Synthesis, structure and in vitro anticancer, DNA binding and cleavage activity of palladium (II) complexes based on isatin thiosemicarbazone derivatives (original) (raw)
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New trends in platinum and palladium complexes as antineoplastic agents
Coordination Chemistry Reviews, 2016
The discovery of cisplatin (cis-Pt(NH3)2Cl2) as an antineoplastic agent has focused attention on the rational design of metal complexes that can be potentially used in cancer chemotherapy. Today, the pharmaceutical industry invests more than $1 billion each year in the development of new metalbased drugs to improve biological activities, in terms of cellular selectivity, therapeutic efficiency and minimization of side effects. Chemotherapies based on transition metals play a key role in cancer treatment, and among them platinum and palladium are the most fruitful. This article reviews the main recent advances in the design and synthesis of platinum-and palladium-based drugs, their structural features and biological studies of them. The rationale for the choice of the ligand, related to leaving groups, the geometry of the complex and the oxidation state of the metal ion, is discussed. An overview of the main biological techniques and approaches for testing the interaction of these molecules with the biological environment, mainly DNA, to validate the effect is also provided.
Journal of Inorganic Biochemistry, 2018
Four new complexes [Pd(H 2 L tBu)Cl]Cl (Pd1), [Pt(H 2 L tBu)Cl]Cl (Pt1), [Pd(Me 2 L tBu)Cl]Cl (Pd2) and [Pt (Me 2 L tBu)Cl]Cl (Pt2) (where H 2 L tBu = 2,6-bis(5-(tert-butyl)-1H-pyrazol-3-yl)pyridine and Me 2 L tBu = 2,6-bis(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)pyridine) were synthesized and characterized by elemental microanalysis, IR, 1 H NMR and ESI-MS methods. The reactivity of complexes towards thiourea (Tu), L-methionine (L-Met), Lcysteine (L-Cys) and guanosine-5′-monophosphate (5′-GMP) was investigated. The obtained order was established as follows: Tu > L-Cys > L-Met > 5′-GMP. Complexes Pd1 and Pt1, that contain H 2 L tBu as chelator, showed higher reactivity towards biomolecules than those with Me 2 L tBu. The interaction of complexes with calf thymus DNA (CT-DNA) and bovine serum albumin (BSA) was studied by UV-Vis and fluorescence spectroscopy. The results have shown that complexes can bind to DNA exhibiting high binding constants (K b = 10 4 M −1). Obtained results during the examination of competitive reaction with ethidium bromide (EB) showed that complexes can replace EB-bound DNA. High values of binding constants indicate good binding affinity of complexes towards BSA. We evaluated the stability differences between complexes based on terpy as well as H 2 L tBu /Me 2 L tBu by DFT calculations (B3LYP(CPCM)/LANL2DZp), showing that both tridentate ligand systems lead to complexes of similar stability. The results of biological testing showed that all complexes exert moderate to high selective cytotoxicity, inducing apoptosis and autophagy in HeLa and PANC-1 tumor cell lines. Pd1 exhibited the strongest cytotoxic effect. Finally, cell cycle analysis showed that in HeLa cells Pd1, Pd2 and Pt1 induced accumulation of cells in S phase, whereas in PANC-1 cells Pd2 and Pt1 induced G2/M cycle arrest and Pd1 induced G0/G1 arrest. 1. Introduction Platinum-based drugs are widely used anticancer agents with a broad range of antitumor activities [1,2]. Although, cisplatin, cis-[Pt (NH 3) 2 Cl 2 ], is one of the most common chemotherapy drugs, the acquired resistance and serious side effects limit its clinical use [3-5]. These limitations have stimulated the investigations for improvement of existing platinum antitumor drugs and development of new derivatives that display better therapeutic properties. Therefore, a significant number of different platinum complexes were synthesized with the goal to overcome the disadvantages of cisplatin [6-11]. However, the long-term application of platinum complexes was leading to examination of complexes of some other metals, such as palladium [12-14]. It is well established that palladium(II) complexes
European Scientific Journal, 2014
Binary and ternary complexes derived from ligands containing Oxygen, suppler and Nitrogen as donor atoms with Pd 2+ and Pt 2+ ions were synthesized. The isolated solid complexes were characterized by elemental analyses and spectral (IR, 1 H-NMR, mass spectrometry) measurements. The biological efficiency of the synthesized complexes on antitumor, antibacterial and antifungal was investigated. The results reveal that these complexes have strong affinity against the growth of bacteria and fungi. The mode of action may involve the formation of hydrogen bonding between the O and N donors and the active centers of the cell constituents, resulting in interference with the normal cell process. The biological results obtained were compared with that obtained using standard tetracycline as antibacterial and amphotericin B as antifungal. The complexes, PtL 3 L 9 and PtL 3 L 10 , are considered as strong anticancer drugs, which have enhanced high biological activity.
