📚 BiometalDB

Elucidation of the communication between metal complexes and cell membrane may provide useful information for rational design of metal-based anticancer drugs. Herein we synthesized a novel class of ruthenium (Ru) complexes containing phtpy derivatives (phtpy = phenylterpyridine), analyzed their structure-activity relationship and revealed their action mechanisms. The result showed that, the increase in the planarity of hydrophobic Ru complexes significantly enhanced their lipophilicity and cellular uptake. Meanwhile, the introduction of nitro group effectively improved their anticancer efficacy. Further mechanism studies revealed that, complex (2c), firstly accumulated on cell membrane and interacted with death receptors to activate extrinsic apoptosis signaling pathway. The complex was then transported into cell cytoplasm through transferrin receptor-mediated endocytosis. Most of the intracellular 2c accumulated in cell plasma, decreasing the level of cellular ROS, inducing the activation of caspase-9 and thus intensifying the apoptosis. At the same time, the residual 2c can translocate into cell nucleus to interact with DNA, induce DNA damage, activate p53 pathway and enhance apoptosis. Comparing with cisplatin, 2c possesses prolonged circulation time in blood, comparable antitumor ability and importantly, much lower toxicity in vivo. Taken together, this study uncovers the role of membrane receptors in the anticancer actions of Ru complexes, and provides fundamental information for rational design of membrane receptor targeting anticancer drugs. Show less

This paper reports the synthesis, structure characterization, and anticancer properties of 13 organometallic Ru(ii)-arene complexes: [Ru(η6-p-cymene)Cl-(L1)] (1), [Ru(η6-p-cymene)Cl-(L2)] (2), [Ru(η6-p-cymene)Cl-(L3)] (3), [Ru(η6-p-cymene)Cl-(L4)] (4), [Ru(η6-p-cymene)Cl-(L5)] (5), [Ru(η6-p-cymene)I-(L1)] (6), [Ru(η6-p-cymene)I-(L2)] (7), [Ru(η6-p-cymene)I-(L3)] (8), [Ru(η6-p-cymene)I-(L4)] (9), [Ru(η6-p-cymene)I-(L5)] (10), [Ru(η6-p-cymene)I-(L6)] (11), [Ru(η6-p-cymene)I-(L7)] (12), and [Ru(η6-p-cymene)Cl-(L8)] (13) respectively containing deprotonated 5,7-dichloro-2-methyl-8-quinolinol (H-L1), 5,7-dibromo-2-methyl-8-quinolinol (H-L2), 5-chloro-7-iodo-8-hydroxy-quinoline (H-L3), 5,7-dibromo-8-quinolinol (H-L4), 5,7-diiodo-8-hydroxyquinoline (H-L5), 8-hydroxy-2-methylquinoline (H-L6), 2,8-quinolinediol (H-L7), or 6,7-dichloro-5,8-quinolinedione (H-L8). MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay showed that 13 organometallic Ru(ii)-arene complexes 1-13 are more selective for HeLa cells than normal HL-7702 cells. In addition, 1, 2, 5, and 6, which contain the active ligands H-L1 and H-L2, showed remarkable cell cytotoxicity, giving the respective IC50 values of 2.00 ± 0.20 nM, 0.89 ± 0.62 μM, 25.00 ± 0.30 nM, and 2.18 ± 0.35 μM on HeLa cancer cells. These values indicated higher activity than 6,7-dichloro-5,8-quinolinedione and other 8-hydroxyquinoline derivative Ru(ii)-arene complexes. Interestingly, all these Ru(ii)-arene complexes 1-13 were significantly less toxic to human hepatic (HL-7702) cells. Moreover, 1- and 2-induced HeLa cell apoptosis was mediated by the inhibition of telomerase activity and dysfunction of mitochondria, and resulted in DNA damage and increased anti-migration activity on HeLa cells. The organometallic Ru(ii)-arene complex 1 exhibited evident priority to the antitumor activity compared to 2, which should be highly associated with the key roles of the 5,7-dichloro substituted groups in the L1 ligand of organometallic Ru(ii)-arene complexes 1. Remarkably, 1 showed higher inhibitory activity against the xenograft tumor growth of human cervical cells (HeLa) in vivo (tumor growth inhibition rate (TGIR) = 58.5%) than cisplatin. This study was the first to show that the 5,7-dihalogenated-2-methyl-8-quinolinol organometallic Ru(ii)-arene complexes 1 and 2 are novel Ru(ii) anticancer drug candidates. Show less

