📚 BiometalDB

Herein we discuss five ruthenium(ii) complexes with good cytotoxicity against cancer cells. These complexes are named [Ru(tzdt)(bipy)(dppb)]PF6 (1), [Ru(mmi)(bipy)(dppb)]PF6 (2), [Ru(dmp)(bipy)(dppb)]PF6 (3), [Ru(mpca)(bipy)(dppb)]PF6 (4) and [Ru(2mq)(bipy)(dppb)]PF6 (5), where tzdt = 1,3-thiazolidine-2-thione, mmi = mercapto-1-methyl-imidazole, dmp = 4,6-diamino-2-mercaptopyrimidine, mpca = 6-mercaptopyridine-3-carboxylic acid, 2mq = 2-mercapto-4(3H)-quinazolinone, bipy = 2,2'-bipyridine and dppb = 1,4-bis(diphenylphosphino)butane. In vitro cell culture experiments revealed significant cytotoxic activity for 1-5 against MDA-MB-231, MCF-7, A549, DU-145 and HepG2 tumor cells, higher than that for the standard anticancer drug cisplatin. Compound/DNA interaction studies were carried out showing that 1-5 interact with DNA by electrostatic force of attraction or by hydrogen bonding. Moreover, the complexes interact, moderately and spontaneously, with human serum albumin (HSA) through the hydrophobic region. The five complexes are able to inhibit the DNA supercoiled relaxation mediated by human topoisomerase IB (TopIB), and complex 1 is found to be the most efficient TopIB inhibitor among the five compounds. The inhibitory effect and analysis of different steps of the TopIB catalytic cycle indicate that complex 1 inhibits the cleavage reaction impeding the binding of the enzyme to DNA and has no effect on the religation step. Complexes 1, 2 and 3 did not show mutagenic activity when they were evaluated by the cytokinesis-block micronucleus cytome assay in HepG2 cells and the Ames test in the presence and absence of mouse liver S9 metabolic activation. Therefore, it is necessary to perform further in-depth analysis of the therapeutic potential of these promising ruthenium complexes as anticancer drugs. Show less

Four structurally related Ru(II)-halide-PTA complexes, of general formula trans- or cis-[Ru(PTA)4X2] (PTA=1,3,5-triaza-7-phosphaadamantane, X=Cl (1, 2), Br (3, 4), were prepared and characterized. Whereas compounds 1 and 2 are known, the corresponding bromo derivatives 3 and 4 are new. The Ru(III)-PTA compound trans-[RuCl4(PTAH)2]Cl (5, PTAH=PTA protonated at one N atom), structurally similar to the well-known Ru(III) anticancer drug candidates (Na)trans-[RuCl4(ind)2] (NKP-1339, ind=indazole) and (Him)trans-[RuCl4(dmso-S)(im)] (NAMI-A, im=imidazole), was also prepared and similarly investigated. Notably, the presence of PTA confers to all complexes an appreciable solubility in aqueous solutions at physiological pH. The chemical behavior of compounds 1-5 in water and in physiological buffer, their interactions with two model proteins - cytochrome c and ribonuclease A - as well as with a single strand oligonucleotide (5'-CGCGCG-3'), and their in vitro cytotoxicity against a human colon cancer cell line (HCT-116) and a myeloid leukemia (FLG 29.1) were investigated. Upon dissolution in the buffer, sequential halide replacement by water molecules was observed for complexes 1-4, with relatively slow kinetics, whereas the Ru(III) complex 5 is more inert. All tested compounds manifested moderate antiproliferative properties, the cis compounds 2 and 4 being slightly more active than the trans ones (1 and 3). Mass spectrometry experiments evidenced that all complexes exhibit a far higher reactivity towards the reference oligonucleotide than towards model proteins. The chemical and biological profiles of compounds 1-5 are compared to those of established ruthenium drug candidates in clinical development. Show less

