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Two new ligand PTTP (2-phenoxy-1,4,8,9-tetraazatriphenylene) and FTTP (2-(3-fluoronaphthalen-2-yloxy)-1,4,8,9-tetraazatriphenylene) and their six ruthenium(II) polypyridyl complexes [Ru(N-N)₂(PTTP)](ClO₄)₂ and [Ru(N-N)₂(FTTP)](ClO₄)₂ (N-N=dmb: 4,4'-dimethyl-2,2'-bipiridine; dmp: 2,9-dimethyl-1,10-phenanthroline; ttbpy: 4,4'-ditertiarybutyl-2,2'-bipyridine) were synthesized and characterized. The cytotoxic activity of the complexes against cancer cells HeLa, BEL-7402, A549, HepG-2, HOS and normal cell LO2 was evaluated by MTT method. The IC₅₀ values range from 1.5±0.1 to 55.9±7.5μM. Complex 3 shows the highest cytotoxic activity toward BEL-7402 cells (IC₅₀=1.5±0.1μM). Complex 5 displays most effective inhibition of the cell growth in A549 and HOS cells with low IC₅₀ values of 2.5±0.6 and 2.6±0.1μM, respectively. The apoptosis, reactive oxygen species, mitochondrial membrane potential, DNA damage, autophagy and anti-metastasis assay were investigated under a fluorescent microscope. The cell cycle arrest was assayed by flow cytometry, and the expression of caspases and Bcl-2 family proteins was studied by western blot. The results obtained show that the complexes induce apoptosis in BEL-7402 cells through a ROS-mediated mitochondrial dysfunction pathway. Show less

Two novel series of (salen)ruthenium(iii) complexes bearing guanidine and amidine axial ligands were synthesized, characterized, and evaluated for anticancer activity. In vitro cytotoxicity tests demonstrate that these complexes are cytotoxic against various cancer cell lines and the leading complexes have remarkable cancer-cell selectivity. A detailed study of the guanidine complex 7 and the amidine complex 13 reveals two distinguished modes of action. Complex 7 weakly binds to DNA and induces DNA damage, cell cycle arrest, and typical apoptosis pathways in MCF-7 cells. In contrast, complex 13 induces paraptosis-like cell death hallmarked by massive vacuole formation, mitochondrial swelling, and ER stress, resulting in significant cytotoxicity against human breast cancer cells. Our results provide an extraordinary example of tuning the mechanism of action of (salen)ruthenium(iii) anticancer complexes by modifying the structure of the axial ligands. Show less

Ruthenium coordination complexes have the potential to serve as novel theranostic agents for cancer. However, a major limitation in their clinical implementation is effective tumor accumulation. In this study, we have developed a liposome-based theranostic nanodelivery system for [Ru(phen)₂dppz](ClO₄)₂ (Lipo-Ru). This ruthenium polypyridine complex emits a strong fluorescent signal when incorporated in the hydrophobic lipid bilayer of the delivery vehicle or in the DNA helix, enabling visualization of the therapeutic agent in tumor tissues. Incubation of MDA-MB-231 breast cancer cells with Lipo-Ru induced double-strand DNA breaks and triggers apoptosis. In a mouse model of triple-negative breast cancer, treatment with Lipo-Ru dramatically reduced tumor growth. Biodistribution studies of Lipo-Ru revealed that more than 20% of the injected dose accumulated in the tumor. These results suggest that Lipo-Ru could serve as a promising theranostic platform for cancer. Show less

Ru(II)-arene complexes are attracting increasing attention due to their considerable antitumoral activity. However, it is difficult to clearly establish a direct relationship between their structure and antiproliferative activity, as substantial structural changes might not only affect their anticancer activity but also tightly control their activation site(s) and/or their biological target(s). Herein, we describe the synthesis and characterization of four ruthenium(II) arene complexes bearing bidentate N,O-donor Schiff-base ligands ([Ru(η⁶-benzene)(N-O)Cl]) that display a significantly distinct antiproliferative activity against cancer cells, despite their close structural similarity. Furthermore, we suggest there is a link between their respective antiproliferative activity and their lipophilicity, as the latter affects their ability to accumulate into cancer cells. This lipophilicity-cytotoxicity relationship was exploited to design another structurally related ruthenium complex with a much higher antiproliferative activity (IC₅₀ > 25.0 μM) against three different human cancer cell lines. Whereas this complex shows a slightly lower activity than that of clinically approved cis-platin against the same human cancer cell lines, it displays a lower toxicity in zebrafish (Danio rerio) embryos at concentrations up to 20 μM. Show less