The novel steroidal conjugate 17-α-[2-phenylpyridyl-4-ethynyl]-19-nortestosterone (LEV-ppy) (1) and the steroid-C,N-chelate ruthenium(II) conjugate [Ru(η(6)-p-cymene)(LEV-ppy)Cl] (2) have been prepared. At 48 h incubation time, complex 2 is more active than cisplatin (about 8-fold) in T47D (breast cancer) and also shows an improved efficiency when compared to its nonsteroidal analogue [Ru(η(6)-p-cymene)(ppy)Cl] (ppy = phenylpyridine) (3) in the same cell line. The act of conjugating a levonorgestrel group to a ruthenium(II) complex resulted in synergistic effects between the metallic center and the steroidal ligand, creating highly potent ruthenium(II) complexes from the inactive components. The interaction of 2 with DNA was followed by electrophoretic mobility. Theoretical density functional theory calculations on complex 2 show the metal center far away from the lipophilic steroidal moiety and a labile Ru-Cl bond that allows easy replacement of Cl by N-nucleophiles such as 9-EtG, thus forming a stronger Ru-N bond. We also found a minimum energy location for the chloride counteranion (4(+)·Cl(-)) inside the pseudocavity formed by the α side of the steroid moiety, the phenylpyridine chelating subsystem, and the guanine ligand, i.e., a host-guest species with a rich variety of nonbonding interactions that include nonclassical C-H···anion bonds, as supported by electrospray ionization mass spectra. Show less

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

Chelating neutral (N,O) and cationic (N,N) first- and second-generation ruthenium(II) arene metallodendrimers based on poly(propyleneimine) dendrimer scaffolds were obtained from dinuclear arene ruthenium precursors by reactions with salicylaldimine and iminopyridyl dendritic ligands, respectively. The N,N cationic complexes were isolated as hexafluorophosphate salts and were characterised by NMR and IR spectroscopy, and MALDI-TOF mass spectrometry. Related mononuclear complexes were obtained in a similar manner and their molecular structures have been determined by X-ray diffraction analysis. The cytotoxicities of the mono- and multinuclear complexes were established using A2780 and A2780cisR human ovarian carcinoma cancer cell lines. Show less

Inhibition of the growth of LoVo human colon adenocarcinoma and MiaPaCa pancreatic cancer cell lines by two new organometallic ruthenium(II) complexes of general formula [Ru(eta(5)-C(5)H(5))(PP) L][CF(3)SO(3)], where PP is 1,2-bis(diphenylphosphino)ethane and L is 1,3,5-triazine (Tzn) 1 or PP is 2x triphenylphosphine and L is pyridazine (Pyd) 2 has been investigated. Crystal structures of compounds 1 and 2 were determined by X-ray diffraction studies. Atomic force microscopy (AFM) images suggest different mechanisms of interaction with the plasmid pBR322 DNA; while the mode of binding of compound 1 could be intercalation between base pairs of DNA, compound 2 might be involved in a covalent bond formation with N from the purine base. Show less

We report a novel ruthenium(II) complex for selective release of the imidazole-based drug econazole. While the complex is highly stable and luminescent in the dark, irradiation with green light induces release of one of the econazole ligands, which is accompanied by a turn-off luminescence response and up to a 34-fold increase in cytotoxicity towards tumour cells. Show less

Poor selectivity between cancer cells and normal cells is one of the major limitations of cancer chemotherapy. Lysosome-targeted ruthenium-based complexes target tumor cells selectively, only displaying rather weak cytotoxicity or inactivity toward normal cells. Confocal microscopy was employed for the first time to determine the cellular localization of the half-sandwich Ru complex. Show less

