The synthesis and characterization of novel hetrometallic complexes {cis‐PtCl(NH3)2(μ‐4,4′‐bipyridyl)ZnCl(terpy‐Cl)}(ClO4)2 (C1a), {trans‐PtCl(NH3)2(μ‐4,4′‐bipyridyl)ZnCl(terpy)}(ClO4)2 (C2a), ...{cis‐PtCl(NH3)2(μ‐pyrazine)ZnCl(terpy‐Cl)}(ClO4)2 (C3a) and {trans‐PtCl(NH3)2(μ‐pyrazine)ZnCl(terpy‐Cl)}(ClO4)2 (C4a) (where terpy‐Cl = 4′‐chloro‐2,2′:6′,2′′‐terpyridine) was done. Acid–base titrations were performed by UV–Vis spectrophotometric method to evaluate the pKa values of corresponding aqua complexes. Interactions between complexes and important biomolecules, guanosine‐5′‐monophosphate (5′‐GMP) and glutathione (GSH) were examined by 1H NMR spectroscopy. The chloride substituent at the 4′ position on the middle pyridine ring of terpyridine ligand significantly affects the coordination of biomolecules, as well as overall stability of complexes. The complexes were evaluated in vitro for the antioxidant prevention of DNA damages. All tested novel complexes demonstrated a significant reduction in DNA damage against oxidative modifications of DNA caused by the hydroxyl and peroxyl radicals. Also, cytotoxicity evaluation showed that significant cytotoxicity occurs only after long‐term effect of C1a, C2a and C3a, complexes in HCT‐116 cells. Molecular docking studies predict results in agreement with experimental research.
The four novel complexes {cis‐PtCl(NH3)2(μ‐4,4′‐bipy)ZnCl(terpy‐Cl)}(ClO4)2, {trans‐PtCl(NH3)2(μ‐4,4′‐bipyridyl)ZnCl(terpy)}(ClO4)2, {cis‐PtCl(NH3)2(μ‐pyrazine)ZnCl(terpy‐Cl)}(ClO4)2 and {trans‐PtCl(NH3)2(μ‐pyrazine)ZnCl(terpy‐Cl)}(ClO4)2 were synthesized and characterized. The chloride in 4′ position of 2,2′:6′,2′′‐terpyridine has great influence on the stability of the complexes and their antitumor activity.
Three oxorhenium(V) complexes ReOLCl2(PPh3) (C1–C3) were synthesized in the reaction of 2,3‐pyridinedicarboxylic acid (HL1), 2,5‐pyridinedicarboxylic acid (HL2), and 2,6‐pyridinedicarboxylic acid ...(HL3) with ReOCl3(PPh3)2. Chemical structures of synthesized compounds were confirmed using standard analytical techniques. The most stable geometry of complexes was proposed using density functional theory calculations. The antiproliferative activity of the synthesized complexes was evaluated in a panel of human tumor cell lines (A549, PANC‐1, OVCAR‐3, and MDA‐MB‐231) and in one nontumor cell line (MRC‐5), in comparison with the activity of cisplatin as a reference drug. The complex C3 exhibited the highest antiproliferative potential in PANC‐1 cells, with IC50 48.73 ± 0.31 μM. Our previous research of oxorhenium(V) complexes suggested the involvement of drug‐efflux transporter P‐glycoprotein (Pgp) in the detoxification of rhenium complexes in pancreatic adenocarcinoma cells. In the present study, the effect of verapamil hydrochloride, the specific pharmacological blocker of Pgp, was tested in combination with novel rhenium complexes C1–C3 or cisplatin (CDDP), in PANC‐1 cells. The verapamil enhanced the antiproliferative activity of complex C3, indicating again the role of Pgp in detoxification of oxorhenium(V) complexes in highly invasive and resistant PANC‐1 cells.
The presence of an ester group on picolinate ligand (L) near the metal center in complex ReOCl2L(PPh3) improved the complex's biological activity with selectivity for PANC‐1 cells, which was additionally increased by synergistic effects with the well‐known drug verapamil.