Nanohybrids can in most cases kill cancer cells more efficiently as compared with free photosensitizers. In this work, we constructed nanohybrid Ru1@CDs composed of carbon nanodots (CDs) and a phosphorescent Ru(ii) complex (Ru1) for one- and two-photon photodynamic therapy of cancer. The photosensitizer and imaging agent Ru1 is decorated onto the nanocarrier CDs covalently. Ru1 and Ru1@CDs can penetrate into cancer cells through an energy-dependent mechanism and endocytosis, respectively. Both Ru1 and Ru1@CDs are capable of lysosome-targeted phosphorescence imaging and photodamage under either 450 nm (one-photon) or 810 nm (two-photon) excitation. Conjugation with CDs can increase the cellular uptake efficacy of Ru1. Mechanism investigations show that both Ru1 and Ru1@CDs can induce apoptosis through generation of reactive oxygen species and cathepsin-initiated apoptotic signaling pathways. Upon two-photon excitation, Ru1@CDs show better penetrability, as well as higher inhibitory effects on cancer cell growth in both 2D cell and 3D multicellular tumor spheroid models. Our work provides an effective strategy for the construction of multifunctional imaging and phototherapeutic nanohybrids for the treatment of cancer. Show less

Synergistic photodynamic therapy (PDT) that combines photosensitizers (PSs) to attack different key sites in cancer cells is very attractive. However, the use of multiple PSs may increase dark cytotoxicity. Additionally, realizing the multiple vein passage of several PSs through dosing could be a challenge in clinical treatment. To address these issues, a novel strategy that enables a single PS to ablate two key sites (i.e., cytomembranes on the outside and mitochondria on the inside) of cancer cells synergistically was proposed. Five new fluorinated ruthenium (II) complexes (Ru1-Ru5), which possessed excellent two-photon properties and good singlet oxygen quantum yields, were designed and synthesized. When incubated with HeLa cells, the complexes were observed on the cytomembranes at first. With an extension of the treatment time, both the cytomembranes and mitochondria were lit up by the complexes. Under two-photon laser irradiation, the mitochondria and cytomembranes were ablated simultaneously, and the HeLa cells were destroyed effectively by the complexes, whether the cells were in a monolayer or in multicellular spheroids. With the largest phototoxicity index under the two-photon laser, Ru4 was used for two-photon PDT of in vivo xenograft tumors and successfully inhibited the growth of the tumors. Our results emphasized that the strategy of attacking two key sites with a single PS is an efficient method for PDT. Show less

A glutathione (GSH)-activatable ruthenium(ii)-azo photosensitizer was prepared. The complex had low toxicity towards cells under dark conditions. It exhibited excellent phototoxicity under two-photon excitation (810 nm) and thus was developed as a two-photon photodynamic anticancer agent for cancer therapy. Show less

Two [Ru(phen)₂ dppz]²⁺ derivatives (phen=1,10-phenantroline, dppz=dipyrido[3,2-a:2',3'-c]phenazine) with different functional groups on the dppz ligand [dppz-7,8-(OMe)₂ (1), dppz-7,8-(OH)₂ (2)] have been synthesized, characterized and investigated as photosensitizers (PSs) for photodynamic therapy (PDT) against cancer. Both complexes showed intense red phosphorescence and promising singlet oxygen (¹ O₂ ) quantum yields of 75 % (1) and 54 % (2) in acetonitrile. Complex 1 (logP_o/w =-0.52, 2.4 nmol Ru per mg protein) was found to be more lipophilic, having also a higher cellular uptake efficiency compared to 2 (logP_o/w =-0.20, 0.9 nmol Ru per mg protein). Complex 1 localized evenly in HeLa cells whereas 2, was mainly visualized in the cell membrane by confocal microscopy. In the dark, complex 1 (IC₅₀ =36.5 μm) was found to be more toxic than complex 2 (IC₅₀ >100 μm) on a HeLa cells monolayer. Importantly, in view of PDT applications, both complexes were found to be non-toxic in the dark towards multicellular HeLa spheroids (IC₅₀ >100 μm). Upon one-photon irradiation (420 nm, 9.27 J cm^-2 ), 1 exhibited higher phototoxicity (IC₅₀ =3.1 μm) than 2 (IC₅₀ =16.7 μm) on HeLa cell monolayers. When two-photon irradiation (800 nm, 9.90 J cm^-2 ) was applied, only 1 (IC₅₀ =9.5 μm) was found to be active toward HeLa spheroids. This study demonstrates that the functional group on the intercalative ligand has a strong influence on the cellular localization and anticancer activity of Ru^II polypyridyl complexes. Show less

