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Cisplatin was the first metal-based therapeutic agent approved for the treatment of human cancers, but its clinical activity is greatly limited by tumor drug resistance. This work utilized the parent complex [Ru(phen)2(PIP)](2+) (1) to develop three Ru(II) complexes (2-4) with different positional modifications. These compounds exhibited similar or superior cytotoxicities compared to cisplatin in HeLa, A549 and multidrug-resistant (A549R) tumor cell lines. Complex 4, the most potent member of the series, was highly active against A549R cancer cells (IC50 = 0.8 μM). This complex exhibited 178-fold better activity than cisplatin (IC50 = 142.5 μM) in A549R cells. 3D multicellular A549R tumor spheroids were also used to confirm the high proliferative and cytotoxic activity of complex 4. Complex 4 had the greatest cellular uptake and had a tendency to accumulate in the mitochondria of A549R cells. Further mechanistic studies showed that complex 4 induced A549R cell apoptosis via inhibition of thioredoxin reductase (TrxR), elevated intracellular ROS levels, mitochondrial dysfunction and cell cycle arrest, making it an outstanding candidate for overcoming cisplatin resistance. Show less

An important challenge in the field of anticancer chemotherapy is the search for new species to overcome the resistance of standard drugs. An interesting approach is to link bioactive ligands to metal fragments. In this work, we have synthesized a set of p-cymene-Ru or cyclopentadienyl-M (M = Rh, Ir) complexes with four chrysin-derived pro-ligands with different -OR substituents at position 7 of ring A. The introduction of a piperidine ring on chrysin led to the highly cytotoxic pro-ligand HL4 and its metal complexes L4-M (SW480 and A549 cell lines, cytotoxic order: L4-Ir > L4-Ru ≈ L4-Rh). HL4 and its complexes induce apoptosis and can overcome cis-platinum resistance. However, HL4 turns out to be more cytotoxic in healthy than in tumor cells in contrast to its metal complexes which displayed higher selectivity than cisplatin towards cancer cells. All L4-M complexes interact with double stranded DNA. Nonetheless, the influence of the metal is clear because only complex L4-Ir causes DNA cleavage, through the generation of highly reactive oxygen species (¹O₂). This result supports the hypothesis of a potential dual mechanism consisting of two different chemical pathways: DNA binding and ROS generation. This behavior provides this complex with a great effectivity in terms of cytotoxicity. Show less

Herein, we report the synthesis and characterization of a bishomoleptic and a trisheteroleptic ruthenium (II) polypyridyl complex, namely, [Ru(bpy)2(2, 2'-pq)](PF6)2 (1) and [Ru(bpy) (phen) (2, 2'-pq)](PF6)2 (2), respectively, where bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline, and 2, 2'-pq = 2-(2'-pyridyl)-quinoxaline. The complexes were characterized by elemental analysis, TGA, ¹H-NMR, FT-IR, UV-Vis, emission spectroscopy, and electrochemistry. Their structures were confirmed by single-crystal X-ray diffraction analysis. Complexes 1 and 2 were crystalized in orthorhombic, Pbca, and monoclinic, P21/n systems, respectively. Various spectroscopic techniques were employed to investigate the interaction of both complexes with calf thymus DNA (CT-DNA). The experimental data were confirmed by molecular docking studies, employing two different DNA sequences. Both complexes, 1 and 2, bind with DNA via a minor groove mode of binding. MTT experiments revealed that both complexes induce apoptosis of MCF-7 (breast cancer) cells in low concentrations. Confocal microscopy indicated that 2 localizes in the nucleus and internalizes more efficiently in MCF-7 than in HEK-293. Show less

Title: Polydiacetylene/lipid-coated red-emissive silica nanorods for the sustained release and ameliorated anticancer efficacy of a Ru(arene) complex bearing piperlongumine natural product. Abstract: A suitable drug delivery strategy for metallodrugs is as significant as the strategies adopted for an efficient metallodrug design. In this study, piperlongumine, which is isolated from long pepper, is coordinated with a Ru(II)-p-cymene moiety to obtain an organoruthenated complex containing the natural product (Ru(pip)). The isolated complex shows higher cytotoxicity in MCF-7 breast cancer cells than in THP-1 leukemia and HepG2 liver cancer cells. The IC50 value of the complex in non-cancerous HEK-239 cells is also almost equal to that in MCF-7 cells. Next, with an aim to modulate the antiproliferative activity of Ru(pip) using a drug delivery strategy, the complex is loaded into mesoporous silica nanorods (MSNRs), which have a higher surface area than spherical silica nanoparticles. Furthermore, the outer surface of the loaded nanorods is covered with a polydiacetylene-lipid (PL) hybrid bilayer. Given the unique optical properties of polydiacetylene, the PL coating modifies non-fluorescent MSNRs into red-emissive particles (PL-Ru(pip)@MSNRs), which can be useful for diagnostic applications. The release profile studies reveal that the ene-yne conjugation in the PL coating ensures the sustained release of the complex from nanoparticles in both physiological and simulated cancer cell media. While Ru(pip) exhibits both necrotic and apoptotic modes of cell death, PL-Ru(pip)@MSNRs preferably induce the apoptotic mode of cell death in MCF-7 and THP-1 cells. Also, the nanoformulation exhibits a higher percentage of cell cycle arrest in the G0/G1 phase than Ru(pip), as measured by flow cytometry analysis. In contrast, the in vitro antioxidant potency of the complex is decreased after being loaded into PL-coated silica nanoparticles. Show less