Despite extensive research on the anticancer properties of Ru complexes with dipyrido3,2-a:2′,3′-cphenazine (dppz) ligands, their in vivo efficacy is rarely investigated. Aiming to understand ...whether the coordination of certain half-sandwich Ru(II)-arene fragments might improve the therapeutic potential of dppz ligands, we prepared a series of Ru(II)-arene complexes with the general formula (η6-arene)Ru(dppz-R)ClPF6, where the arene fragment was benzene, toluene, or p-cymene and R was -NO2, -Me, or -COOMe. All compounds were fully characterized by 1H and 13C NMR spectroscopy and high-resolution ESI mass-spectrometry, and their purity was verified by elemental analysis. The electrochemical activity was investigated using cyclic voltammetry. The anticancer activity of dppz ligands and their respective Ru complexes was assessed against several cancer cell lines, and their selectivity toward cancer cells was assessed using healthy MRC5 lung fibroblasts. The substitution of benzene with a p-cymene fragment resulted in a more than 17-fold increase of anticancer activity and selectivity of Ru complexes and significantly enhanced DNA degradation in HCT116 cells. All Ru complexes were electrochemically active in the biologically accessible redox window and were shown to markedly induce the production of ROS in mitochondria. The lead Ru-dppz complex significantly reduced tumor burden in mice with colorectal cancers without inducing liver and kidney toxicity.
Novel ruthenium(III) complexes of general formula NaRuCl
2
(L
1−3
-N,O)
2
where L
(1–3)
denote deprotonated Schiff bases (HL
1
-HL
3
) derived from 5-substituted salicyladehyde and alkylamine ...(propyl- or butylamine) were prepared and characterized based on elemental analysis, mass spectra, infrared, electron spin/paramagnetic resonance (ESR/EPR) spectroscopy, and cyclovoltammetric study. Optimization of five isomers of complex C1 was done by DFT calculation. The interaction of
C1
–
C3
complexes with DNA (Deoxyribonucleic acid) and BSA (Bovine serum albumin) was investigated by electron spectroscopy and fluorescence quenching. The cytotoxic activity of
C1
–
C3
was investigated in a panel of four human cancer cell lines (K562, A549, EA.hy926, MDA-MB-231) and one human non-tumor cell line (MRC-5). Complexes displayed an apparent cytoselective profile, with IC
50
values in the low micromolar range from 1.6 ± 0.3 to 23.0 ± 0.1 µM. Cisplatin-resistant triple-negative breast cancer cells MDA-MB-231 displayed the highest sensitivity to complexes, with Ru(III) compound containing two chlorides and two deprotonated
N
-propyl-5-chloro-salicylidenimine (hereinafter
C1
) as the most potent (IC
50
= 1.6 µM), and approximately ten times more active than cisplatin (IC
50
= 21.9 µM). MDA-MB-231 cells treated for 24 h with
C1
presented with apoptotic morphology, as seen by acridine orange/ethidium bromide staining, while 48 h of treatment induced DNA fragmentation, and necrotic changes in cells, as seen by flow cytometry analysis. Drug-accumulation study by inductively coupled plasma mass spectrometry (ICP-MS) demonstrated markedly higher intracellular accumulation of
C1
compared with cisplatin.
Graphical abstract
Three new ruthenium(II)–arene complexes, namely (η6-p-cymene)Ru(Me2dppz)ClPF6 (1), (η6-benzene)Ru(Me2dppz)ClPF6 (2) and (η6-p-cymene)Ru(aip)ClPF6 (3) ...(Me2dppz=11,12-dimethyldipyrido3,2-a:2′,3′-cphenazine; aip=2-(9-anthryl)-1H-imidazo4,5-f 1,10 phenanthroline) have been synthesized and characterized using different spectroscopic techniques including elemental analysis. The complexes were found to be well soluble and stable in DMSO. The biological activity of the three complexes was tested in three different human cancer cell lines (A549, MDA-MB-231 and HeLa) and in one human non-cancerous cell line (MRC-5). Complexes 1 and 3, carrying η6-p-cymene as the arene ligand, were shown to be toxic in all cell lines in the low micromolar/subnanomolar range, with complex 1 being the most cytotoxic complex of the series. Flow cytometry analysis revealed that complex 1 caused concentration- and time-dependent arrest of the cell cycle in G2-M and S phases in HeLa cells. This event is followed by the accumulation of the sub-G1 DNA content after 48h, in levels higher than cisplatin and in the absence of phosphatidylserine externalization. Fluorescent microscopy and acridine orange/ethidium bromide staining revealed that complex 1 induced both apoptotic and necrotic cell morphology characteristics. Drug-accumulation and DNA-binding studies performed by inductively coupled plasma mass spectrometry in HeLa cells showed that the total ruthenium uptake increased in a time- and concentration-dependent manner, and that complex 1 accumulated more efficiently than cisplatin at equimolar concentrations. The introduction of a Me2dppz ligand into the ruthenium(II)-p-cymene scaffold was found to allow the discovery of a strongly cytotoxic complex with significantly higher cellular uptake and DNA-binding properties than cisplatin.