A new ligand MHPIP (MHPIP = 2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) and its three ruthenium (II) complexes [Ru(N-N)₂(MHPIP)](ClO₄)₂ (N-N = phen: 1,10-phenanthroline 1; dmp = 2,9-dimethyl-1,10-phenanthroline 2; ttbpy = 4,4'-ditertiarybutyl-2,2'-bipyridine 3) were synthesized and characterized. The cytotoxic activity in vitro was studied by MTT method. The complexes 1-3 show moderate cytotoxic effects on the cell growth in HepG2 cells with an IC₅₀ value of 25.5 ± 3.5, 35.6 ± 1.9 and 27.4 ± 2.3 μM, respectively. The apoptosis was investigated with AO/EB and Annex V/PI staining methods and comet assay. The reactive oxygen species, mitochondrial membrane potential were investigated under a fluorescent microscope. Autophagy assay shows that the complexes can cause autophagy and up-regulate the expression of Beclin-1 protein. Additionally, the complexes inhibit the cell growth in HepG2 cells at G0/G1 phase, and the complexes can regulate the expression of caspase 3 and Bcl-2 family proteins. The studies demonstrate that the complexes induce apoptosis in HepG2 cells through DNA damage and ROS-mediated mitochondrial dysfunction pathways. Show less

Background

The RAPTA-EA1 complex [ruthenium(II)-arene 1,3,5-triaza-7-phosphaadamantane (pta) complex with an arene-tethered ethacrynic acid ligand] has been reported to overcome drug resistance that developed due to the current use of platinum-based treatments. However, the exact mechanism of action of RAPTA-EA1 remains largely unexplored and unknown.

Objective

Here we have further studied the effect of RAPTA-EA1 on BRCA1-defective HCC1937 breast cancer cells and compared its effects on BRCA1-competent MCF-7 breast cancer cells.

Method

HCC1937 and MCF-7 breast cancer cells were treated with the RAPTA-EA1 complex. The cytotoxicity of ruthenium-induced cells was evaluated by a MTT assay. Cellular uptake of ruthenium was determined by ICP-MS. Cell cycle and apoptosis were assessed using a flow cytometer. Expression of BRCA1 mRNA and its encoded protein was quantitated by a real-time RT-PCR and Western blotting.

Results

Differences in cytotoxicity were correlated with the differential accumulations of ruthenium and the induction of apoptosis. The ruthenium complex caused dramatically more damage to the BRCA1 gene in the BRCA1-defective HCC1937 cells than to the BRCA1-competent MCF-7 cells. It decreased the expression of BRCA1 mRNA in the BRCA1-competent cells, while in contrast, its expression increased in the BRCA1-defective cells. However, the expression of the BRCA1 protein was significantly reduced in both types of breast cancer cells.

