The history of effective anti-cancer medications begins with the discovery of cisplatin’s anti-cancer properties. Second-generation analogue, carboplatin, with a similar range of effectiveness, made ...progress in improving these drugs with fewer side effects and better solubility. Renewed interest in platinum-based drugs has been increasing in the past several years. These developments highlight a revitalized enthusiasm and ongoing exploration in platinum chemotherapy based on the series of dinuclear platinum(II) complexes, {Pt(L)Cl}2(μ-bridging ligand)2+, which have been synthesized and evaluated for their biological activities. These complexes are designed to target various cancerous conditions, exhibiting promising antitumor, antiproliferative, and apoptosis-inducing activities. The current work aims to shed light on the potential of these complexes as next-generation platinum-based therapies, highlighting their enhanced efficacy and reduced side effects, which could revolutionize the approach to chemotherapy.
Three new dinuclear palladium(II) complexes with general formula {Pd(en)Cl}2(μ-L)2+ (L is pyridine-based bridging ligand 4,4′-bipyridine (4,4′-bipy, 1), 1,2-bis(4-pyridyl)ethane (bpa, 2), ...1,2-bis(4-pyridyl)ethylene (bpe, 3) and en is bidentate coordinated ethylenediamine) were synthesized and characterized by elemental microanalyses, NMR (1H and 13C), IR and UV–Vis spectroscopy. In vitro cytotoxic activity of these complexes against human A549 and murine LLC1 lung cancer cells, as well as two human HCT116 and SW480 and one murine CT26 colon cancer cells was investigated using MTT assay (MTT is 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). The potential of complexes 1–3 to induce apoptosis was tested by flow cytometric analysis of Annexin V and propidium iodide stained treated cells, while their antiproliferative activity was analyzed by detection of Ki67 expression in treated cancer cells. The DNA binding affinity of complexes 1–3 was evaluated by UV–Vis, fluorescence emission spectroscopy and by viscosity measurements in aqueous phosphate buffer solution at pH 7.40. Furthermore, interaction of these complexes with bovine serum albumin was investigated by fluorescence spectrometry. The present study showed that the nature of pyridine-based bridging ligand (L) in dinuclear {Pd(en)Cl}2(μ-L)2+ complex has an influence on the complex preference for the cytotoxic activity and CT-DNA/BSA (CT-DNA is calf thymus DNA and BSA is bovine serum albumin) binding affinity.
The results showed that the structure of pyridine-based bridging ligands (L) has an influence on the antitumor activity and DNA- and BSA-binding affinity (BSA is bovine serum albumin) of {Pd(en)Cl}2(μ-L)2+ complexes (en is ethylenediamine). Display omitted
•New dinuclear Pd(II) complexes with pyridine-based bridging ligands•Dinuclear Pd(II) complexes reduced viability of human and murine lung cancer cells.•Dinuclear Pd(II) complexes induced apoptosis toward murine lung carcinoma cells.•The pyridine bridging ligands influence binding affinity to DNA and bovine serum albumin.
Three new dinuclear Pd(II) complexes with general formula {Pd(en)Cl}
2
(
μ
-L)(NO
3
)
2
L is bridging ligand quinoxaline (
Pd1
), quinazoline (
Pd2
) and phthalazine (
Pd3
) were synthesized and ...characterized by elemental microanalyses, UV–Vis, IR and NMR (
1
H and
13
C) spectroscopy. The interaction of dinuclear
Pd1–Pd3
complexes with calf thymus DNA (CT-DNA) has been monitored by viscosity measurements, UV–Vis and fluorescence emission spectroscopy in aqueous phosphate buffer solution (PBS) at pH 7.40 and 37 °C. In addition, these experimental conditions have been applied to investigate the binding affinities of
Pd1–Pd3
complexes to the bovine serum albumin (BSA) by fluorescence emission spectroscopy. In vitro antiproliferative and apoptotic activities of the dinuclear Pd(II) complexes have been tested on colorectal and lung cancer cell lines. All tested Pd(II) complexes had lower cytotoxic effect than cisplatin against colorectal cancer cells, but also had similar or even higher cytotoxicity than cisplatin against lung cancer cells. All complexes induced apoptosis of colorectal and lung cancer cells, while the highest antiproliferative effect exerted
Pd2
complex.
