligand was coordinated to the Ru^II(arene) pharmacophore and even less with an Os^II(arene) pharmacophore. Here, we present a systematic study in which we compared symmetrically substituted methyl and benzyl derivatives with the nonsymmetric methyl/benzyl analogues. Through variation of the metal center and the halido ligands, an in-depth study was conducted on ligand exchange properties of these complexes and their biomolecule binding, noting in particular the stability of the M-C_NHC bond. In addition, we demonstrated the ability of the complexes to inhibit the selenoenzyme thioredoxin reductase (TrxR), suggested as an important target for anticancer metal-NHC complexes, and their cytotoxicity in human tumor cells. It was found that the most potent TrxR inhibitor diiodido(1,3-dibenzylbenzimidazol-2-ylidene)(η⁶-p-cymene)ruthenium(II) 1b^I was also the most cytotoxic compound of the series, with the antiproliferative effects in general in the low to middle micromolar range. However, since there was no clear correlation between TrxR inhibition and antiproliferative potency across the compounds, TrxR inhibition is unlikely to be the main mode of action for the compound type and other target interactions must be considered in future. Show less

p53 is a key tumor suppressor gene involved in key cellular processes and implicated in cancer therapy. However, it is inactivated in more than 50% of all cancers due to mutation or overexpression of its negative regulators. This leads to drug resistance and poor chemotherapeutic outcome as most clinical drugs act via a p53-dependent mechanism of action. An attractive strategy to circumvent this resistance would be to identify new anticancer drugs that act via p53-independent mode of action. In the present study, we identified 9 Ru (II)-Arene Schiff-base (RAS) complexes able to induce p53-independent cytotoxicity and discuss structural features that are required for their p53-independent activity. Increasing hydrophobicity led to an increase in cellular accumulation in cells with a corresponding increase in efficacy. We further showed that all nine complexes demonstrated p53-independent activity. This was despite significant differences in their physicochemical properties, suggesting that the iminoquinoline ligand, a common structural feature for all the complexes, is required for the p53-independent activity. Show less

The antitumor activity of ruthenium(II) arene (p-cymene, benzene, hexamethylbenzene) derivatives containing modified curcumin ligands (HCurcI=(1E,4Z,6E)-5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)hepta-1,4,6-trien-3-one and HCurcII=(1E,4Z,6E)-5-hydroxy-1,7-bis(4-methoxyphenyl)hepta-1,4,6-trien-3-one) is described. These have been characterized by IR, ESI-MS and NMR spectroscopy. The X-ray crystal structure of HCurcI has been determined and compared with its related Ru complex. Four complexes have been evaluated against five tumor cell lines, whose best activities [IC₅₀ (μM)] are: breast MCF7, 9.7; ovarian A2780, 9.4; glioblastoma U-87, 9.4; lung carcinoma A549, 13.7 and colon-rectal HCT116, 15.5; they are associated with apoptotic features. These activities are improved when compared to the already known corresponding curcumin complex, (p-cymene)Ru(curcuminato)Cl, about twice for the breast and ovarian cancer, 4.7 times stronger in the lung cancer and about 6.6 times stronger in the glioblastoma cell lines. In fact, the less active (p-cymene)Ru(curcuminato)Cl complex only shows similar activity to two novel complexes in the colon cancer cell line. Comparing antitumor activity between these novel complexes and their related curcuminoids, improvement of antiproliferative activity is seen for a complex containing CurcII in A2780, A549 and U87 cell lines, whose IC₅₀ are halved. Therefore, after replacing OH curcumin groups with OCH₃, the obtained species HCurcI and its Ru complexes have increased antitumor activity compared to curcumin and its related complex. In contrast, HCurcII is less cytotoxic than curcumin but its related complex [(p-cymene)Ru(CurcII)Cl] is twice as active as HCurcII in 3 cell lines. Results from these novel arene-Ru curcuminoid species suggest that their increased cytotoxicity on tumor cells correlate with increase of curcuminoid lipophilicity. Show less