Conclusion

The results presented here have demonstrated a differential cellular response for the BRCA1-defective and BRCA1-competent breast cancer cells to RAPTA-EA1. These findings have provided more insight into the actions and development of the ruthenium-based compounds for use for the treatment of breast cancer. Show less

Looking for new metal-based anticancer treatments, in recent years many ruthenium complexes have been proposed as effective and safe potential drugs. In this context we have recently developed a novel approach for the in vivo delivery of Ru(III) complexes, preparing stable ruthenium-based nucleolipidic nanoaggregates endowed with significant antiproliferative activity. Herein we describe the cellular response to our ruthenium-containing formulations in selected models of human breast cancer. By in vitro bioscreens in the context of preclinical studies, we have focused on their ability to inhibit breast cancer cell proliferation by the activation of the intrinsic apoptotic pathway, possibly via mitochondrial perturbations involving Bcl-2 family members and predisposing to programmed cell death. In addition, the most efficient ruthenium-containing cationic nanoaggregates we have hitherto developed are able to elicit both extrinsic and intrinsic apoptosis, as well as autophagy. To limit chemoresistance and counteract uncontrolled proliferation, multiple cell death pathways activation by metal-based chemotherapeutics is a challenging, yet very promising strategy for targeted therapy development in aggressive cancer diseases, such as triple-negative breast cancer with limited treatment options. These outcomes provide valuable, original knowledge on ruthenium-based candidate drugs and new insights for future optimized cancer treatment protocols. Show less

CHS-828 (N-(6-(4-chlorophenoxy)hexyl)-N'-cyano-N″-4-pyridyl guanidine) is an anticancer agent with low bioavailability and high systemic toxicity. Here we present an approach to improve the therapeutic profile of the drug using photolabile ruthenium complexes to generate light-activated prodrugs of CHS-828. Both prodrug complexes are stable in the dark but release CHS-828 when irradiated with visible light. The complexes are water-soluble and accumulate in tumour cells in very high concentrations, predominantly in the mitochondria. Both prodrug complexes are significantly less cyototoxic than free CHS-828 in the dark but their toxicity increases up to 10-fold in combination with visible light. The cellular responses to light treatment are consistent with release of the cytotoxic CHS-828 ligand. Show less

A series of Ruthenium-Quinolinol complexes (3a-d &4a-d) has been synthesized by employing a simple, efficient and environmental friendly condition. Catalytic role of Amberlite IRA-120(H) has been demonstrated. The structures of the new compounds were elucidated by the analysis of spectroscopic data. The stability of these complexes was measured by UV spectroscopy & time dependent NMR spectroscopy. These newly developed complexes were represented as potential anticancer agent against human breast carcinoma cell line (MCF-7), human Epitheloid Cervix Carcinoma (HeLa), human lung adenocarcinoma epithelial cell line (A549) and human colon cancer cell line (Caco-2). Most of the ruthenium complexes showed higher anticancer activity in MCF-7, HeLa and Caco-2 cell lines than cisplatin. A high selectivity (9-28 folds) was observed with these newly developed organoruthenium compounds in human cancer cell lines (MCF-7, HeLa and Caco-2) with respect to normal fibroblast cell line (MRC-5). Complex [(η6-hexamethylbenzene)RuCl(κ2-O,N-5-chloro-HyQ)]·Cl (4b), [(η6-hexamethylbenzene)RuCl(κ2-O,N-5,7-dibromo-HyQ)]·Cl (4c) and [(η6-hexamethylbenzene)RuCl(κ2-O,N-5-chloro-7-iodo-HyQ)]·Cl (4d) exhibited best cytotoxicity profiles in three reported human cancer cell lines (MCF-7, HeLa, Caco-2). Cellular imaging study was also performed with these newly developed organoruthenium compounds. Compound 4c might be utilized for cancer theranostic agents because of its significant quantum yield in water, high potency, selectivity and high cellular uptake in cancer cell lines. Show less

Within this work we aimed to improve the pharmacodynamics and toxicity profile of organoruthenium and -rhodium complexes which had previously been found to be highly potent in vitro but showed unselective activity in vivo. Different organometallic complexes were attached to a degradable poly(organo)phosphazene macromolecule, prepared via controlled polymerization techniques. The conjugation to hydrophilic polymers was designed to increase the aqueous solubility of the typically poorly soluble metal-based half-sandwich compounds with the aim of a controlled, pH-triggered release of the active metallodrug. The synthesized conjugates and their characteristics have been thoroughly studied by means of ³¹P NMR and UV-Vis spectroscopy, ICP-MS analyses and SEC coupled to ICP-MS. In order to assess their potential as possible anticancer drug candidates, the complexes, as well as their respective macromolecular prodrug formulations were tested against three different cancer cell lines in cell culture. Subsequently, the anticancer activity and organ distribution of the poly(organo)phosphazene drug conjugates were explored in vivo in mice bearing CT-26 colon carcinoma. Our investigations revealed a beneficial influence of this macromolecular prodrug by a significant reduction of adverse effects compared to the free metallodrugs. Show less