In this work, four naphthalene diimide (NDI)-functionalized half-sandwich Ru(II) complexes Ru1-Ru4 bearing the general formula [(η⁶-arene)Ru^II(N^N)Cl]PF₆, where arene = benzene (bn), p-cymene (p-cym), 1,3,5-trimethylbenzene (tmb), and hexamethylbenzene (hmb), have been synthesized and characterized. By introducing the NDI unit into the N,N-chelating ligand of these half-sandwich complexes, the poor luminescent half-sandwich complexes are endowed with excellent emission performance. Besides, modification on the arene ligand of arene-Ru(II) complexes can influence the electron density of the metal center, resulting in great changes in the kinetic properties, catalytic activities in the oxidative conversion of NADH to NAD⁺, and biological activities of these compounds. Particularly, Ru4 exhibits the highest reactivity and the strongest inhibitory activity against the growth of three tested cancer cell lines. Further study revealed that Ru4 can enter cells quickly in an energy-dependent manner and preferentially accumulate in the mitochondria of MDA-MB-231 cells, inducing cell apoptosis via reactive oxygen species overproduction and mitochondrial dysfunction. Significantly, Ru4 can effectively inhibit the cell migration and invasion. Overall, the complexation with NDI and modification on the arene ligand endowed the half-sandwich Ru(II) complexes with improved spectroscopic properties and anticancer activities, highlighting their potential applications for cancer treatment. Show less

Title: Pyrene-based fluorescent Ru(II)-arene complexes for significant biological applications: catalytic potential, DNA/protein binding, two photon cell imaging and Abstract: Ruthenium complexes are being studied extensively as anticancer drugs following the inclusion of NAMI-A and KP1019 in phase II clinical trials for the treatment of metastatic phase and primary tumors. Herein, we designed and synthesized four organometallic Ru(II)-arene complexes [Ru(η6-p-cymene)(L)Cl] (1), [Ru(η6-benzene)(L)Cl] (2), [Ru(η6-p-cymene)(L)N3] (3) and [Ru(η6-benzene)(L)N3] (4) [HL = (E)-N'-(pyren-1-ylmethylene)thiopene-2-carbohydrazide] that have anticancer, antimetastatic and two-photon cell imaging abilities. Moreover, in the transfer hydrogenation of NADH to NAD+, these compounds also display good catalytic activity. All the complexes, 1-4, are well characterized by spectroscopic techniques (NMR, mass, FTIR, UV-vis and fluorescence). The single crystal X-ray diffraction technique proved that the ligand L coordinates through an N,O-bidentate chelating fashion in the solid-state structures of complexes 1 and 2. The stability study of the complexes was performed through UV-visible spectroscopy. The cytotoxicities of all the complexes were screened through MTT assay and the results revealed that the complexes have potential anticancer activity against various cancerous cells (HeLa, MCF7 and A431). Studies with spectroscopic techniques revealed that complexes 1-4 exhibit strong interactions with biological molecules i.e. proteins (HSA and BSA) and CT-DNA. The density functional theory (DFT-D) method has been employed in the present study to know the interaction between DNA and complexes by calculating the HOMO and LUMO energy. A plausible mechanism for NADH oxidation has also been explored and the DFT calculations are found to be in accord with the experimental observation. Furthermore, we have investigated intracellular reactive oxygen species (ROS) generation capabilities in the MCF7 breast cancer cell line. The Hoechst/PI dual staining method confirmed the apoptosis mode of cell death. Meanwhile, complexes 1-4 show capabilities to prevent the metastasis phase of cancer cells by inhibiting cell migration. Show less

The facile modification of the ligands in organometallic Ru(II)-arene complexes offers more opportunities to optimize their pharmacological profiles. Herein, three Ru(II)-arene complexes containing a glutathione S-transferase (GST) inhibitor (NBDHEX) in chelate ligand have been designed and synthesized in this study. In vitro results indicated that the ligation with NBDHEX significantly increased the activities and selectivities of the organometallic Ru(II)-arene complexes against tumor cells, especially complex 3, which was the most active compound among the tested compounds. DFT calculations and hydrolysis results demonstrated that complex 3 with more alkyl groups in the arene ligand has increased electron density at the Ru(II) center as compared with complexes 1 and 2, thus resulting in the improved hydrolysis rate, which may be responsible for its higher anticancer activity. Further studies showed that complexes 1-3 can cause the loss of the mitochondrial membrane potential and upregulate the expression of Bcl-2 and Bax in A549 cells, suggesting that complexes 1-3-induced cell death may be mediated via the mitochondrial apoptotic pathway. Thus, these findings suggested that simultaneous modification of the chelate ligands and arene rings in the organometallic Ru(II)-arene complexes is an effective way to improve their pharmacological properties. Show less