Three new ruthenium(II)–arene complexes, (arene)Ru(L1,2)ClPF6, where arene is benzene or p-cymene, and L1 and L2 are 11,12-dimethyldipyrido3,2-a:2′,3′-cphenazine and 2-(9-anthryl)-1H-imidazo4,5-f 1,10 phenanthroline, have been synthesized and characterized and their cytotoxicity was examined. Fluorescent microscopy revealed that the most active complex induced both apoptotic and necrotic cell morphology characteristics. Display omitted
•Three new organometallic Ru(II) complexes were synthesized and characterized.•Two complexes were highly toxic against three cancer cell lines and one non-tumor cell line.•The mechanism of action of the most potent complex was studied.•Intracellular accumulation and DNA binding were detected for the most potent complex.
Two p-cymenerutheniumchlorido complexes with thiourea derivative of 7-chloroquinoline (C1) and pyridine-3-imidazole (C2) were synthesized starting from (η6-p-cymene)RuCl22 and corresponding ligands. ...The structures of complexes were determined with elemental analysis and IR, ESIMS, 1H and 13C{1H} NMR, and 2D 1H–15N correlation NMR spectroscopy. Cytotoxic activities examined by the MTT assay were performed in five human neoplastic cell lines (HeLa, K562, A549, MDA-MB-231, EA.hy926) and one nontumor human fetal lung fibroblast cell line (MRC-5). Tested complexes exhibited low micromolar activities with IC50 in the range 11.03–56.45 μM, while ligands L1 and L2 were significantly less active. Complex C1 showed cytoselective activity toward the K562 cell line (IC50 = 11.03 ± 1.39 μM) and was 3 times less active against the nontumor MRC-5 cell line. Flow cytometry analysis indicated that complexes C1 and C2 after 24 h treatment caused a concentration-dependent increase of the apoptotic sub-G1 fraction (up to 18.4%), comparable to cis-diamminedichloridoplatinum(II) (cisplatin, CDDP), although without other substantial alterations of the cell cycle. A drug-accumulation and DNA-binding study performed by ICP-MS in the K562 cell line revealed that complex C1 had a high intracellular uptake (1.38 μg Ru/106 cells), which significantly exceeded the intracellular uptake levels of CDDP (0.29 μg Pt/106 cells) and C2 (0.08 μg Ru/106 cells). However, both ruthenium complexes C1 and C2 bind to cellular DNA less efficiently in comparison to CDDP. The structure–activity relationship clearly suggested that introduction of a 7-chloroquinoline moiety in the ruthenium(II)-p-cymene complex significantly contributed to the intracellular uptake of C1 and higher cytotoxicity and cytoselectivity.
Coordinate and redox interactions of epinephrine (Epi) with iron at physiological pH are essential for understanding two very different phenomena - the detrimental effects of chronic stress on the ...cardiovascular system and the cross-linking of catecholamine-rich biopolymers and frameworks. Here we show that Epi and Fe
form stable high-spin complexes in the 1:1 or 3:1 stoichiometry, depending on the Epi/Fe
concentration ratio (low or high). Oxygen atoms on the catechol ring represent the sites of coordinate bond formation within physiologically relevant bidentate 1:1 complex. Redox properties of Epi are slightly impacted by Fe
. On the other hand, Epi and Fe
form a complex that acts as a strong reducing agent, which leads to the production of hydrogen peroxide via O
reduction, and to a facilitated formation of the Epi-Fe
complexes. Epi is not oxidized in this process, i.e. Fe
is not an electron shuttle, but the electron donor. Epi-catalyzed oxidation of Fe
represents a plausible chemical basis of stress-related damage to heart cells. In addition, our results support the previous findings on the interactions of catecholamine moieties in polymers with iron and provide a novel strategy for improving the efficiency of cross-linking.
