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•This review focusses on the structural features of Ru(II) complexes.•The review provides an overview of the anticancer activity of Ru(II) complexes.•The kinetic and mechanistic ...studies form an essential part of the review.•DNA/protein binding mode of ruthenium(II) complexes is high-lighted.
In this review we summarize our work on development of Ru complexes with potential antitumor activity, which was performed over the last few years. In order to establish the structure-activity relationship for Ru(II) compounds, we have designed, synthesized and thoroughly studied several Ru(II) complexes, which were divided in three main groups: i) organometallic Ru(II)-arene complexes, ii) Ru(II) half-sandwich coordination complexes bearing neutral face-capping macrocyclic ligands, such as 1,4,7-trithiacyclononane (9aneS3) and 1,4,7-triazacyclononane (9aneN3), and iii) Ru(II)-polypyridyl complexes. Our most recent experiments moved toward synthesis, chemistry and reactivity of the heteronuclear ruthenium(II)/ferrocene complexes. The first part of the present review gives a brief overview of the structural features and anticancer activity of ruthenium complexes. The second part is focused mainly on the results obtained from the kinetic and mechanistic studies of the reactions between Ru(II) complexes and guanine derivatives, such as 9-methylguanine (9MeG), guanosine (Guo) and guanosine-5′-monophosphate (5′-GMP), as well as on structural characterization of the final products of these reactions. In the final part we deal with the reactions of Ru(II) complexes with DNA, which is widely accepted as a potential target for cytotoxic ruthenium compounds. We have also described the interactions of Ru(II) compounds with the most abundant transport proteins from human serum: human serum albumin (HSA) and transferrin (Tf). We believe that a systematic review of the aforementioned studies will not only contribute to the future development of ruthenium complexes as potential antitumor agents, but will also help to understand the potential toxicity of ruthenium-based drugs.
This paper presents the synthesis and structural characterization of a series of new ruthenium(II) complexes 1-7, with the general formula
-RuL
(
-
)ClCl, where L is 2,2':6',2''-terpyridine (tpy) or ...4'-(4-chlorophenyl)-2,2':6',2''-terpyridine (Cl-Ph-tpy) and
-
is
-benzoquinonediimine (
-bqdi), 2,3-naphthoquinonediimine (nqdi), 4,4'-dimethyl-2,2'-bipyridine (dmbpy) or 2,2'-bipyridine-4,4'-dicarboxylic acid (dcbpy). The kinetic results showed that the ligand substitution reactions of new Ru(II)-polypyridyl complexes with biomolecules were affected by different substituents and the aromaticity of meridional tridentate and bidentate spectator ligands as well as by the nature of the entering nucleophile. The reactivity of the complexes increases in the order: dmbpy < dcbipy < nqdi <
-bqdi. In addition, quantum chemical calculations were performed to support the interpretation and discussion of the experimental data. Furthermore, combining ethidium bromide (EB) and Hoechst 33258 (2-(4-hydroxyphenyl)-5-5-(4-methylpiperazine-1-yl)benzimidazo-2-yl-benzimidazole) fluorescence assay results implied that 1-7 might interact with calf thymus DNA through partial intercalation and/or minor groove binding. The human serum albumin (HAS)-fluorescence binding studies involving the site markers, eosin Y, as a marker for site I of subdomain IIA, and ibuprofen, as a marker for site II of subdomain IIIA, showed that Ru(II) compounds bind to both sites with moderately strong affinity (
= 10
-10
M
). Moreover, these DNA/HSA experimental results were confirmed by molecular docking. Complexes 2, 5 and 6 exerted good to strong and highly selective cytotoxic activity against breast adenocarcinoma (MDA-MB 231), colorectal carcinoma (HCT116) and cervix adenocarcinoma (HeLa). Depending on their structure and cell line, the complexes acted differently in terms of their influence on autophagy, the cell cycle and the engaged apoptotic pathway.
Interactions of three Ru(II) chlorophenyl terpyridine complexes: Ru(Cl-Ph-tpy)(en)ClCl (1), Ru(Cl-Ph-tpy)(dach)ClCl (2) and Ru(Cl-Ph-tpy)(bpy)ClCl (3) ...(Cl-Ph-tpy = 4′-(4-chlorophenyl)-2,2′:6′,2′′-terpyridine, en = 1,2-diaminoethane, dach = 1,2-diaminocyclohexane, bpy = 2,2′-bipyridine) with human serum albumin (HSA), calf thymus DNA and a double-helical oligonucleotide d(CGCGAATTCGCG)2 (1BNA) were examined. Fluorescence emission studies were used to assess the interactions of complexes with HSA, which were of moderate strength for 1 and 2. Molecular docking allowed us to predict mostly π-π stacking and van der Waals interactions between the complexes and the protein. We suggest that the complexes bind to a novel site on HSA, which is different from its druggable sites I, II or III. We suggest a partial intercalation of complexes through the minor groove as a possible mode of interaction with double-helical DNA. Finally, when applied to normal extravillous cell line HTR8/SVneo and JAr choriocarcinoma cell line, complexes 1 and 2 exerted anti-adhesive properties at very low doses, whereas complex 3 had a negligible effect. The obtained results are completion of our studies of Ru(II) terpyridyl complexes that carry N-N ancillary ligands. We suggest a new research direction towards studying the cellular effects of Ru(II) polypyridyl compounds.