Journal of Inorganic Biochemistry, 2009
Three new palladium complexes with general formula [PdCl 2 L 2 ], where L = heterofunctional organoarsenic ligand: (2-isopropoxyphenyl)diphenylarsine (1), (2-methoxyphenyl)-diphenylarsine (2) and (2-hydroxyphenyl)diphenylarsine (3) have been synthesized and fully characterized, including X-ray crystallographic data. Their potential antitumor effect and genotoxicity have been studied as well. The viability test performed on human tumor (MLS) and normal (Hfl-1) cell lines indicates significant cytotoxicity of complexes, which is higher in tumor cells than in normal cells. The lethal doses are comparable with those of standard metal-based chemotherapeutical drugs (carboplatin and oxaliplatin). These palladium complexes exhibit a higher cytotoxicity against tumor cells as against normal cells in vitro. A new static cytometric method was developed and simultaneously the classic AnnexinV test was performed. Complex 2 has an important capacity to induce apoptosis in tumor cells. The apoptotic process is triggered due to the interaction of these complexes with secondary structure of DNA in treated cells. The alkaline single-cell gel assay shows that the level of DNA damages induced by compounds 2 and 3 are significantly higher in tumor cells as in normal cells. These studies shown that complexes 1, 2 and 3 have biologic activity, the effect of complex 2 being superior to its platinum analogues, attributable to its structure.
Inorganic Chemistry, 2008
Pd(II) and Pt(II) complexes with the anions of the model nucleobases 1-methylthymine (1-MethyH), 1-methyluracil (1-MeuraH), and 1-methylcytosine (1-MecytH) of the types [Pd(dmba)(µ-L)] 2 [dmba) N,C-chelating 2-((dimethylamino)methyl)phenyl; L) 1-Methy, 1-Meura or 1-Mecyt] and [M(dmba)(L)(L′)] [L) 1-Methy or 1-Meura; L′) PPh 3 (M) Pd or Pt), DMSO (M) Pt)] have been obtained. Palladium complexes of the types [Pd(C 6 F 5)(N−N)(L)] [L) 1-Methy or 1-Meura; N−N) N,N,N′,N′-tetramethylethylenediamine (tmeda), 2,2′-bipyridine (bpy), or 4,4′dimethyl-2,2′-bipyridine (Me 2 bpy)] and [NBu 4 ][Pd(C 6 F 5)(1-Methy) 2 (H 2 O)] have also been prepared. The crystal structures of [Pd(dmba)(µ-1-Methy)] 2 , [Pd(dmba)(µ-1-Mecyt)] 2 ‚2CHCl 3 , [Pd(dmba)(1-Methy)(PPh 3)]‚3CHCl 3 , [Pt(dmba)-(1-Methy)(PPh 3)], [Pd(tmeda)(C 6 F 5)(1-Methy)], and [NBu 4 ][Pd(C 6 F 5)(1-Methy) 2 (H 2 O)]‚H 2 O have been established by X-ray diffraction. The DNA adduct formation of the new platinum complexes synthesized was followed by circular dichroism and electrophoretic mobility. Atomic force microscopy images of the modifications caused by the platinum complexes on plasmid DNA pBR322 were also obtained. Values of IC 50 were also calculated for the new platinum complexes against the tumor cell line HL-60. All the new platinum complexes were more active than cisplatin (up to 20-fold in some cases).