Title: Ru(III) complexes with pyrazolopyrimidines as anticancer agents: bioactivities and the underlying mechanisms. Abstract: Three ruthenium(III) complexes with pyrazolopyrimidine [Ru(Ln)(H2O)Cl3] (1-3, n = 1-3) were prepared and characterized. These Ru(III) compounds show strong cytotoxicity against six cancer cell lines and low toxicity to normal human liver cells. Particularly, they exhibited stronger cytotoxicity to SK-OV-3 cells than cisplatin. Mechanism studies revealed that complex 1 inhibited tumor cell invasion and suppressed cell proliferation, induced apoptosis by elevating the levels of intracellular ROS (reactive oxygen species) and free calcium (Ca2+), and reduced mitochondrial membrane potential (ΔΨ). It also activated the caspase cascade, accompanied with upregulation of cytochrome c, Bax, p53, Apaf-1 and downregulation of Bcl-2. Moreover, complex 1 caused cell cycle arrest at S phase by inhibiting the expression of CDC 25, cyclin A2 and CDK 2 proteins, and induced DNA damage by interacting with DNA and inhibiting the topoisomerase I enzyme. Complex 1 exhibited efficient in vivo anticancer activity in a model of SK-OV-3 tumor xenograft. Show less

Ruthenium(II) complexes are currently considered attractive alternatives to the widely used platinum-based drugs. We present herein the synthesis and characterization of half-sandwich ruthenium compounds formulated as [Ru(p-cymene)(L)Cl][CF₃SO₃] (L = 1,1-bis(methylenediphenylphosphano)ethylene, 1; L = 1,1-bis(diphenylphosphano)ethylene, 2), which were characterized by elemental analysis, mass spectrometry, ¹H and ³¹P{¹H} NMR, UV-vis and IR spectroscopy, conductivity measurements and cyclic voltammetry. The molecular structures for both complexes were determined by single-crystal X-ray diffraction. Their cytotoxic activity was evaluated using the MTT assay against human tumor cells, namely ovarian (A2780) and breast (MCF7 and MDA-MB-231). Both complexes were active against breast adenocarcinoma cells, with complex 1 exhibiting a quite remarkable cytotoxicity in the submicromolar range. Interestingly, at concentrations equivalent to the IC₅₀ values in the MCF7 cancer cells, complexes 1 and 2 presented lower cytotoxicity in normal human primary fibroblasts. The antiproliferative effects of 1 and 2 in MCF7 cells might be associated with the induction of reactive oxygen species (ROS), leading to a combined cell death mechanism via apoptosis and autophagy. Despite the fact that in vitro a partial intercalation between complexes and DNA was observed, no MCF7 cell cycle delay or arrest was observed, indicating that DNA might not be a direct target. Complexes 1 and 2 both exhibited a moderate to strong interaction with human serum albumin, suggesting that protein targets may be involved in their mode of action. Their acute toxicity was evaluated in the zebrafish model. Complex 1 (the most toxic of the two) exhibited a lethal toxicity LC₅₀ value about 1 order of magnitude higher than any IC₅₀ concentrations found for the cancer cell models used, highlighting its therapeutic relevance as a drug candidate in cancer chemotherapy. Show less

Title: Asymmetrically Coordinated Heterodimetallic Ir-Ru System: Synthesis, Computational, and Anticancer Aspects. Abstract: Herein, we present an unprecedented formation of a heterodinuclear complex [{(ppy)2IrIII}(μ-phpy){RuII(tpy)}](ClO4)2 {[1](ClO4)2} using terpyridyl/phenylpyridine as ancillary ligands and asymmetric phpy as a bridging ligand. The asymmetric binding mode (N∧N-∩-N∧N∧C-) of the phpy ligand in {[1](ClO4)2} is confirmed by 1H, 13C, 1H-1H correlated spectroscopy (COSY), high-resolution mass spectrum (HRMS), single-crystal X-ray crystallography techniques, and solution conductivity measurements. Theoretical investigation suggests that the highest occupied molecular orbital (HOMO) and the least unoccupied molecular orbital (LUMO) of [1]2+ are located on iridium/ppy and phpy, respectively. The complex displays a broad low energy charge transfer (CT) band within 450-575 nm. The time-dependent density functional theory (TDDFT) analysis suggests this as a mixture of metal-to-ligand charge transfer (MLCT) and ligand-to-ligand charge transfer (LLCT), where both ruthenium, iridium, and ligands are involved. Complex {[1](ClO4)2} exhibits RuIIIrIII/RuIIIIrIII- and RuIIIIrIII/RuIIIIrIV-based oxidative couples at 0.83 and 1.39 V, respectively. The complex shows anticancer activity and selectivity toward human breast cancer cells (IC50; MCF-7: 9.3 ± 1.2 μM, and MDA-MB-231: 8.6 ± 1.2 μM) over normal breast cells (MCF 10A: IC50 ≈ 21 ± 1.3 μM). The Western blot analysis and fluorescence microscopy images suggest that combined apoptosis and autophagy are responsible for cancer cell death. Show less