New water-soluble bis(2-phenylazopyridine)ruthenium(II) complexes, all derivatives of the highly cytotoxic alpha-[Ru(azpy)(2)Cl(2)] (alpha denoting the coordinating pairs Cl, N(py), and N(azo) as cis, trans, cis, respectively) have been developed. The compounds 1,1-cyclobutanedicarboxylatobis(2-phenylazopyridine)ruthenium(II), alpha-[Ru(azpy)(2)(cbdca-O,O')] (1), oxalatobis(2-phenylazopyridine)ruthenium(II), alpha-[Ru(azpy)(2)(ox)] (2), and malonatobis(2-phenylazopyridine)ruthenium(II), alpha-[Ru(azpy)(2)(mal)] (3), have been synthesized and fully characterized. X-ray analyses of 1 and 2 are reported, and compound 1 is the first example in which the cbdca ligand is coordinated to a ruthenium center. The cytotoxicity of this series of water-soluble bis(2-phenylazopyridine) complexes has been determined in A2780 human ovarian carcinoma and A2780cisR, the corresponding cisplatin-resistant cell line. For comparison reasons, the cytotoxicity of the complexes alpha-[Ru(azpy)(2)Cl(2)], alpha-[Ru(azpy)(2)(NO(3))(2)], beta-[Ru(azpy)(2)Cl(2)] (beta indicating the coordinating pairs Cl, N(py), and N(azo) as cis, cis, cis, respectively), and beta-[Ru(azpy)(2)(NO(3))(2)] have been determined in this cell line. All the bis(2-phenylazopyridine)ruthenium(II) compounds display a promising cytotoxicity in the A2780 cell line (IC(50) = 0.9-10 microM), with an activity comparable to that of cisplatin and even higher than the activity of carboplatin. Interestingly, the IC(50) values of this series of ruthenium compounds (except the beta isomeric compounds) are similar in the cisplatin-resistant A2780cisR cell line compared to the normal cell line A2780, suggesting that the activity of these compounds might not be influenced by the multifactorial resistance mechanism that affect platinum anticancer agents. Show less

Ruthenium(II)-arene complexes of general formulae [(eta(6)-p-cymene)Ru(L(1-3))Cl(2)], where L(1-3) is 3-acetylpyridine (1), 4-acetylpyridine (2) and 2-amino-5-chloropyridine (3), correspondingly, [(eta(6)-p-cymene)Ru(HL(4,5))Cl(2)], where HL(4) and HL(5) are respectively isonicotinic acid (4) and nicotinic acid (5) and [(eta(6)-p-cymene)Ru(HL(6-9))Cl], where H(2)L(6-9) represent 2,3-pyridinedicarboxylic acid (6), 2,4-pyridinedicarboxylic acid (7), 2,5-pyridinedicarboxylic acid (8) and 2,6-pyridinedicarboxylic acid (9), were prepared by the reaction of [(eta(6)-p-cymene)(2)RuCl(2)](2) (10) with the corresponding ligand in 1:2 molar ratio in isopropanol. The complexes were characterized by elemental analysis, mass spectrometry, IR and NMR spectroscopies. According to these data the molecules adopt the usual "three-leg piano-stool" geometry which is common for this type of complexes. The structures of 1 and 7 were determined by X-ray crystallography. The complexes revealed low antiproliferative activity in six investigated tumor cell lines (HeLa, B16, FemX, MDA-MB-361, MDA-MB-453 and LS-174). The reaction of 6 with 9-methyladenine was studied by (1)H NMR, (1)H, (1)H COSY and (1)H, (1)H NOESY spectroscopy. Show less

Various interaction modes between a group of six ruthenium polypyridyl complexes and DNA have been studied using a number of spectroscopic techniques. Five mononuclear species were selected with formula [Ru(tpy)L(1)L(2)]((2-n)+), and one closely related dinuclear cation of formula [{Ru(apy)(tpy)}(2){mu-H(2)N(CH(2))(6)NH(2)}](4+). The ligand tpy is 2,2':6',2''-terpyridine and the ligand L(1) is a bidentate ligand, namely, apy (2,2'-azobispyridine), 2-phenylazopyridine, or 2-phenylpyridinylmethylene amine. The ligand L(2) is a labile monodentate ligand, being Cl(-), H(2)O, or CH(3)CN. All six species containing a labile L(2) were found to be able to coordinate to the DNA model base 9-ethylguanine by (1)H NMR and mass spectrometry. The dinuclear cationic species, which has no positions available for coordination to a DNA base, was studied for comparison purposes. The interactions between a selection of four representative complexes and calf-thymus DNA were studied by circular and linear dichroism. To explore a possible relation between DNA-binding ability and toxicity, all compounds were screened for anticancer activity in a variety of cancer cell lines, showing in some cases an activity which is comparable to that of cisplatin. Comparison of the details of the compound structures, their DNA binding, and their toxicity allows the exploration of structure-activity relationships that might be used to guide optimization of the activity of agents of this class of compounds. Show less