Journal of Organometallic Chemistry, 2017
Novel organometallic palladium(II) complexes [Pd 2 {(C,N)-C 12 H 8 NH 2)} 2 (µ-dppf)Cl 2 ] (2) [Pd 2 {(C,N)-C 12 H 8 NH 2)} 2 (µ-dpp)Cl 2 ] (3) [1,1-bis(diphenylphosphine)-ferrocene (dppf), 1,3-Bis(4-pyridyl)propane (bpp)] have been synthesized, fully characterized by elemental analysis, multi-nuclear (1 H, 31 P{1H}, 13 C{1H}) NMR and IR spectroscopic techniquesand their biological activities such as anti-tumoralactivity and DNA-protein interactions have been investigated. The crystal structure of (2), established by X-ray diffraction, shows that the dppf ligand is bound to the two palladium atoms in bridgedform. The interaction of the complexes with calf thymus DNA (CT-DNA) has been explored by UV-Vis spectroscopy, emission titration and thermal denaturation (T m) methods, which have revealed that these complexes interact with DNA through intercalation mode. Competitive studies with methylene blue (MB) have shown the ability of the complexes to displace the DNAbound MB, suggesting a competition with MB. Furthermore, the microenvironment and the secondary structure of BSA are changed in the presence of the complexes. Competitive binding using Warfarin, Digoxin and site markers, which have definite binding sites, demonstrated that the complexes bind to site I on BSA. Notably, the complexes exhibit significant in vitro selective cytotoxicity against two human cancer cell lines (JURKAT and SKOV3) with IC 50 values varying from 2.3 to 6.7 μM. This indicates that they are more active than cisplatin and showing low cytotoxic activity on normal cells. Finally, molecular modelling studies have been conducted to determine the binding site of the DNA and BSA with the complexes.
Journal of Inorganic Biochemistry, 2007
The preparation of new palladium(II) and platinum(II) complexes derived from a-diphenyl ethanedione bis(thiosemicarbazone), 1, and a-diphenyl ethanedione bis(4-ethylthiosemicarbazone), 2, is described. The palladium complexes 3 and 4 and platinum complexes 5 and 6 have been characterized by elemental analyses, fast atom bombardment mass spectrometry (FAB + ) and spectroscopic studies (IR, 1 HNMR). The crystal and molecular structures of the dimeric cyclopalladated compound 4 and the mononuclear platinum complex 6 have been determined by single crystal X-ray diffraction. The cytotoxic activity of the free ligands and palladium and platinum complexes against human A2780 and A2780cisR (acquired resistance to cisplatin) epithelial ovarian carcinoma cells lines is also reported. The IC 50 values for compounds 1, 5 and 6 were found to be higher than that of cisplatin but the maximum antiproliferative activity was similar. Furthermore, the compounds largely retain their activity in the A2780cisR cell line, having a much better resistance factor than cisplatin in the pair of cell lines tested.
newjournal.kcsnet.or.kr
The complexes [Pd(bpy)(Hex-dtc)]NO 3 and [Pt(bpy)(Hex-dtc)]NO 3 (bpy is 2,2'-bipyridine and Hex-dtc is hexyldithiocarbamato ligands) were synthesized and characterized by elemental analysis and spectroscopic studies. The cytotoxicity assay of the complexes has been performed on chronic myelogenous leukemia cell line, K562, at micromolar concentration. Both complexes showed cytotoxic activity far better than that of cisplatin under the same experimental conditions. The binding parameters of the complexes with calf thymus DNA (CT-DNA) was investigated using UV-visible and fluorescence techniques. They show the ability of cooperatively intercalating in CT-DNA. Gel filtration studies demonstrated that platinum complex could cleave the DNA. In the interaction studies between the Pd(II) and Pt(II) complexes with CT-DNA, several binding and thermodynamic parameters have been determined, which may provide deeper insights into the mechanism of action of these types of complexes with nucleic acids.
DNA-Binding and Antiproliferative Properties of Palladium(II) Complexes with Tridentate Ligands
Inorganica Chimica Acta, 2024
Tridentate ligands of the type N^{N^{OH }}were obtained from the reactions between salicylaldehyde derivatives (3-ethoxy, 4-diethylamino, 4-hydroxy) and primary amines (2-picolylamine or N-phenylethylenediamine), and were used to synthesize a set of five palladium complexes of the general formula Pd(N^{NO})Cl. The new complexes were characterized by NMR spectroscopy and mass spectrometry; further confirmation of the structure of Pd-Py-OEt was provided by single-crystal XRD. A DNA-binding study confirmed the importance of the ligand on the mode of binding with ct-DNA. Four complexes possess apparent binding constants in the same range, and all are higher than that of Pd-EN-NEt2. The BSA-binding proceeds via the formation of BSA-compound adducts, with higher binding constants for the ethylene-containing example due to the more flexible ligand. Molecular docking studies identified the binding site at the cleft of BSA. Anticancer properties of the palladium complexes are poorer than those of their platinum analogues, although Pd-Py-OEt and Pd-Py-NEt2 exhibit cytotoxicity similar to that of cisplatin, and significantly better cytotoxicity towards the cancer cell line over a normal cell line. Flow cytometry analysis suggests a late apoptotic cell death pathway for Pd-Py-OEt. Pd-Py-OEt; they afford different cell cycle accumulation patterns compared to Pt-Py-OEt and cisplatin, which suggests mechanistic differences in their anticancer activities.