Triple negative breast cancer (TNBC) is a heterogeneous subtype of breast tumors that does not exhibit the expression of estrogen and progesterone receptors, neither the amplification of the human epidermal growth factor receptor 2 (HER-2) gene. Despite all the advances in cancer treatments, the development of new anticancer drugs for TNBC tumors is still a challenge. There is an increasing interest in new agents to be used in cancer treatment. Ruthenium is a metal that has unique characteristics and important in vivo and in vitro results achieved for cancer treatment. Thus, in this work, with the aim to develop anticancer drugs, three new ruthenium complexes containing acylthiourea ligands have been synthesized and characterized: trans-[Ru(PPh₃)₂(N,N-dibutyl-N'-benzoylthioureato-k²O,S)(2,2'-bipyridine (bipy))]PF₆(1), trans-[Ru(PPh₃)₂(N,N-dimethyl-N'-thiophenylthioureato-k²O,S)(bipy)]PF₆(2) and trans-[Ru(PPh₃)₂(N,N-dimethyl-N'-benzoylthioureato-k²O,S)(bipy)]PF₆(3). Then, the cytotoxicity of these three new ruthenium complexes was investigated in TNBC MDA-MB-231 and in non-tumor MCF-10A cells. Complex (2) was the most selective complex and was chosen for further studies to verify its effects on cell morphology, adhesion, migration, invasion, induction of apoptosis and DNA damage in vitro, as well as its toxicity and capacity of causing DNA damage in vivo. Complex (2) inhibited proliferation, migration, invasion, adhesion, changed morphology and induced apoptosis, DNA damage and nuclear fragmentation of TNBC cells at lower concentrations compared to non-tumor MCF-10A cells, suggesting an effective action for this complex on tumor cells. Finally, complex (2) did not induce toxicity or caused DNA damage in vivo when low doses were administered to mice. Show less

A slow hydrolyzing imidazole-based Ru(II)-arene complex [(L)Ru(II)(η(6)-p-cym)(Cl)](PF6) (1) with excellent stability in the extracellular chloride concentration shows better activity under hypoxia and strong resistance to glutathione (GSH) in vitro under hypoxic conditions. 1 arrests the cell cycle in sub G1 and G2/M phases and leads to apoptosis. Show less

Fourteen new Ru^II -arene (p-cymene/benzene) complexes (C1-C14) have been synthesized by varying the N-terminal substituent in the furoylthiourea ligand and satisfactorily characterized by using analytical and spectroscopic techniques. Electrostatic potential maps predicted that the electronic effect of the substituents was mostly localized, with some influence seen on the labile chloride ligands. The structure-activity relationships of the Ru-p-cymene and Ru-benzene complexes showed opposite trends. All the complexes were found to be highly toxic towards IMR-32 cancer cells, with C5 (Ru-p-cymene complex containing C₆ H₂ (CH₃ )₃ as N-terminal substituent) and C13 (Ru-benzene complex containing C₆ H₄ (CF₃ ) as N-terminal substituent) showing the highest activity among each set of complexes, and hence they were chosen for further study. These complexes showed different behavior in aqueous solutions, and were also found to catalytically oxidize glutathione. They also promoted cell death by apoptosis and cell cycle arrest. Furthermore, the complexes showed good binding ability with the receptors Pim-1 kinase and vascular endothelial growth factor receptor 2, commonly overexpressed in cancer cells. Show less

