In a search for new antitumoral agents, a series of homoleptic copper(II) complexes with amino acids and dipeptides, as well as heteroleptic complexes containing both dipeptides and ...1,10-phenanthroline, were studied. Furthermore, a single-crystal structure containing alanyl-leucinato (Cu
(AlaLeu)
(H
O)
(CO
)·PF
·H
O), which is the first homotrinuclear carbonato-bridged copper(II) complex with a dipeptide moiety, is presented. To assess possible antitumor action mechanisms, we focused on the comparative analysis of pro- and antioxidant behaviors. Pro-oxidant activity, in which the reactive oxygen species (ROS) formed by the reaction of the complexes with H
O
produce oxidative damage to 2-deoxy-d-ribose, was evaluated using the TBARS method. Additionally, the antioxidant action was quantified through the superoxide dismutase (SOD)-like activity, using a protocol based on the inhibitory effect of SOD on the reduction of nitrobluetetrazolium (NBT) by the superoxide anion generated by the xanthine/xanthine oxidase system. Our findings show that Cu-amino acid complexes are strong ROS producers and moderate SOD mimics. Conversely, Cu-dipeptide-phen complexes are good SOD mimics but poor ROS producers. The activity of Cu-dipeptide complexes was strongly dependent on the dipeptide. A DFT computational analysis revealed that complexes with high SOD-like activity tend to display a large dipole moment and condensed-to-copper charge, softness and LUMO contribution. Moreover, good ROS producers have higher global hardness and copper electrophilicity, lower copper softness and flexible and freely accessible coordination polyhedra.
Organometallic ruthenium complexes as potential anticancer agents have been explored due to their suitable properties, such as stability in the solid state and in solution, water solubility and low ...toxicity. In this study, eight metal complexes of this class were synthesized, characterized and their important biological activities against a human breast tumor cell line (MDA-MB-231) were studied. Complexes 1-8 were obtained in good yields and have been characterized by satisfactory elemental analyses, IR, 1D and 2D
H and
C{
H} NMR, UV-Vis spectroscopy, cyclic voltammetry, ESI-MS and X-ray diffractometry (1, 2, 3 and 6). All complexes exhibit growth inhibition on human breast and lung tumor cell lines, with IC
values ranging from 6.0 to 45.0 μM in 48 h. Four compounds were selected to evaluate the changes in the morphology, clonogenic, migration, cell cycle arrest and cell death in MDA-MB-231 cells. The complexes are able to induce morphological changes and inhibit the size, number of colonies and cell migration, and induce cell cycle arrest in the sub-G1 phase and apoptosis cell death. The interaction of the complexes with DNA was determined by performing spectroscopic titration, a competitive assay with thiazole orange, circular dichroism, gel electrophoresis and interactions with guanosine or guanosine monophosphate by
H NMR, indicating the non-covalent interaction. The HSA binding affinity measured by spectrophotometric titration, revealed the hydrophobic and spontaneous association with the human protein. Overall, the studies indicated that these metal complexes are potential agents against MDA-MB-231 cells, encouraging us to continue studies of these types of compounds.
In this study, half-sandwich Ru(II) complexes containing acylthiourea ligands of the general type Ru(η6-p-cymene)(PPh3)(S)ClPF6 (1m–6m) and Ru(η6-p-cymene)(PPh3)(S–O)PF6 (1b–6b) where S/S–O ...= N’,N’-disubstituted acylthiourea were synthesized and characterized (via elemental analyses, IR spectroscopy, 1H NMR spectroscopy, 13C{1H} NMR spectroscopy, and X-ray diffractometry), and their cytotoxic activity was evaluated. The different coordination modes of the acylthiourea ligands, monodentately via S (1m–6m) and bidentately via S,O (1b–6b), to ruthenium were modulated from different synthetic routes. The cytotoxicity of the complexes was evaluated in five human cell lines (DU-145, A549, MDA-MB-231, MRC-5, and MCF-10A) by MTT assay. The IC50 values for prostate cancer cells (2.89–7.47 μM) indicated that the complexes inhibited cell growth, but that they were less cytotoxic than cisplatin (2.00 μM). Unlike for breast cancer cells (IC50 = 0.28–0.74 μM) and lung cancer cells (IC50 = 0.51–1.83 μM), the complexes were notably more active than the reference drug, and a remarkable selectivity index (SI 4.66–19.34) was observed for breast cancer cells. Based on both the activity and selectivity, complexes 5b and 6b, as well as their respective analogous complexes in the monodentate coordination 5m and 6m, were chosen for further investigation in the MDA-MB-231 cell line. These complexes not only induced morphology changes but also were able to inhibit colony formation and migration. In addition, the complexes promoted cell cycle arrest at the sub-G1 phase inducing apoptosis. Interaction studies by viscosity measurements, gel electrophoresis, and fluorescence spectroscopy indicated that the complexes interact with the DNA minor groove and exhibit an HSA binding affinity.