Best docked poses of complex-Ru(Cl-Ph-tpy)(dach)Cl+ (Cl-Ph-tpy, 4′-(4-chlorophenyl)-2,2′:6′,2′′-terpyridine; dach, 1,2-diaminocyclohexane) on human serum albumin and dodecamer double-stranded oligonucleotide as assessed by molecular docking. Linear dichroism study of intercalation of the complex into a full-length double-helical DNA. The complex inhibits the adhesion of normal cells -HTR-8/SVneo and tumour cells - JAr choriocarcinoma. Display omitted
•Ru(II) terpyridine coordination complexes are potential anti-tumour compounds.•Confident assessment of metallodrugs-to-DNA binding mode through linear dichroism.•Different binding of Ru(II) terpyridine complexes to human and bovine serum albumin.•Novel druggable site on human serum albumin for Ru(II) terpyridine complexes.•DNA accommodates Ru(II) terpyridines using an intercalation through minor groove.
With the aim of assessing whether Au(iii) compounds with pincer type ligands might be utilized as potential antitumor agents, three new monofunctional Au(iii) complexes of the general formula ...Au(N-N'-N)ClCl2, where N-N'-N = 2,6-bis(5-tert-butyl-1H-pyrazol-3-yl)pyridine (H2LtBu, 1), 2,6-bis(5-tert-butyl-1-methyl-1H-pyrazol-3-yl)pyridine (Me2LtBu, 2) or 2,6-bis((4S,7R)-1,7,8,8-tetramethyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)pyridine (Me2*L, 3) were synthesized. All complexes were characterized by elemental analysis, spectroscopic techniques (IR, UV-Vis, 1D and 2D NMR) and mass spectrometry (MALDI TOF MS). The chemical behavior of the complexes under physiological conditions was studied by UV-Vis spectroscopy, which showed that all compounds were remarkably stable and that the gold center remained in the 3+ oxidation state. The kinetics and the mechanism of the reaction of complexes 1-3 with guanine derivatives (i.e. guanosine (Guo) and guanosine-5'-monophosphate (5'-GMP)) and calf thymus DNA (CT DNA) were studied by stopped-flow spectroscopy. The three complexes displayed moderately different rate constants in their reactions with Guo, 5'-GMP and CT DNA, which can be explained by the steric hindrance and σ-donicity of the methyl substituent on the bis-pyrazolylpyridine fragment in complexes 2 and 3. The measured enthalpies and entropies of activation (ΔH≠ > 0, ΔS≠ < 0) supported an associative mechanism for the substitution process. The interaction of the newly synthesized complexes 1-3 with CT DNA was investigated by UV-Vis and fluorescence spectroscopy, and also by viscosity measurements, which all indicated that complexes 1-3 bound to CT DNA with moderate binding affinity (Kb = 1.6-5.7 × 103 M-1) and stabilized the duplex of CT DNA. Molecular docking indicated that complexes 1-3 interacted with DNA via intercalation. Complex 1 reduced the cell survival of all the investigated cell lines (A549, A375, and LS-174) with IC50 values being up to 20 μM. We have shown that 1 induced perturbations of the cell cycle and led to apoptosis in human melanoma A375 cells. Complex 1 also affected the level of reactive oxygen species (ROS) in the same cells. However, pre-treatment of A375 cells with NAC (ROS scavenger) reversed the effect of 1 on their survival.