Near-IR-emitting and/or efficiently photodynamic water-soluble Ru(II) complexes that hold great application potentials as photodynamic therapy and/or photodetection agents for cancers have been poorly explored. In this paper, the solvatochromism, calf thymus DNA binding, and singlet oxygen generation properties of a known ruthenium(II) complex of visible-emitting [Ru(bpy)₂(dtdpq)](ClO₄)₂ (Ru1) and a new homoleptic complex of near-IR-emitting [Ru(dtdpq)₃](ClO₄)₂ (Ru2) (bpy = 2,2'-bipyridine, dtdpq = 2,3-bis(thiophen-2-yl)pyrazino[2,3-f][1,10]phenanothroline) in water are reported. Moreover, DNA photocleavage, singlet oxygen generation in HeLa cells, cellular uptake/localization, and in vitro photodynamic therapy for cancer cells of water-soluble Ru1 are described in detail. The results show that Ru1 acted as potent photodynamic cancer therapy and mitochondrial imaging agents. Ru2 exhibited very strong solvatochromism from a visible emission maximum at 588 nm in CH₂Cl₂ to the near-IR region at 700 nm in water and singlet oxygen generation yield in water (23%) and DNA binding properties (intercalative DNA binding constant on the order of 10⁶ M^-1) comparable to those of Ru1, which should make Ru2 attractive for the aforementioned applications of Ru1 if the water solubility of Ru2 can be improved enough for the studies above. Show less

Ru(II)-polypyridyl complexes are of increasing interest in photodynamic therapy (PDT) due to their easily tunable photophysical and photochemical properties. However, short-wavelength absorption of Ru(II)-polypyridyl complexes has limited their penetration depth in PDT. Herein, the series of Ru(II)-polypyridyl complexes 1-4 was designed by replacing one bipyridine in [Ru(bpy)₃]Cl₂ with Schiff bases (iminopyridine or iminoquinoline analogues) to achieve red-shifted absorption of Ru(II)-polypyridyl photosensitizers. To further shift the absorption to longer wavelength and improve the photobiological activity of Ru(II)-polypyridyl complexes, the three tris-heteroleptic Ru(II) complexes 5-7 with benzo[i]dipyrido[3,2-a:2',3'-c]phenazine (dppn) as a ligand were designed to achieve long-lived intraligand (³IL) excited states. Cytotoxicity data against A549 and HepG2 cells revealed that complex 7 showed extraordinarily high cytotoxicity under 650 nm irradiation, resulting in IC₅₀ values of 56 and 63 nM with exceptionally large phototoxicity index (PI) values of 763 and 613, respectively. Thus, the resulting complex 7 with considerable red-light photocytotoxicity and high PI values shows a promising potential for therapeutic applications, which represents a new scaffold of Ru(II)-polypyridyl photosensitizers for PDT in the "therapeutic window". This study delivers a rational strategy for the design of tris-heteroleptic Ru(II) complexes as promising photosensitizers for cancer therapy. Show less

In the present study, the potential anti-neoplastic properties of a series of ruthenium half-sandwich complexes of formula [Ru(η⁶-arene)Cl₂(PR¹R²(1-pyrenyl))] (η⁶-arene = p-cymene and R¹ = R² = methyl for 1; η⁶-arene = methylbenzoate and R¹ = R² = methyl for 2; η⁶-arene = p-cymene and R¹ = R² = phenyl for 3; η⁶-arene = methylbenzoate and R¹ = R² = phenyl for 4; η⁶-arene = p-cymene, R¹ = methyl and R² = phenyl for 5; η⁶-arene = methylbenzoate, R¹ = methyl and R² = phenyl for 6) have been investigated. The six structurally related organoruthenium(II) compounds have been prepared in good yields and fully characterized; the X-ray structures of three of them, i.e., 1, 2, and 4, were determined. Although the piano-stool compounds contain a large polycyclic aromatic moiety, viz. a 1-pyrenyl group, they do not appear to interact with DNA. However, all the piano-stool complexes show significant cytotoxic properties against five human cell lines, namely, lung adenocarcinoma (A549), melanoma (A375), colorectal adenocarcinoma (SW620), breast adenocarcinoma (MCF7), and nontumorigenic epithelial breast (MCF10A), with IC₅₀ values in the micromolar range for most of them. In addition, the most active compound, i.e., 2, induces a remarkable decrease of cell viability, that is in the nanomolar range, against two human neuroblastoma cell lines, namely, SK-N-BE(2) and CHLA-90. Complexes 1-6 are all capable of inducing apoptosis, but with various degrees of magnitude. Whereas 1, 3, 5, and 6 have no effect on the cell cycle of A375 cells, 2 and 4 can arrest it at the G₂/M phase; furthermore, 2 (which is the most efficient compound of the series) also stops the cycle at the S phase, behaving as the well-known anticancer agent cisplatin. Finally, 2 is able to inhibit/reduce the cell migration of neuroblastoma SK-N-BE(2) cells. Show less