Herein, we report the synthesis and characterization of the new di-iron(III) complex (bbpmp)(H2O)(Cl)FeIII(μ-Ophenoxo)FeIII(H2O)Cl)Cl (1), with the symmetrical ligand ...2,6-bis{(2-hydroxybenzyl)(pyridin-2-yl)methylaminomethyl}-4-methylphenol (H3bbpmp). Complexes 2 with the unsymmetrical ligand H2bpbpmp — {2-(2-hydroxybenzyl)(2-pyridylmethyl)aminomethyl-6-bis(pyridylmethyl) aminomethyl}-4-methylphenol and 3 with the ligand L1=4,11-dimethyl-1,8-bis{2-N-(di-2-pyridylmethyl)aminoethyl}cyclam were included for comparison purposes. Complex 1 was characterized through elemental analysis, X-ray crystallography, magnetochemistry, electronic spectroscopy, electrochemistry, mass spectrometry and potentiometric titration. The magnetic data show a very weak antiferromagnetic coupling between the two iron centers of the dinuclear complex 1 (J=−0.29cm−1). Due to the presence of labile coordination sites in both iron centers the hydrolysis of both the diester model substrate 2,4-BDNPP and DNA was studied in detail. Complex 1 was also able to catalyze the oxidation of the substrate 3,5-di-tert-butylcatechol (3,5-DTBC) to give the corresponding quinone, and thus it can be considered as a catalytically promiscuous system.
The synthesis, X-ray structure and catalytic promiscuity (diesterase and catecholase activity) of a new dinuclear FeIII complex are here reported. Display omitted
•Dinuclear Iron(III) complex using a symmetric ligand•Synthesis, X-ray structure, magnetic properties and solution studies of the dinuclear catalyst•Ability of the complex to catalyze different reactions (catalytic promiscuity)
In this study, Ru(II)-arene complexes with acylthiourea ligands of the type Ru(η6‑p‑cymene)(PPh3)(T)ClPF6(1–5) and Ru(η6‑p‑cymene)(PPh3)(T)PF6(1a, 4a), where PPh3 = triphenylphosphine and ...T = N‑acyl‑N′(monosubstituted)thiourea, were synthesized and characterized, and their cytotoxic properties were also evaluated. 1a and 4a were obtained from the hydrolysis reaction of 1 and 4. All complexes showed unusual coordination modes for acylthiourea ligands, which are coordinated in a monodentate fashion (S) in 1–5, while they found to be bidentate (S,N), in 1a and 4a. To the best of our knowledge, 1a and 4a are the first crystallographically reported ruthenium compounds with acylthiourea coordinated via S and N(amide) atoms. The cytotoxicity of the compounds was evaluated in human lung cells, A549 and MRC-5. The IC50 values ranging from 0.25 to 0.61 μM after 48 h incubation in lung cancer cells indicate that the compounds showed high cytotoxicity with values significantly lower than the reference drug, cisplatin (11.84 μM). Interaction studies were carried out using human serum albumin (HSA) and DNA. All complexes showed similar cytotoxic activity, however complex 1a, which is the hydrolysis product of 1, presented the highest activity and selectivity among all seven compounds synthesized here. Complexes 1 and 1a inhibited the colony formation decreasing the colony size and inducing morphology changes in A549 cells. These complexes induced apoptosis cell death and promoted cell cycle arrest in the Sub-G1 phase with a decrease in the cell number at the S phase.