Three ruthenium(II) phosphine/diimine/picolinate complexes were selected aimed at investigating anticancer activity against several cancer cell lines and the capacity of inhibiting the supercoiled DNA relaxation mediated by human topoisomerase IB (Top 1). The structure-lipophilicity relationship in membrane permeability using the Caco-2 cells have also been evaluated in this study. SCAR 5 was found to present 45 times more cytotoxicity against breast cancer cell when compared to cisplatin. SCAR 4 and 5 were both found to be capable of inhibiting the supercoiled DNA relaxation mediated by Top 1. Interaction studies showed that SCAR 4 and 5 can bind to DNA through electrostatic interactions while SCAR 6 is able to bind covalently to DNA. The complexes SCAR were found to interact differently with bovine serum albumin (BSA) suggesting hydrophobic interactions with albumin. The permeability of all complexes was seen to be dependent on their lipophilicity. SCAR 4 and 5 exhibited high membrane permeability (P _app  > 10 × 10^-6 cm·s^-1) in the presence of BSA. The complexes may pass through Caco-2 monolayer via passive diffusion mechanism and our results suggest that lipophilicity and interaction with BSA may influence the complexes permeation. In conclusion, we demonstrated that complexes have powerful pharmacological activity, with different results for each complex depending on the combination of their ligands. Show less

A series of octahedral Ru(II) polypyridyl complexes, [Ru(phen)(2)L](2+) (L=R-PIP and PIP=2-phenylimidazo[4,5-f][1,10]phenanthroline) were synthesized and characterized by elementary analysis, (1)H NMR and ES-MS, as well as UV-visible spectra and emission spectra. The antitumor activities of these complexes and their corresponding ligands were investigated against mouse leukemia L1210 cells, human oral epidermoid carcinoma KB cells, human promyelocytic leukemia cells (HL-60) and Bel-7402 liver cancer cells by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. It was found that the complexes [Ru(phen)(2)L](2+) (L=R-PIP) exert rather potent activities against all of these cell lines, especially for the KB cells (IC(50)=4.7+/-1.3 microM). The binding affinities of these Ru(II) complexes to CT-DNA (calf thymus DNA), as well as the DNA-unwinding properties on supercoiled pBR322 DNA were also investigated. The results showed that these Ru(II) polypyridyl complexes not only had an excellent DNA-binding property but also possessed a highly effective DNA-photocleavage ability. The structure-activity relationships and antitumor mechanism were also carefully discussed. Show less

The synthesis and full characterization of the new aqua-complex [(η(6)-p-cymene)Ru(OH2)(κ(2)-N,N-2-pydaT)](BF4)2, [2](BF4)2, and the nucleobase derivative [(η(6)-p-cymene)Ru(9-MeG)(κ(2)-N,N-2-pydaT)](BF4)2, [4](PF6)2, where 2-pydaT = 2,4-diamino-6-(2-pyridyl)-1,3,5-triazine and 9-MeG = 9-methylguanine, are reported here. The crystal structures of both [4](PF6)2 and the chloro complex [(η(6)-p-cymene)RuCl(κ(2)-N,N-2-pydaT)](PF6), [1](PF6), have been elucidated by X-ray diffraction. The former provided relevant information regarding the interaction of the metallic fragment [(η(6)-p-cymene)Ru(κ(2)-N,N-2-pydaT)](2+) and a simple model of DNA. NMR and kinetic absorbance studies have proven that the aqua-complex [2](BF4)2 binds to the N7 site of guanine in nucleobases, nucleotides, or DNA. A stable bifunctional interaction (covalent and partially intercalated) between the [(η(6)-p-cymene)Ru(κ(2)-N,N-2-pydaT)](2+) fragment and CT-DNA has been corroborated by kinetic, circular dichroism, viscometry, and thermal denaturation experiments. The reaction mechanism entails the very fast formation of the Ru-O-(PO3) linkage prior to the fast intercalation of the 2-pydaT fragment. Then, a Ru-N7-(G) covalent bond is formed at the expense of the Ru-O-(PO3) bond, yielding a bifunctional complex. The dissociation rate of the intercalated fragment is slow, and this confers additional interest to [2](BF4)2 in view of the likely correlation between slow dissociation and biological activity, on the assumption that DNA is the only biotarget. Furthermore, [2](BF4)2 displays notable pH-dependent cytotoxic activity in human ovarian carcinoma cells (A2780, IC50 = 11.0 μM at pH = 7.4; IC50 = 6.58 μM at pH = 6.5). What is more, complex [2](BF4)2 is not cross-resistant with cisplatin, exhibiting a resistance factor, RF(A2780cis), of 0.28, and it shows moderate selectivity toward the cancer cell lines, in particular, A2780cis (IC50 = 3.0 5 ± 0.08 μM), relative to human lung fibroblast cells (MRC-5; IC50 = 24 μM), the model for healthy cells. Show less