Ruthenium-based anticancer complexes are promising antitumor agents for their low system toxicity and versatile chemical structures. Epidermal growth factor receptor (EGFR) has been found to be overexpressed in a broad range of tumor cells and is regarded as a drug target in developing novel antitumor drugs. In this work, five ruthenium(II) polypyridyl complexes containing EGFR-inhibiting 4-anilinoquinazoline pharmacophores were synthesized and characterized. These complexes showed both high EGFR-inhibiting activity and strong DNA minor groove-binding activity. In vitro antiproliferation screening demonstrated that the prepared ruthenium complexes are highly cytotoxic against a series of cancer cell lines, in particular non-small-cell lung A549 and human epidermoid carcinoma A431. Fluorescence-activated cell sorting analysis and fluorescence microscopy revealed that the most active complex, K4, induced much more late-stage cell apoptosis and necrosis than gefitinib, the first EGFR-targeting antitumor drug in clinical use. These results indicate that the ruthenium(II) polypyridyl complexes bearing EGFR-inhibiting 4-anilinoquinazolines possess highly active dual-targeting anticancer activity and are promising in developing new anticancer agents. Show less

Sulfonamides have a broad range of therapeutic applications, which include the inhibition of various isoforms of carbonic anhydrases (CAs). Among the various CA isoforms, CA IX is overexpressed in tumors and regulates the pH of the tumor microenvironment. Herein we present five new ruthenium(II) p-cymene complexes (1-5) of Schiff base ligands (L1-L4) of 4-(2-aminoethyl)benzenesulfonamide by varying the aldehyde to enhance the selective cytotoxicity toward cancer cells. All of the complexes are stable to aquation for the observed period of 24 h except 1, which aquated within 1 h, but the monoaquated species is stable for 24 h. The two imidazole derivatives, 1 and 2, are cytotoxic to the cancer cells MDA-MB-231 and MIA PaCa-2 but not to the noncancerous cells CHO and MDCK. The enhanced toxicity in hypoxia against MDA-MB-231 may be due to the greater expression of CA IX in hypoxia, as per the immunofluorescence data. The most cytotoxic complexes, 1 and 2, are lipophilic, whereas 3-5 show high hydrophilicity and are not cytotoxic up to 200 μM. Complexes 1 and 2 also show a higher cellular accumulation in MDA-MB-231 than the nontoxic yet solution-stable complex 5. The cytotoxic complexes bind with the model nucleobase 9-ethylguanine but have slow reactivity toward cellular tripeptide glutathione. Both 1 and 2 induce apoptosis by depolarizing the mitochondrial membrane potential and arrest the cell cycle in the SubG1 phase. Show less

Title: Insights into the anticancer photodynamic activity of Ir(III) and Ru(II) polypyridyl complexes bearing β-carboline ligands. Abstract: Ir(III) and Ru(II) polypyridyl complexes are promising photosensitizers (PSs) for photodynamic therapy (PDT) due to their outstanding photophysical properties. Herein, one series of cyclometallated Ir(III) complexes and two series of Ru(II) polypyridyl derivatives bearing three different thiazolyl-β-carboline N^N' ligands have been synthesized, aiming to evaluate the impact of the different metal fragments ([Ir(C^N)2]+ or [Ru(N^N)2]2+) and N^N' ligands on the photophysical and biological properties. All the compounds exhibit remarkable photostability under blue-light irradiation and are emissive (605 < λem < 720 nm), with the Ru(II) derivatives displaying higher photoluminescence quantum yields and longer excited state lifetimes. The Ir PSs display pKa values between 5.9 and 7.9, whereas their Ru counterparts are less acidic (pKa > 9.3). The presence of the deprotonated form in the Ir-PSs favours the generation of reactive oxygen species (ROS) since, according to theoretical calculations, it features a low-lying ligand-centered triplet excited state (T1 = 3LC) with a long lifetime. All compounds have demonstrated anticancer activity. Ir(III) complexes 1-3 exhibit the highest cytotoxicity in dark conditions, comparable to cisplatin. Their activity is notably enhanced by blue-light irradiation, resulting in nanomolar IC50 values and phototoxicity indexes (PIs) between 70 and 201 in different cancer cell lines. The Ir(III) PSs are also activated by green (with PI between 16 and 19.2) and red light in the case of complex 3 (PI = 8.5). Their antitumor efficacy is confirmed by clonogenic assays and using spheroid models. The Ir(III) complexes rapidly enter cells, accumulating in mitochondria and lysosomes. Upon photoactivation, they generate ROS, leading to mitochondrial dysfunction and lysosomal damage and ultimately cell apoptosis. Additionally, they inhibit cancer cell migration, a crucial step in metastasis. In contrast, Ru(II) complex 6 exhibits moderate mitochondrial activity. Overall, Ir(III) complexes 1-3 show potential for selective light-controlled cancer treatment, providing an alternative mechanism to chemotherapy and the ability to inhibit lethal cancer cell dissemination. Show less