Four mononuclear [(L-L)₂ Ru(tatpp)]²⁺ and two dinuclear [(L-L)₂ Ru(tatpp)Ru(L-L)₂ ]⁴⁺ ruthenium(II) polypyridyl complexes (RPCs) containing the 9,11,20,22-tetraazatetrapyrido[3,2-a:2',3'-c:3'',2''-l:2''',3'''-n]pentacene (tatpp) ligand were synthesized, in which L-L is a chelating diamine ligand such as 2,2'-bipyridine (bpy), 1,10-phenanthroline (phen), 3,4,7,8-tetramethyl-1,10-phenanthroline (Me₄ phen) or 4,7-diphenyl-1,10-phenanthroline (Ph₂ phen). These Ru-tatpp analogues all undergo reduction reactions with modest reducing agents, such as glutathione (GSH), at pH 7. These, plus several structurally related but non-redox-active RPCs, were screened for DNA cleavage activity, cytotoxicity, acetylcholinesterase (AChE) inhibition, and acute mouse toxicity, and their activities were examined with respect to redox activity and lipophilicity. All of the redox-active RPCs show single-strand DNA cleavage in the presence of GSH, whereas none of the non-redox-active RPCs do. Low-micromolar cytotoxicity (IC₅₀ ) against malignant H358, CCL228, and MCF7 cultured cell lines was mainly restricted to the redox-active RPCs; however, they were substantially less toxic toward nonmalignant MCF10 cells. The IC₅₀ values for AChE inhibition in cell-free assays and the acute toxicity of RPCs in mice revealed that whereas most RPCs show potent inhibitory action against AChE (IC₅₀ values <15 μm), Ru-tatpp complexes as a class are surprisingly well tolerated in animals relative to other RPCs. Show less

The in vitro cytotoxic properties of antimicrobial copper(II) complexes with 3,4,7,8-tetramethyl-1,10-phenanthroline (TMP) or 4,7-dipyridyl-1,10-phenanthroline (DIP) ligands and ruthenium(II) complexes coordinated with TMP or 2,9-dimethyl-1,10-phenanthroline ligands were investigated. Both copper(II) complexes were found to have similar inhibitory concentrations (IC₅₀~2-2.5μM). Their cytotoxicity was found to be necrotic, associated with cytoplasmic vacuolisation, rounding, detachment and lack of apoptosis-associated DNA fragmentation, in comparison to the apoptotic effects of cisplatin which demonstrate adherent cell enlargement or detachment, membrane blebbing and condensation. Antimicrobial ruthenium(II) complexes demonstrated a lower renal cytotoxicity than copper(II) complexes or cisplatin (IC₅₀>60μM). [Cu(DIP)(dach)](ClO₄)₂ and [Cu(TMP)(dach)](ClO₄)₂ (where dach=1,2-diaminocyclohexane) induced dihydroethidium-sensitive ROS and the cytotoxicity of both TMP and DIP coordinated copper(II) complexes was mitigated by catalase, highlighting a role of H₂O₂ generation in their mode of action. The cytotoxicity of either copper(II) complex was not affected by coincubation with organic cation transporter (OCT) inhibitors cimetidine or disopyramide, in contrast to cisplatin, suggesting a non-OCT dependent mode of uptake for the copper(II) complexes in human cells. Coincubation with copper sulfate reduced the cytotoxicity of [Cu(TMP)(dach)](ClO₄)₂ (3-6×). The TMP complex induced a greater degree of G2/M accumulation and micronuclei generation than the DIP complex, possibly attributable to its greater DNA binding affinity. These results highlight the potentially low genotoxicity of copper(II) complexes coordinated with TMP or DIP and polypyridyl ruthenium(II) complexes as potential antimicrobial agents. Show less