We synthesized and characterized the ruthenium(iii) pincer-type complex RuCl3(H2Lt-Bu (H2Lt-Bu = 2,6-bis(5-tert-butyl-1H-pyrazol-3-yl)pyridine, 1) by elemental analysis, IR and UV-Vis spectroscopy, ...and the mass spectrometry (MS) method ESI Q-TOF. For comparison reasons, we also studied ruthenium(iii) terpyridine complexes of the general formula Ru(N-N-N)Cl3, where N-N-N = 4'-chloro-terpyridine (Cl-tpy; 2) or 4'-chlorophenyl-terpyridine (Cl-Ph-tpy; 3). A kinetic study of the substitution reactions of 1-3 with biomolecules showed that the rate constants depend on the properties of the spectator ligand and the nature of the entering nucleophile. The DNA/HSA binding study showed that in comparison to complex 1 (bis-pyrazolylpyridine), the other two (2 and 3) terpyridine complexes had a slightly better binding affinity to calf thymus DNA (CT DNA), while in the case of human serum albumin (HSA), complex 1 exhibited the strongest quenching ability. We demonstrated that 1 possesses significant in vitro cytotoxic activity against mouse colon carcinoma CT26 cells and in vivo antitumor activity in murine heterotopic colon carcinoma. Complex 1 induced G0/G1 cell cycle arrest and apoptotic death in CT26 cells. Additionally, 1 showed antiproliferative activity, as evaluated by the detection of the expression levels of the Ki67 protein. Furthermore, the in vivo results showed that 1 reduced primary tumour growth and the number and growth of lung and liver metastases, significantly prolonging the treated mice's survival rate. This study highlighted that 1 does not show hepato- and nephrotoxicity. Our data demonstrated the considerable antitumor activity of the ruthenium(iii) pincer complex against CT26 tumour cells and implicated further investigations of its role as a potential chemotherapeutic agent for colon carcinoma.
The two new heterometallic Ru(II)-tpy/ferrocene complexes Ru(tpy)Cl2(mtefc) (1) and Ru(tpy)Cl2(mtpfc) (2) (where tpy = 2,2′:6′,2′′-terpyridine, mtefc = (2-(methylthio)ethyl)ferrocene, and ...mtpfc = (3-(methylthio)propyl)ferrocene) have been synthesized and then characterized through elemental analysis, followed by various spectroscopic (IR, UV–vis, 1D and 2D NMR) and mass spectrometric techniques (MALDI TOF and ESI Q-TOF MS). UV–vis and fluorescence spectroscopy and viscometry were employed to study the interactions of the complexes 1 and 2 with calf thymus DNA. Both 1 and 2 expelled ethidium bromide (EB) from the EB/DNA complex (K sv = (1.5–1.8) × 104 M–1), which suggested that the complexes intercalated into the double helix of DNA. Both complexes strongly quenched the fluorescence of tryptophan residues in serum albumin through both static and dynamic quenching. Molecular docking confirmed the intercalative mode of complex interaction with DNA. The docking results implied that 1 and 2 interacted with hydrophobic residues of albumin, particularly with those lying in the proximity of Tyr 160. We here demonstrate the high cytotoxic potential of complexes 1 and 2 against the breast cancer cells that originated either from humans (MDA-MB-231) or from mice (4T1), with apoptosis being the main mechanism of complex-induced cell death. It is worth noting that both complexes promoted activation of innate and acquired antitumor immunity, which contributed to the reduced growth and progression of mammary carcinoma in vivo.
Ruthenium complexes have attracted considerable interest as potential antitumor agents. Therefore, antitumor activity and systemic toxicity of ruthenium(II) terpyridine complexes were evaluated in ...heterotopic mouse colon carcinoma. In the present study, cytotoxic effects of recently synthesized ruthenium(II) terpyridine complexes Ru(Cl-tpy)(en)ClCl (en = ethylenediamine, tpy = terpyridine,
) and Ru(Cl-tpy)(dach)ClCl (dach = 1,2-diaminocyclohexane,
) towards human and murine colon carcinoma cells were tested in vitro and in vivo and compared with oxaliplatin, the most commonly used chemotherapeutic agent against colorectal carcinoma. Ruthenium(II) complexes showed moderate cytotoxicity with IC
values ranging between 19.1 to 167.3 μM against two human, HCT116 and SW480, and one mouse colon carcinoma cell line, CT26. Both ruthenium(II) terpyridine complexes exerted a moderate apoptotic effect in colon carcinoma cells, but induced significant necrotic death. Additionally, both complexes induced cell cycle disturbances, but these effects were specific for the cell line. Further,
significantly reduced the growth of primary heterotopic tumor in mice, similarly to oxaliplatin. Renal damage in
treated mice was lower in comparison with oxaliplatin treated mice, as evaluated by serum levels of urea and creatinine and histological evaluation, but
induced higher liver damage than oxaliplatin, evaluated by the serum levels of alanine aminotransferase. Additionally, the interaction of these ruthenium(II) terpyridine complexes with the tripeptide glutathione (GSH) was investigated by proton nuclear magnetic resonance (
H NMR) spectroscopy. All reactions led to the formation of monofunctional thiolate adducts Ru(Cl-tpy)(en)GS-
(
) and Ru(Cl-tpy)(dach)GS-
(
). Our data highlight the significant cytotoxic activity of Ru(Cl-tpy)(en)ClCl against human and mouse colon carcinoma cells, as well as in vivo antitumor activity in CT26 tumor-bearing mice similar to standard chemotherapeutic oxaliplatin, accompanied with lower nephrotoxicity in comparison with oxaliplatin.