Although different types of metal-based anticancer complexes have been synthesized, novel complexes to reduce the serious side effect of cisplatin and conquer cancer metastasis are still highly desired. Here, we report the synthesis, characterization, and biological activity of a novel heterodinuclear Pt(IV)-Ru(II) anticancer prodrug. The Pt(IV)-Ru(II) complex exhibits good stability in both water and PBS solution. Biological evaluation revealed that this bifunctional Pt(IV)-Ru(II) complex utilizes the advantages of two metal centers to have both cytotoxicity and antimetastatic property as designed. Although the complex has comparable cytotoxicities to cisplatin in tested cancer cell lines, this prodrug selectively kills cancer but not normal cells, and the IC₅₀ values of the Pt(IV)-Ru(II) complex are 7-10 times higher than those of cisplatin toward normal cells. The cancer cell selectivity is further demonstrated by a cancer-normal cell coculture system. In addition, the antimetastatic properties of the heterodinuclear complex are assessed by using highly metastatic human breast cancer cells, and the results show that the migration and invasion of cancer cells are effectively restrained after the treatment. Moreover, the Pt(IV)-Ru(II) complex displays lower toxicity than cisplatin in developing zebrafish embryos. We, therefore, report an example of heterodinuclear Pt(IV)-Ru(II) complex not only to defeat both drug resistance and cancer metastasis but also having significantly improved cancer cell selectivity and reduced in vivo toxicity than cisplatin. Show less

Smart design and efficient synthesis of benzimidazole Ru, Ir and Rh cyclometalated complexes are reported with promising cytotoxic activity against HT29, T47D, A2780 and A2780cisR cancer cell lines. Their apoptosis, accumulation, cell cycle arrest, protein binding and DNA binding effects are also discussed. Show less

Organometallic ruthenium complexes as potential anticancer agents have been explored due to their suitable properties, such as stability in the solid state and in solution, water solubility and low toxicity. In this study, eight metal complexes of this class were synthesized, characterized and their important biological activities against a human breast tumor cell line (MDA-MB-231) were studied. Complexes 1-8 were obtained in good yields and have been characterized by satisfactory elemental analyses, IR, 1D and 2D ¹H and ¹³C{¹H} NMR, UV-Vis spectroscopy, cyclic voltammetry, ESI-MS and X-ray diffractometry (1, 2, 3 and 6). All complexes exhibit growth inhibition on human breast and lung tumor cell lines, with IC₅₀ values ranging from 6.0 to 45.0 μM in 48 h. Four compounds were selected to evaluate the changes in the morphology, clonogenic, migration, cell cycle arrest and cell death in MDA-MB-231 cells. The complexes are able to induce morphological changes and inhibit the size, number of colonies and cell migration, and induce cell cycle arrest in the sub-G1 phase and apoptosis cell death. The interaction of the complexes with DNA was determined by performing spectroscopic titration, a competitive assay with thiazole orange, circular dichroism, gel electrophoresis and interactions with guanosine or guanosine monophosphate by ¹H NMR, indicating the non-covalent interaction. The HSA binding affinity measured by spectrophotometric titration, revealed the hydrophobic and spontaneous association with the human protein. Overall, the studies indicated that these metal complexes are potential agents against MDA-MB-231 cells, encouraging us to continue studies of these types of compounds. Show less