Two ruthenium(II) complexes Ru1 and Ru2 bearing as a one ligand 2,2'-bipyridine substituted by a semicarbazone 2-formylopyridine moiety (bpySC: 5-(4-{4'-methyl-[2,2'-bipyridine]-4-yl}but-1-yn-1-yl)pyridine-2-carbaldehyde semicarbazone) and as the others 2,2'-bipyridine (bpy) and 4,7-diphenyl-1,10-phenanthroline (dip), respectively, as auxiliary ligands have been prepared. Their biological activity has been studied on murine colon carcinoma (CT26) and human lung adenocarcinoma (A549) cell lines. The anti-proliferative activity was dependent on the presence of bpy or dip in the complex, with one order of magnitude higher cytotoxicity for Ru2 (dip ligands). Ru1 (bpy ligands) exhibited a distinct increase in cytotoxicity going from 24 to 72h of incubation with cells as was not observed for Ru2. Even though both studied compounds were powerful apoptosis inducing agents, the mechanism of their action was entirely different. Ru1-incubated A549 cells showed a notable increase in cells number in the S-phase of the cell cycle, with concomitant decrease in the G2/M phase, while Ru2 promoted a cell accumulation in the G0/G1 phase. In contrast, Ru1 induced marginal oxidative stress in A549 cell lines even upon increasing the incubation time. Even though Ru1 preferably accumulated in lysosomes it triggered the apoptotic cellular death via an intrinsic mitochondrial pathway. Ru1-incubated A549 cells showed swelling and enlarging of the mitochondria. It was not observed in case of Ru2 for which mitochondria and endoplasmic reticulum were found as primarily localization site. Despite this the apoptosis induced by Ru2 was caspase-independent. All these findings point to a pronounced role of auxiliary ligands in tuning the mode of biological activity. Show less

Reaction of {[Ru(η⁶-p-cymene)Cl]₂(μ-Cl)₂} (1) with aminomethylphosphane derived from morpholine (P{CH₂N(CH₂CH₂)₂O}₃ (A), PPh₂{CH₂N(CH₂CH₂)₂O} (B)) or piperazine (P{CH₂N(CH₂CH₂)₂NCH₂CH₃}₃ (C), PPh₂{CH₂N(CH₂CH₂)₂NCH₂CH₃} (D)) results in four new piano stool ruthenium(II) coordination compounds: [Ru(η⁶-p-cymene)Cl₂(A)] (2A), [Ru(η⁶-p-cymene)Cl₂(B)] (2B), [Ru(η⁶-p-cymene)Cl₂(C)] (2C) and [Ru(η⁶-p-cymene)Cl₂(D)] (2D). Every complex was fully characterized using spectroscopic methods (¹H, ¹³C{¹H}, ³¹P{¹H} NMR and ESI-MS), elemental analysis, X-ray single crystal diffraction and DFT calculations. Preliminary studies of in vitro cytotoxicity on the A549 (human lung adenocarcinoma) and MCF7 (human breast adenocarcinoma) cell lines revealed 2A-2D activity in the same order of magnitude as in the case of cisplatin. Additionally, the study confirmed the ability of 2A-2D to interact with DNA helix and transferrin. Show less

Mitochondrial metabolism is essential for tumorigenesis, and the development of cancer is usually accompanied by alternations of mitochondrial function. Emerging studies have demonstrated that targeting mitochondria and mitochondrial metabolism is an effective strategy for cancer therapy. In this work, eight phosphorescent organometallic rhenium(I) complexes have been synthesized and explored as mitochondria-targeted theranostic agents, capable of inducing and tracking the therapeutic effect simultaneously. Complexes 1b-4b can quickly and efficiently penetrate into A549 cells, specifically localizing within mitochondria, and their cytotoxicity is superior to cisplatin against the cancer cells screened. Notably, complex 3b [Re(CO)₃(DIP) (py-3-CH₂Cl)]⁺ containing thiol-reactive chloromethylpyridyl moiety for mitochondria immobilization shows higher cytotoxicity and selectivity against cancer cells than other Re(I) complexes without mitochondria-immobilization properties. Mechanistic studies show that complexes 1b-4b induce a cascade of mitochondria-dependent events including mitochondrial damage, mitochondrial respiration inhibition, cellular ATP depletion, reactive oxygen species (ROS) elevation, and caspase-dependent apoptosis. By comparison, mitochondria-immobilized 3b causes more effective repression of mitochondrial metabolism than mitochondrial-nonimmobilized complexes. The excellent phosphorescence and O₂-sensitive lifetimes of mitochondria-immobilized 3b can be utilized for real-time tracking of the morphological changes of mitochondria and mitochondrial respiration repression during therapy process, accordingly providing reliable information for understanding anticancer mechanisms. Show less