Background/Aim. The use of cisplatin as a chemotherapeutic opened the door to the new metal-based drug research. New complexes containing metals such as platinum, palladium, ruthenium and gold have ...recently been analyzed as potential antitumor agents. The aim of the study was to investigate the cytotoxicity of Au(III) complexes with pincer-type ligands against cervical carcinoma cells (HeLa), breast cancer cells (MDA-MB-231 and 4T1) and colon carcinoma cells (HCT116 and CT26), as well as to examine the type and mechanism of cell death that these complexes induced in cancer cells. Methods. The cytotoxicity of Au(III) complexes was investigated by MTT assay. The apoptosis of the treated cancer cells was measured by flow cytometry and applying Annexin V/7AAD staining. The expressions of active proapoptotic protein Bax, antiapoptotic protein Bcl-2 and the percentage of cells containing cleaved caspase-3 in the treated cancer cells were determined by flow cytometry. Results. Complex 1 showed the most potent antitumor effect on HeLa cells, both compared to other two examined gold complexes and compared to cisplatin. The IC50 values on HeLa cells after 72 hours were 1.3 ? 0.4 ?M, 3.4 ? 1.3 ?M, 5.7 ? 0.6 ?M, 26.7 ? 6.5 ?M for complexes 1, 2, 3 and cisplatin, respectively. Complex 1 also exhibited the highest cytotoxicity against MDA-MB-231 and HCT116 cells compared to other tested compounds. The results of Annexin V/7AAD staining showed that all three gold complexes induced apoptosis in the treated cells. Our Au(III) complexes induced apoptosis by caspase-dependent mechanism, but we did not observe that the activation of an internal pathway of apoptosis occurred in the treated cancer cells. Conclusion. According to the results of our in vitro study, all three gold compounds, and especially complex 1, are promising candidates for a new generation of anticancer drugs.
In order to discover new anticancer drugs, novel ruthenium(III) complexes Ru(L)Cl(H2O), where L is tetradentate Schiff base bis(acetylacetone)ethylendiimine (acacen, 1), ...bis(benzoylacetone)ethylendiimine (bzacen, 2), (acetylacetone)(benzoylaceton)ethylendiimine (acacbzacen, 3), bis(acetylacetone)propylendiimine (acacpn, 4), bis(benzoylacetone)propylendiimine (bzacpn, 5) or (acetylacetone)(benzoylaceton)propylendiimine (acacbzacpn, 6), were synthesized. The complexes 1 – 6 were characterized by elemental analysis, molar conductometry, and by various spectroscopic techniques, such as UV–Vis, IR, EPR, and ESI-MS. Based on in vitro DNA/BSA experiments, complexes 2 (bzacen) and 5 (bzacpn) with two aromatic rings showed the highest DNA/BSA-activity, suggesting that the presence of the aromatic ring on the tetradentate Schiff base ligand contributes to increased activity. Moreover, these two compounds showed the highest cytotoxic effects toward human, A549 and murine LLC1 lung cancer cells. These complexes altered the ratio of anti- and pro-apoptotic molecules and induced apoptosis of A549 cells. Further, complexes 2 and 5 reduced the percentage of Mcl1 and Bcl2 expressing LLC1 cells, induced their apoptotic death and exerted an antiproliferative effect against LLC1. Finally, complex 5 reduced the volume of mouse primary heterotopic Lewis lung cancer, while complex 2 reduced the incidence and mean number of metastases per lung. Additionally, molecular docking with DNA revealed that the reduced number of aromatic rings or their absence causes lower intercalative properties of the complexes in order: 2 > 5 > 6 > 3 > 4 > 1. It was observed that conventional hydrogen bonds and hydrophobic interactions contribute to the stabilization of the structures of complex-DNA. A molecular docking study with BSA revealed a predominance of 1 – 6 in binding affinity to the active site III, a third D-shaped hydrophobic pocket within subdomain IB.
We described the synthesis and structural characterization of novel ruthenium(III)-Schiff base complexes, alongside with their interactions with DNA and BSA. Furthermore, we demonstrated that Ru(III) complex 5 reduced the volume of mouse primary heterotopic Lewis lung cancer, while complex 2 reduced the incidence and mean number of metastases per lung. Display omitted
•Synthesis and characterization of novel Ru(III) Schiff base complexes.•Ru complexes 2 (bzacen) and 5 (bzacpn) showed the highest CT-DNA/BSA activity.•BSA molecular docking revealed a predominance of 1–6 to bind to the active site III.•Complex 2 reduced the incidence and mean number of metastases per lung.•Complex 5 reduced the volume of mouse primary heterotopic Lewis lung cancer.
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