Herein, we describe and investigate biological activity of three octahedral ruthenium(II) complexes of the type [Ru(C^∧N)(phen)₂]⁺, RuL1-RuL3, containing a π-expansive cyclometalating substituted benzo[g]quinoxaline ligand (C^∧N ligand) (phen = 1,10-phenanthroline). Compounds RuL1-RuL3 in cervical, melanoma, and colon human cancer cells exhibit high phototoxicity after irradiation with light (particularly blue), with the phototoxicity index reaching 100 for the complex RuL2 in most sensitive HCT116 cells. RuL2 accumulates in the cellular membranes. If irradiated, it induces lipid peroxidation, likely connected with photoinduced ROS generation. Oxidative damage to the fatty acids leads to the attenuation of the membranes, the activation of caspase 3, and the triggering of the apoptotic pathway, thus implementing membrane-localized photodynamic therapy. RuL2 is the first photoactive ruthenium-based complex capable of killing the hardly treatable colon cancer stem cells, a highly resilient subpopulation within a heterogeneous tumor mass, responsible for tumor recurrence and the metastatic progression of cancer. Show less

Subtle ligand modifications on Ru^II -polypyridyl complexes may result in different excited-state characteristics, which provides the opportunity to tune their photo-physicochemical properties and subsequently change their biological functions. Here, a DNA-targeting Ru^II -polypyridyl complex (named Ru1) with highly photosensitizing ³ IL (intraligand) excited state was designed based on a classical DNA-intercalator [Ru(bpy)₂ (dppz)]⋅2 PF₆ by incorporation of the dppz (dipyrido[3,2-a:2',3'-c]phenazine) ligand tethered with a pyrenyl group, which has four orders of magnitude higher potency than the model complex [Ru(bpy)₂ (dppz)]⋅2 PF₆ upon light irradiation. This study provides a facile strategy for the design of organelle-targeting Ru^II -polypyridyl complexes with dramatically improved photobiological activity. Show less

A series of arene Ru(II) complexes coordinated with phenanthroimidazole derivatives, [(η⁶-C₆H₆)Ru(l)Cl]Cl(1b L = p-ClPIP = 2-(4-Chlorophenyl)imidazole[4,5f] 1,10-phenanthroline; 2b L = m-ClPIP = 2-(3-Chlorophenyl)imidazole[4,5f] 1,10-phenanthroline; 3b L = p-NPIP = 2-(4-Nitrophenyl)imidazole[4,5f] 1,10-phenanthroline; 4b L = m-NPIP = 2-(3-Nitrophenyl) imidazole [4,5f] 1,10-phenanthroline) were synthesized in yields of 89.9%-92.7% under conditions of microwave irradiation heating for 30 min to liberate four arene Ru(II) complexes (1b, 2b, 3b, 4b). The anti-tumor activity of 1b against various tumor cells was evaluated by MTT assay. The results indicated that this complex blocked the growth of human lung adenocarcinoma A549 cells with an IC₅₀ of 16.59 μM. Flow cytometric analysis showed that apoptosis of A549 cells was observed following treatment with 1b. Furthermore, the in vitro DNA-binding behaviors that were confirmed by spectroscopy indicated that 1b could selectively bind and stabilize bcl-2 G-quadruplex DNA to induce apoptosis of A549 cells. Therefore, the synthesized 1b has impressive bcl-2 G-quadruplex DNA-binding and stabilizing activities with potential applications in cancer chemotherapy. Show less

A unique V-shaped "chiral" supramolecular scaffold, N-(4-pyridyl)-4-amino-1,8-naphthalimide Tröger's base (TBNap), was synthesized in good yield from a precursor N-(4-pyridyl)-4-amino-1,8-naphthalimide (Nap). TBNap was characterized using different spectroscopic methods and the molecular structure was elucidated by diffraction analysis. A new p-cymene-Ru(II)-curcumin conjugate (TB-Ru-Cur) was designed by reacting TBNap dipyridyl donor and ruthenium-curcuminato acceptor [RuCur = (p-cymene)Ru-(curcuminato)Cl] in the presence of silver triflate. TB-Ru-Cur was isolated in quantitative yield and characterized using Fourier transform infrared (FT-IR), NMR (¹H, ¹³C, and ¹⁹F), and electrospray ionization mass spectrometry (ESI-MS), and the molecular structure has been predicted using a computational study. Both TBNap and TB-Ru-Cur exhibited intramolecular charge transfer (ICT)-based fluorescence emission. Furthermore, the anticancer properties of TBNap, Ru-Cur, and TB-Ru-Cur were assessed in different cancer cell lines. Gratifyingly, the conjugate TB-Ru-Cur displayed fast-cellular internalization and good cytotoxicity against HeLa, HCT-116, and HepG2 cancer cells and the estimated IC₅₀ value was much lower than that of the precursors (TBNap and Ru-Cur) and the well-known chemotherapeutic drug cisplatin. Show less