Ruthenium(II)-arene complexes with biotin-containing ligands were prepared so that a novel drug delivery system based on tumor-specific vitamin-receptor mediated endocytosis could be developed. The complexes were characterized by spectroscopic methods and their in vitro anticancer activity in cancer cell lines with various levels of major biotin receptor (COLO205, HCT116 and SW620 cells) was tested in comparison with the ligands. In all cases, coordination of ruthenium resulted in significantly enhanced cytotoxicity. The affinity of Ru(II) -biotin complexes to avidin was investigated and was lower than that of unmodified biotin. Hill coefficients in the range 2.012-2.851 suggest strong positive cooperation between the complexes and avidin. To estimate the likelihood of binding to the biotin receptor/transporter, docking studies with avidin and streptavidin were conducted. These explain, to some extent, the in vitro anticancer activity results and support the conclusion that these novel half-sandwich ruthenium(II)-biotin conjugates may act as biological vectors to cancer cells, although no clear relationship between the cellular Ru content, the cytotoxicity, and the presence of the biotin moiety was observed. Show less

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. Show less

With the aim of systematically studying fundamental structure-activity relationships as a basis for the development of Ru(II) arene complexes (arene = p-cymene or biphenyl) bearing mono-, bi-, or tridentate am(m)ine ligands as anticancer agents, a series of ammine, ethylenediamine, and diethylenetriamine complexes were prepared by different synthetic routes. Especially the synthesis of mono-, di-, and triammine complexes was found to be highly dependent on the reaction conditions, such as stoichiometry, temperature, and time. Hydrolysis and protein-binding studies were performed to determine the reactivity of the compounds, and only those containing chlorido ligands undergo aquation or form protein adducts. These properties correlate well with in vitro tumor-inhibiting potency of the compounds. The complexes were found to be active in anticancer assays when meeting the following criteria: stability in aqueous solution and low rates of hydrolysis and binding to proteins. Therefore, the complexes least reactive to proteins were found to be the most cytotoxic in cancer cells. In general, complexes with biphenyl as arene ligand inhibited the growth of tumor cells more effectively than the cymene analogues, consistent with the increase in lipophilicity. This study highlights the importance of finding a proper balance between reactivity and stability in the development of organometallic anticancer agents. Show less

The monodentate cis-[Ru(phen)(2)(hist)(2)](2+)1R and the bidentate cis-[Ru(phen)(2)(hist)](2+)2A complexes were prepared and characterized using spectroscopic ((1)H, ((1)H-(1)H)COSY and ((1)H-(13)C)HSQC NMR, UV-vis, luminescence) techniques. The complexes presented absorption and emission in the visible region, as well as a tri-exponential emission decay. The complexes are soluble in aqueous and non-aqueous solution with solubility in a buffer solution of pH 7.4 of 1.14 × 10(-3) mol L(-1) for (1R + 2A) and 6.43 × 10(-4) mol L(-1) for 2A and lipophilicity measured in an aqueous-octanol solution of -1.14 and -0.96, respectively. Photolysis in the visible region in CH(3)CN converted the starting complexes into cis-[Ru(phen)(2)(CH(3)CN)(2)](2+). Histamine photorelease was also observed in pure water and in the presence of BSA (1.0 × 10(-6) mol L(-1)). The bidentate coordination of the histamine to the ruthenium center in relation to the monodentate coordination increased the photosubstitution quantum yield by a factor of 3. Pharmacological studies showed that the complexes present a moderate inhibition of AChE with an IC(50) of 21 μmol L(-1) (referred to risvagtini, IC(50) 181 μmol L(-1) and galantamine IC(50) 0.006 μmol L(-1)) with no appreciable cytotoxicity toward to the HeLa cells (50% cell viability at 925 μmol L(-1)). Cell uptake of the complexes into HeLa cells was detected by fluorescence confocal microscopy. Overall, the observation of a luminescent complex that penetrates the cell wall and has low cytotoxicity, but is reactive photochemically, releasing histamine when irradiated with visible light, are interesting features for application of these complexes as phototherapeutic agents. Show less