Ru(II)-arene complexes with acylthiourea ligands showed unusual coordination modes, either (S)-monodentate or (S,N)-bidentate, where the latter is the hydrolysis product of the former coordination situation. Two complexes are the first crystallographically ruthenium compounds with acylthiourea coordinated via S,N(amide) atoms. All complexes showed expressive cytotoxicity, interact with DNA and induced apoptosis. Display omitted
•Ru(II)-Arene complexes with acylthiourea ligands displaying unusual coordination modes•First crystallographical report of Ru/acylthiourea complex coordinated via S/N atoms•IC50 values significantly lower than cisplatin•Complexes/DNA interaction via minor groove and induction of apoptosis
Four ruthenium(II)-based complexes with N-(acyl)-N′,N′-(disubstituted)thiourea derivatives (Th) were obtained. The compounds, with the general formula trans-Ru(PPh3)2(Th)(bipy)PF6, interact with ...bovine serum albumin (BSA) and DNA. BSA-binding constants, which were in the range of 3.3–6.5×104M−1, and the thermodynamic parameters (ΔG, ΔH and ΔS), suggest spontaneous interactions with this protein by electrostatic forces due to the positive charge of the complexes. Also, binding constant by spectrophotometric DNA titration (Kb=0.8–1.8×104M−1) and viscosity studies indicate weak interactions between the complexes and DNA. Cytotoxicity assays against DU-145 (prostate cancer) and A549 (lung cancer) tumour cells revealed that the complexes are more active in tumour cells than in normal (L929) cells, and that they present high cytotoxicity (low IC50 values) compared with the reference metallodrug, cisplatin.
The first examples of complexes of Ru(II) containing N-(acyl)-N′,N′-(disubstituted)thioureas were synthesized and characterized. The complexes interact with DNA and BSA mainly by weak electrostatic interactions and they are very active against prostate (DU-145) and lung (A549) tumour cells, and thus are promising anticancer candidates. Display omitted
•Ru(II) complexes with N-(acyl)-N′,N′-(disubstituted)thioureas.•The compounds interact with DNA and BSA by electrostatic interactions.•Promising agents against prostate (DU-145) and lung (A549) tumour cells.•High cytotoxic activity against tumour cells than cisplatin.
In this paper, a series of new ruthenium complexes of the general formula Ru(NS)(dpphpy)(dppb)PF
(
-
), where dpphpy = diphenyl-2-pyridylphosphine, NS ligands = 2-thiazoline-2-thiol (tzdt,
), ...2-mercaptopyrimidine (pySm,
), and 4,6-diamino-2-mercaptopyrimidine (damp,
), and dppb = 1,4-bis(diphenylphosphino)butane, were synthesized and characterized by elemental analysis, spectroscopic techniques (IR, UV/visible, and 1D and 2D NMR), and X-ray diffraction. In the characterization, the correlation between the phosphorus atoms and their respective aromatic hydrogen atoms of the compounds in the assignment stands outs, by
H-
P HMBC experiments. The compounds show anticancer activities against A549 (lung) and MDA-MB-231 (breast) cancer cell lines, higher than the clinical drug cisplatin. All of the complexes are more cytotoxic against the cancer cell lines than against the MRC-5 (lung) and MCF-10A (breast) nontumorigenic human cell lines. For A549 tumor cells, cell cycle analysis upon treatment with
showed that it inhibits the mitotic phase because arrest was observed in the Sub-G1 phase. Additionally, the compound induces cell death by an apoptotic pathway in a dose-dependent manner, according to annexin V-PE assay. The multitargeted character of the compounds was investigated, and the biomolecules were DNA, topoisomerase IB, and proteasome, as well as the fundamental biomolecule in the pharmacokinetics of drugs, human serum albumin. The experimental results indicate that the complexes do not target DNA in the cells. At low concentrations, the compounds showed the ability to partially inhibit the catalytic activity of topoisomerase IB in the process of relaxation of the DNA plasmid. Among the complexes assayed in cultured cells, complex
was able to diminish the proteasomal chymotrypsin-like activity to a greater extent.