Graphic abstract
New anticancer platinum(II) compounds simultaneously targeting tumor cells and tumor-derived neoangiogenesis, with new DNA interacting mode and large therapeutic window are appealing alternative to ...improve efficacy of clinical platinum chemotherapeutics. Herein, we describe three novel dinuclear {Pt(en)Cl}
2
(
μ
-L)
2+
complexes with different pyridine-like bridging ligands (L), 4,4′-bipyridine
(Pt1)
, 1,2-bis(4-pyridyl)ethane
(Pt2)
and 1,2-bis(4-pyridyl)ethene
(Pt3)
, which highly, positively charged aqua derivatives, {Pt(en)(H
2
O)}
2
(
μ
-L)
4+
, interact with the phosphate backbone forming DNA-Pt adducts with an unique and previously undescribed binding mode, called a minor groove covering. The results of this study suggested that the new binding mode of the aqua-Pt(II) complexes with DNA could be attributed to the higher anticancer activities of their chloride analogues. All three compounds, particularly complex {Pt(en)Cl}
2
(
μ
-4,4′-bipy)Cl
2
·2H
2
O (4,4′-bipy is 4,4′-bipyridine)
(Pt1),
overcame cisplatin resistance in vivo in the zebrafish–mouse melanoma xenograft model, showed much higher therapeutic potential than antiangiogenic drug sunitinib malate, while effectively blocking tumor neovascularization and melanoma cell metastasis. Overall therapeutic profile showed new dinuclear Pt(II) complexes could be novel, effective and safe anticancer agents. Finally, the correlation with the structural characteristics of these complexes can serve as a useful tool for developing new and more effective anticancer drugs.
Platinum-based drugs are widely recognized efficient anti-tumor agents, but faced with multiple undesirable effects. Here, four dinuclear platinum(II) complexes, {Pt(1,2-pn)Cl}
2
(
μ
-pydz)Cl
2
(
C1
...), {Pt(ibn)Cl}
2
(
μ
-pydz)Cl
2
(
C2
), {Pt(1,3-pn)Cl}
2
(
μ
-pydz)Cl
2
(
C3
) and {Pt(1,3-pnd)Cl}
2
(
μ
-pydz)Cl
2
(
C4
), were designed (pydz is pyridazine, 1,2-pn is ( ±)-1,2-propylenediamine, ibn is 1,2-diamino-2-methylpropane, 1,3-pn is 1,3-propylenediamine, and 1,3-pnd is 1,3-pentanediamine). Interactions and binding ability of
C1
–
C4
complexes with calf thymus DNA (CT-DNA) has been monitored by viscosity measurements, UV–Vis, fluorescence emission spectroscopy and molecular docking. Binding affinities of
C1
–
C4
complexes to the bovine serum albumin (BSA) has been monitored by fluorescence emission spectroscopy. The tested complexes exhibit variable cytotoxicity toward different mouse and human tumor cell lines.
C2
shows the most potent cytotoxicity, especially against mouse (4T1) and human (MDA-MD468) breast cancer cells in the dose- and time-dependent manner.
C2
induces 4T1 and MDA-MD468 cells apoptosis, further documented by the accumulation of cells at sub-G1 phase of cell cycle and increase of executive caspase 3 and caspase 9 levels in 4T1 cells.
C2
exhibits anti-proliferative effect through the reduction of cyclin D3 and cyclin E expression and elevation of inhibitor p27 level. Also,
C2
downregulates c-Myc and phosphorylated AKT, oncogenes involved in the control of tumor cell proliferation and death. In order to measure the amount of platinum(II) complexes taken up by the cells, the cellular platinum content were quantified. However,
C2
failed to inhibit mouse breast cancer growth in vivo. Chemical modifications of tested platinum(II) complexes might be a valuable approach for the improvement of their anti-tumor activity, especially effects in vivo.
Graphical abstract
Dinuclear platinum(II) complex {Pt(ibn)Cl}
2
(
μ
-pydz)Cl
2
shows anti-tumor activity, triggers the apoptosis and reduces the proliferation of mouse breast cancer cells in vitro. However, its inhibitory effect on tumor growth in vivo is absent.