Organometallic Ru(II)-cymene complexes linked to ferrocene (Fc) via nitrogen heterocycles have been synthesized and studied as cytotoxic agents. These compounds are analogues of Ru(II)-arene piano-stool anticancer complexes such as RAPTA-C. The Ru center was coordinated by pyridine, imidazole, and piperidine with 0-, 1-, or 2-carbon bridges to Fc to give six bimetallic, dinuclear compounds, and the properties of these complexes were compared with their non-Fc-functionalized parent compounds. Crystal structures for five of the compounds, their Ru-cymene parent compounds, and an unusual trinuclear compound were determined. Cyclic voltammetry was used to determine the formal M^III/II potentials of each metal center of the Ru-cymene-Fc complexes, with distinct one-electron waves observed in each case. The Fc-functionalized complexes were found to exhibit good cytotoxicity against HT29 human colon adenocarcinoma cells, whereas the parent compounds were inactive. Similarly, antibacterial activity from the Ru-cymene-Fc compounds was observed against Bacillus subtilis, but not from the unfunctionalized complexes. In both cases, the IC₅₀ values correlated quantitatively with the Fc^+/0 reduction potentials. This is consistent with more facile oxidation to give ferrocenium, and subsequent generation of toxic reactive oxygen species, leading to greater cytotoxicity. The antioxidant properties of the complexes were quantified by a 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. EC₅₀ values indicate that linking of the Ru and Fc centers promotes antioxidant activity. Show less

Three Ru(II) polypyridyl complexes with potential high DNA-binding ability have been designed and synthesized by extending the conjugated plane of the intercalative ligand and introducing electropositive pendants to the ancillary ligand. Spectral titration, DNA thermal denaturation, viscosity experiments, and quantum chemistry calculations were performed, and the complexes were found to intercalate into DNA base pairs with very high affinity even at high salt concentrations. Benefiting from their high DNA-binding ability, the complexes can effectively inhibit the DNA transcription activity by blocking the binding of T7 RNA polymerase to the template DNA. As efficient transcription inhibitors, the complexes demonstrated high in vitro antitumor activity against four selected tumor cell lines. Show less

Cationic ruthenium(II) pentamethylcyclopentadienyl benzenesulfonamide sandwich complexes have been synthesized and screened for enzymatic inhibition of the physiologically dominant carbonic anhydrase (CA) isozymes: human CA I and II, mitochondrial isozymes VA and VB, and the cancer-associated isozyme IX. The complexes demonstrated weaker binding to CAs compared with typical aromatic sulfonamides, inhibiting the enzyme at high nanomolar concentrations. An in vitro cytotoxic evaluation of the complexes was also undertaken against a range of tumorigenic cell lines and a healthy human cell line. Complexes inhibited the growth of cancerous cells at low micromolar concentrations while expressing lower levels of toxicity towards the normal human cell line. Factors influencing the synthesis, cytotoxicity, and enzyme affinity for this series of organometallic complexes are discussed. Show less