Four Ru(II) DMSO complexes (M1R-M4R) having substituted flavones viz. 3-Hydroxy-2-(4-methoxyphenyl)-4H-chromen-4-one (HL1), 3-Hydroxy-2-(4-nitrophenyl)-4H-chromen-4-one (HL2), 3-Hydroxy-2-(4-dimethylaminophenyl)-4H-chromen-4-one (HL3) and 3-Hydroxy-2-(4-chlorophenyl)-4H-chromen-4-one (HL4) were synthesized and characterized by elemental analysis, IR, UV-Vis, ¹H NMR spectroscopies and ESI-MS. The molecular structures of the complexes were investigated by integrated spectroscopic and computational techniques (DFT). Both ligands as well as their complexes were screened for anticancer activities against breast cancer cell lines MCF-7. Cytotoxicity was assayed by MTT [3-(4, 5-dimethyl thiazol-2-yl)-2, 5-diphenyl tetrazolium bromide] assay. All ligands and their complexes exhibited significant cytotoxic potential of 5-40μM concentration at incubation period of 24h. The cell cytotoxicity increased significantly in a concentration-dependent manner. In this series of compounds, HL2 (IC₅₀ 17.2μM) and its complex M2R (IC₅₀ 16μM) induced the highest cytotoxicity. Show less

The combination of chemotherapy with photodynamic therapy can lead to improved therapeutic efficiencies and reduced side effects compared to conventional chemotherapy. Chlorambucil (CHL) is a DNA alkylating agent, but problems like drug instability, "off-target" binding and in situ monitoring after administration often limit its clinical application. In this regard, we designed a new heteroleptic Ru(ii) complex CHL-RuL, bearing a CHL conjugated pendant, which is desired to serve as an image-guided chemo-photodynamic combined theranostic agent. CHL-RuL shows considerable promise as a photosensitizer for two-photon excitation photodynamic therapy: strong and wide UV-Vis absorption bands centered around 400 nm, strong red emission (∼702 nm) with a long lifetime at the microsecond level, moderate singlet oxygen quantum yield, and significant two-photon absorption cross-section (118 GM). More interestingly, this chemical modification affords CHL-RuL greater cellular uptake and remarkable mitochondria accumulation in HeLa cells. Furthermore, CHL-RuL shows a slight selective cytotoxicity toward carcinoma HeLa cells over normal MRC-5 cells. MTT assay results and two-photon scanning cell imaging demonstrate that CHL-RuL exhibits obvious chemo-photodynamic dual action against HeLa cells. Show less

The mechanism of cell death induced by the ruthenium polypyridyl complexes comprising two 4,7-diphenyl-1,10-phenanthroline ligands as well as one unmodified 2,2'-bipyridyl or modified with 2-nitroimidazole moiety attached by shorter (C₃H₆) or longer (C₆H₁₂) linker was investigated. Cytotoxicity and proliferation assays revealed that the studied Ru polypyridyl complexes are more toxic against human pancreas carcinoma PANC-1 cell line than normal human keratinocytes HaCaT with IC₅₀ of 3-5μM. The Ru complexes despite accumulation in mitochondria do not lead to mitochondrial disfunction, though decreasing of mitochondrial Ca²⁺ causes mitochondria membrane hyperpolarization. The Ru polypyridyl conjugates induce some phenotypical characteristic of apoptosis, such as condensation of chromatin or phosphatidylserine translocation, however no caspase or calpain activation in the studied cell lines was observed, indicating that detected cell death does not occur via mitochondria- or ER-activated pathways. Caspase-independent cell death is caused by enormous ROS formation, mainly hydrogen peroxide and peroxyl radicals as well as by intracellular Ca²⁺ homeostasis disruption. Accumulation of the Ru compounds inhibits the completion of DNA synthesis, arresting cells in S-phase of cell cycle. Show less