As hypoxia is an important factor to limit chemotherapeutic efficacy in tumors, we herein report three ruthenium(II)-arene complexes containing a hypoxia inducible factor-1α inhibitor (YC-1), which endow the organometallic complexes with potential for hypoxia targeting. In vitro tests showed the resulting complexes had higher anticancer activities in hypoxia than in normoxia against the tested cancer cell lines. Western blot analysis revealed that complexes 1-3 blocked HIF-1α protein accumulation under hypoxic conditions. Moreover, these complexes displayed much less cytotoxicity toward the normal human umbilical vein endothelial cell line (HUVEC), indicating that complexes 1-3 may be selectively cytotoxic for human cancer cell lines. These findings proved that ligation with YC-1 endowed these organometallic ruthenium(II) complexes with potential for hypoxia targeting in addition to enhancing their anticancer activities. Show less

Two functional Ru(II) mixed-ligand complexes, [Ru(phen)(2)(ttbd)](2+) (1) (ttbd = 4-(6-propenyl-pyrido[3,2-a]phenzain-10-yl-benzene-1,2-diamine, phen = 1,10-phenanthroline) and [Ru(bpy)(2)(ttbd)](2+) (2) (bpy = 2,2'-bipyridine), have been synthesized and characterized. The spectral characteristics of complexes 1 and 2 were investigated using fluorescence spectroscopy and revealed that both complexes were very sensitive to solvent polarity and oxygen molecules in nonaqueous solvents. The binding properties of the two complexes towards calf thymus DNA (CT-DNA) were investigated with different spectrophotometric methods, viscosity measurements and quantum chemistry calculations, indicating that both complexes could enantioselectively bind to CT-DNA by means of intercalation, but with different binding strengths and discrimination. On the other hand, the cytotoxicity of both complexes have been evaluated by MTT assays and Giemsa staining experiments. The main results reveal that the hydrophobicity and surface area of the ancillary ligands have a significant effect on their DNA binding behavior and both complexes are likely to be useful for optically probing nonaqueous and oxygen-free environments. Show less

Title: Quaternary Ru(II) complexes of terpyridines, saccharin and 1,2-azoles: effect of substituents on molecular structure, speciation, photoactivity, and photocytotoxicity. Abstract: Six photoactive ruthenium quaternary complexes (a four-component system consisting of three different N-donor ligands and Ru(II)): trans-[Ru(R-tpy)(pyz/ind)(sac)2] (1-6) containing substituted terpyridine (R-tpy), saccharin (sac), and monodentate N-donor heterocycles were designed. Here, R-tpy = 4'-(2-furyl (1, 2); thienyl (3, 4); pyridyl (5, 6))-2,2':6',2'' terpyridines, pyz = 1H-pyrazole for 1, 3 and 5 and ind = 1H-indazole for 2, 4 and 6. The azoles are present in a large number of FDA-approved clinical drugs and bioactive molecules. The saccharin acting as a carbonic anhydrase inhibitor (CA-IX) could potentially target aggressive hypoxic tumors that overexpress CA-IX. Such multi-functional ligands bound to a Ru(II)-photocage provide ample scope to tune the electronic structures, photochemistry, and synergistic effect of the photolabile ligands in photoactivated chemotherapy (PACT). The complexes were characterized using various spectroscopic studies, and the molecular structures were determined from X-ray crystallography. They exhibit a distorted octahedral {RuN6} geometry with equatorial sites coordinated to the tridentate N3-donor R-tpy and N-donor pyz/ind, while two transoidal axial sites bound to the N-donor saccharinate (sac) ligands. The solvolysis kinetics showed these complexes undergo facile ligand-exchange reactions in equilibrium with varying rates reflecting the possible electronic effect of the R-groups in R-tpy. The photoreactivity of the complexes in green (λex = 530 nm) LED light indicates that the complexes undergo photodissociation of the monodentate N-donors (i.e., sac/pyz/ind) and showed an efficient generation of singlet oxygen (Φ1O2 = 0.29-0.47), signifying the potential of these complexes in PACT and/or PDT. All the complexes show good binding affinity with CT-DNA with possible intercalation from extended planar polypyridyl ligands with duplex DNA and BSA. The synchronous fluorescence study with BSA suggested preferential interaction at the tryptophan residue in the protein microenvironment. The confocal microscopy studies showed adequate permeability and localization in the cytosol and nucleus of cervical cancer (HeLa) and breast cancer (MCF7) cells. The dose-dependent cytotoxicity of the complexes for both HeLa and MCF7 cells increases upon low-energy (365 nm) photoirradiation. The mechanistic studies revealed that the complexes induce apoptosis and generate reactive oxygen species (ROS) upon green light (λex = 530 nm) irradiation. Overall, these quaternary Ru(II) complexes equipped with three different types of ligands with distinct roles could pave the way for designing multi-targeted chemotherapeutic metallodrugs with synergistic roles for each bioactive ligand. Show less