We report here on three new ruthenium(II) complexes, Ru(DPEPhos)(mtz)(bipy)PF6 (Ru1), Ru(DPEPhos)(mmi)(bipy)PF6 (Ru2) and Ru(DPEPhos)(dmp)(bipy)PF6 (Ru3). ...DPEPhos = bis-(2-diphenylphosphino)phenylether, mtz = 2-mercapto-2-thiazoline, mmi = 2-mercapto-1-methylimidazole, dmp = 4,6-diamino-2-mercaptopyrimidine and bipy = 2,2′-bipyridine. The compounds were characterized by several spectroscopic techniques, and the molecular structure of Ru1 complex was determined by single-crystal X-ray diffraction. The cytotoxicity of Ru1 – Ru3 complexes were tested against the A549 (human lung) and the MDA-MB-231 (human breast) cancer cell lines and against MRC-5 (non-tumor lung) and MCF-10A (non-tumor breast) cell lines through the MTT assay. All three complexes are cytotoxic against the cell lines studied, with IC50 values lower than those found for the cisplatin. Among them, the Ru2 complex has shown the best selectivity against MDA-MB-231 cancer cell lines, with an IC50 value 12 times lower than that on MCF-10A. The complex Ru2 was capable to induce changes in MDA-MB-231 cells morphology, with loss of cellular adhesion, inhibited colony formation and induce an accumulation of cells at the sub-G1 phase, with an increase in S-phase and decrease of cells at G2 phase. Viscosity, electrochemical and Hoechst 33258 displacement experiments for Ru1 – Ru3 complexes with calf thymus DNA (CT-DNA) showed an electrostatic and groove binding mode of interaction. Additionally, the complexes interact with the protein Human Serum Albumin (HSA) by static mechanism. The negative values for ΔH and ΔS indicate that van der Waals forces and hydrogen bonding may occurs between the complexes and HSA. Therefore, this class of complexes are promising anticancer candidates and may be selected to further detailed studies.
N,S-mercapto ligands can form new ruthenium compounds with promising cytotoxic activity against cancer cell lines. Display omitted
•Ru(II)/N,S-mercapto complexes with promising anticancer properties.•Cytotoxic activity against breast and lung cancer cells.•Selectivity is reported against breast cancer cells.•Complexes interact with CT-DNA and Human Serum Albumin (HSA).•Complex inhibited colony formation and induce an accumulation of cells at the sub-G1 phase.
A novel mixed platinum(II) complex with general formula Pt(PPh3)2(L1‐O,S)PF6 has been synthetized and characterized by elemental analysis, molar conductivity, and by IR and NMR (1H, 13C and 31P) ...spectroscopic methods. The crystal structure has been determined by single‐crystal X‐ray crystallography. The molecule presents an almost ideal square‐planar geometry, and the crystal is stabilized by weak C–H···O and C–H···F hydrogen bonds, and C–H···π stacking interactions. The steric congestion of ligands is described by “exact” cone and solid cone angles, and the percentage of metal surface shielded by the ligands. The results are compared to closely related palladium complexes. The X‐ray structure revealed the proximity of the ortho phenyl proton of one PPh3 ligand to platinum(II) showing rare intramolecular C–H···Pt anagostic binding interaction. The title complex was determined to be active against tumor cells, and it also showed a moderate inhibitory action against mycobacterium tuberculosis.
A new platinum(II) complex with triphenylphosphine and benzoylthiourea ligands has been synthetized. The structure was determined by X‐ray diffraction showing almost perfect square‐planar geometry. Calculations of steric descriptors revealed sterically congested complexes. Furthermore, a rare intramolecular anagostic C–H···Pt interaction was detected. The complex presents interesting biological activity.
A wide series of synthetic flavonoids, with druglikeness properties, were developed and evaluated as antitumoral agents against TK-10, MCF-7, and HT-29 human tumoral cells. Comet assay was performed ...against non-tumoral HK-2 in order to know chromosomal aberrations in normal cells. A QSAR was obtained for anti-HT-29 activities.
A series of synthetic chalcones, flavanones, and flavones has been synthesized and evaluated for antitumor activity against the human kidney carcinoma cells TK-10, human mammary adenocarcinoma cells MCF-7 (estrogen receptor-positive), and human colon adenocarcinoma cells HT-29. The most active series is the chalcone ones with the best results against TK-10 and HT-29 cells. Fourteen out of 53 analyzed compounds resulted very active against at least two of the studied tumoral cells. Alkaline single cell gel electrophoresis, comet assay, was performed as a study of the chromosomal aberrations promoted by the compounds on normal cells. Four active and two inactive chalcones were studied in the comet assay against normal human kidney cells (HK-2). A structure–activity relationship analysis of these compounds was performed and for 4- and 3,4-disubstituted derivatives a quantitative correlation was obtained in the case of anti-HT-29 activity.
PDF