Four Pt(II) complexes of the general formula Pt(L)(5,6-epoxy-1,10-phen), where L is an anion of either malonic acid (mal, Pt1), 2-methylmalonic acid (Me-mal, Pt2), 2,2-dimethylmalonic acid (Me2-mal, ...Pt3) or 1,1-cyclobutanedicarboxylic acid (CBDCA, Pt4) and 5,6-epoxy-1,10-phen is 5,6-epoxy-5,6-dihydro-1,10-phenanthroline, were synthesized and characterized by elemental microanalysis and different spectroscopic techniques. The crystal structure of anhydrous Pt3 complex was determined by single crystal X-ray diffraction. The in vitro anticancer activity of the platinum(II) complexes was investigated in human and murine cancer cell lines as well as in a normal murine cell line by MTT assay. The results show that the investigated platinum(II) complexes exhibit potent cytotoxic activity against murine breast carcinoma cells (4T1), human (HCT116) and murine (CT26) colorectal carcinoma cells. The Pt3 complex shows stronger selectivity against cancer cells compared to other platinum(II) complexes tested and thus exhibits beneficial antitumor activity, mainly by inducing apoptosis and inhibiting cell proliferation and migration. The Pt3 complex also exhibits significant in vivo antitumor activity in the orthotopical 4T1 tumor model without detected liver, kidney, lung, and heart toxicity. All the results indicate that these novel platinum(II) complexes have good antitumor activity on breast and colorectal cancer and have the potential to become possible candidates for cancer treatment.
Complexes Pt1- Pt4 possess significant in vitro cytotoxicity against murine 4T1, CT26 and human HCT116 cells. Pt3 demonstrates highest selectivity toward cancer cells, triggering apoptosis of 4T1 and CT26 cancer cells with inhibition of cell proliferation and migration. Murine breast cancer growth was inhibited after in vivo application of Pt3. Display omitted
•Pt1- Pt4 possess significant in vitro cytotoxicity against 4T1, HCT116, CT26 cells.•Pt3 complex triggered apoptosis of breast and colorectal cancer cells.•Pt3 complex diminished metastasis capacity of cancer cells.•In vivo application of Pt3 inhibited murine breast cancer growth and progression.•In vivo treatment with Pt3 caused low general toxicity.
The mechanism of action of most approved drugs in use today is based on their binding to specific proteins or DNA. One of the achievements of this research is a new perspective for recognition of ...binding modes to DNA by monitoring of changes in measured and stoichiometric values of absorbance at 260 nm. UV–Vis and IR spectroscopy, gel electrophoresis and docking study were used for investigation of binding properties of three dinuclear platinum(II) complexes containing different pyridine-based bridging ligands, {Pt(en)Cl}
2
(
μ
-4,4’-bipy)Cl
2
·2H
2
O (
Pt1
), {Pt(en)Cl}
2
(
μ
-bpa)Cl
2
·4H
2
O (
Pt2
) and {Pt(en)Cl}
2
(
μ
-bpe)Cl
2
·4H
2
O (
Pt3
) to DNA (4,4’-bipy, bpa and bpe are 4,4′-bipyridine, 1,2-
bis
(4-pyridyl)ethane and 1,2-
bis
(4-pyridyl)ethene, respectively). In contrast to the system with well-known intercalated ligand (EtBr), covalently bound ligand (
cis
-Pt) and with minor groove binder (Hoechst 33258), which do not have significant differences in measured and stoichiometric values, the most pronounced deviations are recorded for two dinuclear platinum(II) complexes (
Pt1
and
Pt2
), as a consequence of complex binding to the phosphate backbone and bending of DNA helix. The hydrolysis of complexes and changes in DNA conformation were also analysed as phenomena that may have an impact on the changes in absorbance.