Acute myeloid leukemia (AML) is a lethal hematologic malignancy caused by leukemic blasts that fail to mature normally. AML has a high relapse rate, primarily due to a small subset known as leukemic stem cells (LSCs). In this work, we investigated the ability of a Ru(II)-thymine complex (RTC) with the formula [Ru(PPh₃)₂(Thy)(bipy)]PF₆ (where PPh₃ = triphenylphosphine, Thy = thymine, and bipy = 2,2'-bipyridine) to suppress AML LSCs. RTC exhibited potent cytotoxicity toward both solid and hematologic malignancies and suppressed primary AML LSCs, as observed by the reduction in the CD34 +CD38- cell population. In the AML cell line KG-1a, which has an LSC-like population, RTC reduced the number of CD34 + and CD123 + cells. A reduction in leukemic blasts was detected in the bone marrow of RTC-treated NSG mice bearing KG-1a xenografts. Increased DNA fragmentation, YO-PRO-1 staining, active caspase-3 and cleaved PARP (Asp 214) levels, and mitochondrial superoxide levels were detected in RTC-treated KG-1a cells. The pancaspase inhibitor Z-VAD-(OMe)-FMK, but not the antioxidant N-acetylcysteine, partially prevented RTC-induced cell death in KG-1a cells, indicating that RTC induces caspase-mediated apoptosis in KG-1a cells via an oxidative stress-independent pathway. In molecular mechanism studies, transcripts of the NF-κB inhibitor NFKBIA were upregulated, and the level of NF-κB p65 phosphorylated at the Ser529 residue was reduced in RTC-treated KG-1a cells, indicating that RTC may inhibit NF-κB signaling. Overall, these results indicate the anti-AML potential of RTC in AML LSCs via the suppression of NF-κB signaling. Show less

Six substitutionally inert [Ru(II) (bipy)2 dppz](2+) derivatives (bipy=2,2'-bipyridine, dppz=dipyrido[3,2-a:2',3'-c]phenazine) bearing different functional groups on the dppz ligand [NH2 (1), OMe (2), OAc (3), OH (4), CH2 OH (5), CH2 Cl (6)] were synthesized and studied as potential photosensitizers (PSs) in photodynamic therapy (PDT). As also confirmed by DFT calculations, all complexes showed promising (1) O2 production quantum yields, well comparable with PSs available on the market. They can also efficiently intercalate into the DNA double helix, which is of high interest in view of DNA targeting. The cellular localization and uptake quantification of 1-6 were assessed by confocal microscopy and high-resolution continuum source atomic absorption spectrometry. Compound 1, and especially 2, showed very good uptake in cervical cancer cells (HeLa) with preferential nuclear accumulation. None of the compounds studied was found to be cytotoxic in the dark on both HeLa cells and, interestingly, on noncancerous MRC-5 cells (IC50 >100 μM). However, 1 and 2 showed very promising behavior with an increment of about 150 and 42 times, respectively, in their cytotoxicities upon light illumination at 420 nm in addition to a very good human plasma stability. As anticipated, the preferential nuclear accumulation of 1 and 2 and their very high DNA binding affinity resulted in very efficient DNA photocleavage, suggesting a DNA-based mode of phototoxic action. Show less

The utilization of photodynamic therapy (PDT) for the treatment of various types of cancer has gained increasing attention over the last decades. Despite the clinical success of approved photosensitizers (PSs), their application is sometimes limited due to poor water solubility, aggregation, photodegradation, and slow clearance from the body. To overcome these drawbacks, research efforts are devoted toward the development of metal complexes and especially Ru(II) polypyridine complexes based on their attractive photophysical and biological properties. Despite the recent research developments, the vast majority of complexes utilize blue or UV-A light to obtain a PDT effect, limiting the penetration depth inside tissues and, therefore, the possibility to treat deep-seated or large tumors. To circumvent these drawbacks, we present the first example of a DFT guided search for efficient PDT PSs with a substantial spectral red shift toward the biological spectral window. Thanks to this design, we have unveiled a Ru(II) polypyridine complex that causes phototoxicity in the very low micromolar to nanomolar range at clinically relevant 595 nm, in monolayer cells as well as in 3D multicellular tumor spheroids. Show less