Title: Luminescent 11-{Naphthalen-1-yl}dipyrido[3,2-a:2',3'-c]phenazine-Based Ru(II)/Ir(III)/Re(I) Complexes for HCT-116 Colorectal Cancer Stem Cell Therapy. Abstract: Due to a number of unpleasant considerations, marketed drugs have steadily lost their importance in the treatment of cancer. In order to find a viable cancer cell diagnostic agent, we therefore focused on metal complexes that displayed target adequacy, permeability to cancer cells, high standard water solubility, cytoselectivity, and luminescent behavior. In this aspect, luminescent 11-{naphthalen-1-yl} dipyrido [3,2-a:2',3'-c] phenazine based Ru(II)/Ir(III)/Re(I) complexes have been prepared for HCT-116 colorectal cancer stem cell therapy. Our study successfully established the possible cytotoxicity of IrL complex at different doses on HCT-116 colorectal cancer stem cells (CRCSCs). Additionally, an immunochemistry analysis of the complex IrL showed that the molecule was subcellularly localized in the nucleus and other regions of the cytoplasm, where it caused nuclear DNA damage and mitochondrial dysfunction. The level of BAX and Bcl-2 was further quantified by qRT-PCR. The expression of proapoptotic BAX showed increased expression in the complex IrL-treated cell compared to the control, indicating the potential of complex IrL for apoptotic induction. Upon further validation, complex IrL was developed as an inhibitor of autophagy for the eradication of cancer stem cells. Show less

Title: Cyclometalated Ru(II)-NHC complexes with phenanthroline ligands induce apoptosis mediated by mitochondria and endoplasmic reticulum stress in cancer cells. Abstract: The exploration of ruthenium complexes as anticancer drugs has been the focus of intense investigation. In this study, we synthesized and characterized four C,N-cyclometalated ruthenium(II) complexes (Ru1-Ru4) coordinated with pyridine-functionalized N-heterocyclic carbene (NHC) and auxiliary ligands (e.g., acetonitrile, 1,10-phenanthroline, 3,4,7,8-tetramethyl-1,10-phenanthroline, and 4,7-diphenyl-1,10-phenanthroline). X-ray diffraction analysis showed that all of the four cycloruthenated complexes are hexa-coordinated in a typical octahedral geometry. In vitro cytotoxic studies revealed that cyclometalated Ru-NHC complexes Ru3 and Ru4 had stronger anticancer activity than their corresponding Ru-NHC precursor Ru1 and the clinically used cisplatin. For HeLa cells, Ru3 and Ru4 exhibited potent cytotoxicity with the IC50 value of 4.31 ± 0.42 μM and 3.14 ± 0.23 μM, respectively, which was approximately three times lower than that of cisplatin. More interestingly, Ru3 and Ru4 not only effectively inhibited the proliferation of HeLa cells, but also exhibited potential anti-migration activity. In the scratch wound healing assay, Ru3 and Ru4 treatment significantly reduced the wound healing rate of HUVEC cells. Mechanistic studies showed that Ru3 and Ru4 caused a dual action mode of mitochondrial membrane depolarization and endoplasmic reticulum stress and finally induced apoptosis of HeLa cells. Show less

Half-sandwich Ru^II complexes, [(YZ)Ru^II (η⁶ -arene)(X)]+, (YZ=chelating bidentate ligand, X=halide), with N,N and N,O coordination (1-9) show significant antiproliferative activity against the metastatic triple-negative breast carcinoma (MDA-MB-231). 3-aminobenzoic acid or its methyl ester is used in all the ligands while varying the aldehyde for N,N and N,O coordination. In the N,N coordinated complex the coordinated halide(X) is varied for enhancing stability in solution (X=Cl, I). Rapid aquation and halide exchange of the pyridine analogues, 2 and 3, in solution are a major bane towards their antiproliferative activity. Presence of free -COOH group (1 and 4) make complexes hydrophilic and reduces toxicity. The imidazolyl 3-aminobenzoate based N,N coordinated 5 and 6 display better solution stability and efficient antiproliferative activity (IC₅₀ ca. 2.3-2.5 μM) compared to the pyridine based 2 and 3 (IC₅₀ >100 μM) or the N,O coordinated complexes (7-9) (IC₅₀ ca. 7-10 μM). The iodido coordinated, 6, is resistant towards aquation and halide exchange. The N,O coordinated 7-9 underwent instantaneous aquation at pH 7.4 generating monoaquated complexes stable for at least 6 h. Complexes 5 and 6, bind to 9-ethylguanine (9-EtG) showing propensity to interact with DNA bases. The complexes may kill via apoptosis as displayed from the study of 8. The change in coordination mode and the aldehyde affected the solution stability, antiproliferative activity and mechanistic pathways. The N,N coordinated (5 and 6) exhibit arrest in the G2/M phase while the N,O coordinated 8 showed arrest in the G0/G1 phase. Show less