This study presents the synthesis, characterization, and antitumor action of five new Pt(II) halogenido, chlorido, and iodido complexes with edda type of ligands. ...(S,S)‐Ethylenediamine‐N,N′‐di‐2‐(3‐cyclohexyl)propanoic acid dihydrochloride and its methyl, ethyl, and n‐propyl esters were prepared according to the previously reported procedure. All investigated complexes were characterized by IR, ESI‐MS (1H, 13C, and HMBC) NMR spectroscopy, and elemental analysis. Their cytotoxic action was investigated in four human tumor cell lines: promyelocytic (HL‐60) and lymphocytic (REH) leukemia, glioma (U251), and lung carcinoma (H460). Cell viability was assessed by acid phosphatase and LDH assay, while oxidative stress and cell death parameters were analyzed by flow cytometry. The results showed that novel Pt(II) complexes exhibited antitumor action superior to precursor ligands, with iodido complexes being more efficient than corresponding chlorido complexes. Human promyelocytic cell line (HL‐60) was the most sensitive to antitumor action of all investigated substances and was used for investigation of the underlying mode of antileukemic action. The investigated Pt(II) complexes showed more potent antileukemic action than corresponding Pt(IV) complex, through induction of oxidative stress and apoptosis, evidenced by caspase (8, 9, and 3) activation and phosphatidylserine externalization.
This study presents the synthesis, characterization, and antitumor action of five new Pt(II) halogenido complexes with edda type of ligands. Their cytotoxic action, investigated in four human tumor cell lines, showed that novel Pt(II) complexes exhibited comparable or better antitumor action in comparison with cisplatin, precursor ligands, and corresponding Pt(IV) complex.
Ruthenium(II)–arene complexes of general formulae (η
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, (η
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 (η
6-
p-cymene)Ru(HL
6–9)Cl, where H
2L
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 (η
6-
p-cymene)
2RuCl
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
1H NMR,
1H,
1H COSY and
1H,
1H NOESY spectroscopy.
Display omitted Ruthenium(II)–arene complexes with functionalized pyridines were synthesized and characterized by elemental analysis, mass spectrometry, IR and NMR spectroscopy and X-ray crystallography. The cytotoxicity and reaction with 9-methyladenine were investigated.
The present study describes the synthesis and anticancer activity of novel octahedral PtIV complexes with cyclohexyl functionalized ethylenediamine‐N,N′‐diacetate‐type ligands. Molecular mechanics ...calculations and density functional theory analysis revealed that s‐cis is the preferred geometry of these PtIV complexes with tetradentate‐coordinated (S,S)‐ethylenediamine‐N,N′‐di‐2‐(3‐cyclohexyl)propanoate. The viability of cancer cell lines (U251 human glioma, C6 rat glioma, L929 mouse fibrosarcoma, and B16 human melanoma) was assessed by measuring mitochondrial dehydrogenase activity and lactate dehydrogenase release. Cell‐cycle distribution, oxidative stress, caspase activation, and induction of autophagy were analyzed by flow cytometry using appropriate fluorescent reporter dyes. The cytotoxic activity of novel PtIV complexes against various cancer cell lines (IC50 range: 1.9–8.7 μM) was higher than that of cisplatin (IC50 range: 10.9–67.0 μM) and proceeded through completely different mechanisms. Cisplatin induced caspase‐dependent apoptosis associated with the cytoprotective autophagic response. In contrast, the new PtIV complexes caused rapid, caspase‐independent, oxidative stress‐mediated non‐apoptotic cell death characterized by massive cytoplasmic vacuolization, cell membrane damage, and the absence of protective autophagy.
Octahedral PtIV complexes with cyclohexyl group functionalized edda‐type ligands kill tumor cells via oxidative stress‐mediated caspase‐independent necrosis‐like cell death associated with massive cytoplasmic vacuolization.
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