Title: Impact of aliphatic acyl and aromatic thioamide substituents on the anticancer activity of Ru(II)- Abstract: Six different acylthiourea ligands (L1-L6) and their corresponding Ru(II)-p-cymene complexes (P1-P6) were designed to explore the structure-activity relationship of the complexes upon aliphatic chain and aromatic conjugation on the C- and N-terminals, respectively. The compounds were synthesized and adequately characterized using various analytical and spectroscopic techniques. The structures of P2-P6, solved using single crystal X-ray diffraction (XRD), confirmed the neutral monodentate coordination of the S atoms of the acylthiourea ligands to Ru(II) ions. In silico studies showed an increase of lipophilicity for the ligands with an increase in alkyl chain length or aromatic conjugation at the C- or N-terminal, respectively. Subsequently, mitogen-activated protein kinases (MAPK) were predicted as one of the primary targets for the complexes, which showed good binding affinity towards extracellular signal-regulated kinases (ERK1, ERK2 and ERK5), c-Jun N-terminal kinase (JNK) and p38 of the MAPK pathway. Henceforth, the complexes were tested for their anticancer activity in lung carcinoma (A549) and cisplatin-resistant lung carcinoma (cisA549R) cells and human umbilical vein epithelial normal cells (HUVEC). Interestingly, an increase in chain length or aromatic conjugation led to an increase in the activity of the complexes, with P5 (7.73 and 13.04 μM) and P6 (6.52 and 14.45 μM) showing the highest activity in A549 and cisA549R cells, which is better than the positive control, cisplatin (8.72 and 44.28 μM). Remarkably, we report the highest activity yet observed for complexes of the type [(η6-p-cymene)RuIICl2(S-acylthiourea)] in the tested cell lines. Aqueous solution studies showed that complexes P5 and P6 are rapidly hydrolyzed to produce solely aquated species that remained stable for 24 h. Staining assays and flow cytometric analyses of P5 and P6 in A549 cells revealed that the complexes induced apoptosis and arrested the cell cycle predominantly in the S phase. In vivo studies demonstrated the higher toxicity of cisplatin and a comparatively higher survival rate of mice injected with the most active complex P6. Histological analyses revealed that treatment with P6 at high doses of up to 8 mg kg-1 did not cause any palpable damage to the tested organs. Show less

Two Ru(II) polypyridyl complexes, Ru(DIP)2(bdt) (1) and [Ru(dqpCO2Me)(ptpy)](2+) (2) (DIP = 4,7-diphenyl-1,10-phenanthroline, bdt = 1,2-benzenedithiolate, dqpCO2Me = 4-methylcarboxy-2,6-di(quinolin-8-yl)pyridine), ptpy = 4'-phenyl-2,2':6',2″-terpyridine) have been investigated as photosensitizers (PSs) for photodynamic therapy (PDT). In our experimental settings, the phototoxicity and phototoxic index (PI) of 2 (IC50(light): 25.3 μM, 420 nm, 6.95 J/cm(2); PI >4) and particularly of 1 (IC50(light): 0.62 μM, 420 nm, 6.95 J/cm(2); PI: 80) are considerably superior compared to the two clinically approved PSs porfimer sodium and 5-aminolevulinic acid. Cellular uptake and distribution of these complexes was investigated by confocal microscopy (1) and by inductively coupled plasma mass spectrometry (1 and 2). Their phototoxicity was also determined against the Gram-(+) Staphylococcus aureus and Gram-(-) Escherichia coli for potential antimicrobial PDT (aPDT) applications. Both complexes showed significant aPDT activity (420 nm, 8 J/cm(2)) against Gram-(+) (S. aureus; >6 log10 CFU reduction) and, for 2, also against Gram-(-) E. coli (>4 log10 CFU reduction). Show less

Cancer is the leading cause of death in the developed world. In the last few decades, photodynamic therapy (PDT) has augmented the number of medical techniques to treat this disease in the clinics. As the pharmacological active species to kill cancer cells are only generated upon light irradiation, PDT is associated with an intrinsic first level of selectivity. However, since PDT agents also accumulate in the surrounding, healthy tissue and since it is practically very challenging to only expose the tumor site to light, some side effects can be observed. Consequently, there is a need for a selective drug delivery system, which would give a second level of selectivity. In this work, a dual tumor targeting approach is presented based on mesoporous silica nanoparticles, which act by the enhanced permeability and retention effect, and the conjugation to folic acid, which acts as a targeting moiety for folate receptor-overexpressed cancer cells. The conjugates were found to be nontoxic in noncancerous human normal lung fibroblast cells while showing a phototoxic effect upon irradiation at 480 or 540 nm in the low nanomolar range in folate receptor overexpressing cancerous human ovarian carcinoma cells, demonstrating their potential for cancer targeted treatment. Show less