Graphic abstract
Dinuclear palladium(II) complexes, {Pd(en)Cl}
2
(μ-L)(NO
3
)
2
(L is bridging ligand pirazine (Pd1), pyrimidine (Pd2), pyridazine (Pd3), phenazine (Pd4) and en is ethylenediamine), were synthesized ...and characterized. The interactions of the synthesized palladium(II) complexes with biomolecules such as DNA and BSA were studied using UV-Vis spectroscopy and fluorescence spectroscopy. Analysis of tumoricidal activity of investigated complexes, tested on several tumor cell lines of human and mouse origin, revealed that Pd1 and Pd2 exhibited weak cytotoxic potential at lower concentrations. However, Pd3 showed higher cytotoxicity effects on the human MDA-MB 468 breast carcinoma and A375 melanoma cell lines, while Pd4 exhibited tumoricidal potential against MDA-MB 468 cells and A549 human lung adenocarcinoma cells. Interestingly, A375 human melanoma cells were highly sensitive to Pd4 treatment similarly to the effect of cisplatin. Further, the antimicrobial effects of tested compounds were evaluated using different species of Gram-positive and Gram-negative bacteria, as well as yeasts. Pd1-Pd4 showed variable antimicrobial activity depending on the microorganism species. Among tested complexes, Pd4 exhibited the highest antimicrobial activity. The obtained data suggest that palladium(II) complexes might be further investigated as potential antitumor and antimicrobial agents.
1
H NMR spectroscopy was applied to study the catalytic activity of dinuclear Pd(II)-aqua complexes with different benzodiazine bridging ligands, {Pd(en)(H
2
O)}
2
(
μ
-qx)
4+
(
Pd1
), {Pd(en)(H
2
...O)}
2
(
μ
-qz)
4+
(
Pd2
) and {Pd(en)(H
2
O)}
2
(
μ
-phtz)
4+
(
Pd3
) (qx, qz and phtz denote quinoxaline, quinazoline and phthalazine, respectively), in the hydrolytic cleavage of the amide bond in
N
-acetylated L-methionylglycine (Ac–L–Met–Gly) and L-histidylglycine (Ac–L–His–Gly) dipeptides. All reactions were investigated with an equimolar amount of the reactants at pH = 2.0–2.5 in D
2
O and at 37 °C. The obtained data for the catalytic activity of
Pd1
–
Pd3
complexes are compared with those previously reported for {Pt(en)(H
2
O)}
2
(
μ
-L)
4+
(L denotes benzodiazine: qx, qz and phtz), {Pd(en)(H
2
O)}
2
(
μ
-L)
4+
and {Pt(en)(H
2
O)}
2
(
μ
-L)
4+
(L denotes diazine: pyrazine and pyridazine) complexes. It was found that catalytic activity of these complexes in peptide cleavage is strongly related to the position of the nitrogen atoms in the benzodiazine or diazine bridging ligand. The investigated dinuclear Pd(II) and Pt(II) complexes show catalytic activity in the selective hydrolysis of the Met–Gly amide bond of Ac–L–Met–Gly dipeptide. Moreover, all the above mentioned Pd(II) complexes were also able to catalyze the regioselective hydrolysis of the His–Gly amide bond of Ac–L–His–Gly dipeptide. However, in the reaction with Ac–L–His–Gly, only Pt(II) aqua complexes containing bridging ligands with two nitrogen atoms in the
para
-position (quinoxaline and pyrazine) were able to cleave this dipeptide.
Abstract The interactions of metal complexes with important biomolecules such as deoxyribonucleic acid (DNA) or bovine serum albumin (BSA) are responsible for their antitumor activity due to ...different modes of interaction with DNA and their transport through the blood system to cells and tissues via serum albumin. Therefore, the dinuclear palladium(II) complexes, {Pd(en)Cl} 2 (μ-1,5-nphe)(NO 3 ) 2 (Pd1) and {Pd(1,3-pd)Cl} 2 (μ-1,5-nphe)(NO 3 ) 2 (Pd2) (en is ethylenediamine, 1,3-pd is 1,3-propylenediamine and 1,5-nphe is the bridging 1,5-naphthyridine ligand) were synthesized and characterized by different spectroscopic methods. The UV-Vis and fluorescence emission spectroscopy were applied for evaluation of binding modes of Pd1 and Pd2 complexes to DNA as well as their interaction with BSA. The emission spectra indicate that the investigated Pd1 and Pd2 complexes can displace the ethidium bromide intercalator from DNA/EtBr molecules and act as intercalators showing strong interactions with DNA. The fluorescence intensity showes that Pd1 and Pd2 complexes can bind to BSA and then be transported to the cell.
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