Metallodrugs offer potential for unique mechanism of drug action based on the choice of the metal, its oxidation state, the types and number of coordinated ligands and the coordination geometry. This ...review illustrates notable recent progress in the field of medicinal bioinorganic chemistry as many new approaches to the design of innovative metal-based anticancer drugs are emerging. Current research addressing the problems associated with platinum drugs has focused on other metal-based therapeutics that have different modes of action and on prodrug and targeting strategies in an effort to diminish the side-effects of cisplatin chemotherapy. Examples of metal compounds and chelating agents currently in clinical use, clinical trials or preclinical development are highlighted.
This review gives an overview of the relevant medicinal chemistry of platinum, palladium, gold and ruthenium complexes, which could be used for anticancer or biomedical applications. Display omitted
•Pt complexes that intercalate with DNA typically exhibit anticancer activity.•Pd complexes showed good binding affinity to DNA and proteins.•The thiol–enzymes are considered key molecular targets of anticancer Au complexes.•Ru complexes has been considered to be an attractive alternative to Pt complexes.
With the aim of assessing whether ruthenium(II) compounds with meridional geometry might be utilized as potential antitumor agents, a series of new, water-soluble, monofunctional ruthenium(II) ...complexes of the general formula mer-Ru(L3)(N-N)XYn (where L3 = 2,2':6',2″-terpyridine (tpy) or 4'-chloro-2,2':6',2″-terpyridine (Cl-tpy), N-N = 1,2-diaminoethane (en), 1,2-diaminocyclohexane (dach), or 2,2'-bipyridine (bpy); X = Cl or dmso-S; Y = Cl, PF6, or CF3SO3; n = 1 or 2, depending on the nature of X) were synthesized. All complexes were fully characterized by elemental analysis and spectroscopic techniques (IR, UV/visible, and 1D and 2D NMR), and for three of them, i.e., Ru(Cl-tpy)(bpy)ClCl (3Cl), Ru(Cl-tpy)(en)(dmso-S)Y2 Y = PF6 (6PF6), CF3SO3 (6OTf) and Ru(Cl-tpy)(bpy)(dmso-S)CF3SO32 (8OTf), the X-ray structure was also determined. The new terpyridine complexes, with the exception of 8, are well soluble in water (>25 mg/mL). (1)H and (31)P NMR spectroscopy studies performed on the three selected complexes Ru(Cl-tpy)(N-N)Cl(+) N-N = en (1), dach (2), and bpy (3) demonstrated that, after hydrolysis of the Cl ligand, they are capable of interacting with guanine derivatives i.e., 9-methylguanine (9MeG) or guanosine-5'-monophosphate (5'-GMP) through N7, forming monofunctional adducts with rates and extents that depend strongly on the nature of N-N: 1 ≈ 2 ≫ 3. In addition, compound 1 shows high selectivity toward 5'-GMP compared to adenosine-5'-monophosphate (5'-AMP), in a competition experiment. Quantitative kinetic investigations on 1 and 2 were performed by means of UV/visible spectroscopy. Overall, the complexes with bidentate aliphatic diamines proved to be superior to those with bpy in terms of solubility and reactivity (i.e., release of Cl(-) and capability to bind guanine derivatives). Contrary to the chlorido compounds, the corresponding dmso derivatives proved to be inert (viz., they do not release the monodentate ligand) in aqueous media.
In this study, two representatives of previously synthesized ruthenium(ii) terpyridine complexes, i.e., Ru(Cl-tpy)(en)ClCl (1) and Ru(Cl-tpy)(dach)ClCl (2), were chosen and a detailed study of the ...kinetic parameters of their reactivity toward l-histidine (l-His), using the UV-Vis and (1)H NMR techniques, was developed. The inner molecular rearrangement from N3-coordinated l-His to the N1 bound isomer, observable in the NMR data, was corroborated by DFT calculations favoring N1 coordination by nearly 4 kcal mol(-1). These two ruthenium(ii) terpyridine complexes were investigated for their interactions with DNA employing UV-Vis spectroscopy, DNA viscosity measurements and fluorescence quenching measurements. The high binding constants obtained in the DNA binding studies (Kb = 10(4)-10(5) M(-1)) suggest a strong binding of the complexes to calf thymus (CT) DNA. Competitive studies with ethidium bromide (EB) showed that the complexes can displace DNA-bound EB, suggesting strong competition with EB (Ksv = 1.5-2.5 × 10(4) M(-1)). In fact, the results indicate that these complexes can bind to DNA covalently and non-covalently. In order to gain insight of the behavior of a neutral compound, besides the four previously synthesized cationic complexes Ru(Cl-tpy)(en)ClCl (1), Ru(Cl-tpy)(dach)ClCl (2), Ru(Cl-tpy)(bpy)ClCl (3) and Ru(tpy)Cl3 (P2), a new complex, Ru(Cl-tpy)(pic)Cl (4), was used in the biological studies. Their cytotoxicity was investigated against three different tumor cell lines, i.e., A549 (human lung carcinoma cell line), HCT116 (human colon carcinoma cell line), and CT26 (mouse colon carcinoma cell line), by the MTT assay. Complexes 1 and 2 showed higher activity than complexes 3, 4 and P2 against all the selected cell lines. The results on in vitro anticancer activity confirmed that only compounds that hydrolyze the monodentate ligand at a reasonable rate show moderate activity, provided that the chelate ligand is a hydrogen bond donor.
A brief overview of mechanistic studies on the reactions of different Pt(II) complexes with nitrogen- and sulfur-donor biomolecules is presented. The first part describes the results obtained for ...substitution reactions of mono-functional Pt(II) complexes with different biomolecules, under various experimental conditions (temperature, pH and ionic strength). In addition, an overview of the results obtained for the substitution reactions of bi-functional Pt(II) complexes, analogous to cisplatin, with biomolecules is given. The last part of this report deals with different polynuclear Pt(II) complexes and their substitution behaviour with different biomolecules. The purpose of this perspective is to improve the understanding of the mechanism of action of Pt(II) complexes as potential anti-tumour drugs in the human body.
Three Pd(II) and Pt(II) complexes with chelating mono(imidazolin-2-imine) and bis(imidazolin-2-imine) ligands i.e. Pd(DMEAImiPr)Cl2 (1) (DMEAImiPr, ...2-(1,3-diisopropyl-4,5-dimethylimidazolin-2-imine)ethan-1-dimethylamine), Pd(DACH(ImiPr)2)Cl2 (2) (DACH(ImiPr)2, N,N′-(cyclohexane-1,2-diyl)bis(1,3-diisopropyl-4,5-dimethylimidazolin-2-imine)) and Pt(DMEAImiPr)Cl2 (3), are evaluated here as potential cytotoxic and anticancer agents. An acceptable solution behaviour was found for the three study compounds in terms of solubility and stability. Notably, the three metal complexes demonstrated moderate to high cytotoxic properties in selected cancer cell lines (liquid and solid tumor). To gain deeper mechanistic insight, the reactivity of the study complexes with model DNA oligos and protein molecules was investigated through spectrometric and spectroscopic methods; in both cases adduct formation was clearly documented by ESI-MS measurements. The binding of these metal complexes to calf thymus DNA (CT-DNA) was further examined by absorption (UV–Vis) and emission spectral studies (Ethidium bromide displacement studies, EtBr). Overall, the studied complexes 1–3 exhibited a remarkable DNA binding ability that might be linked to the observed cytotoxic effects. Interestingly our results revealed that DNA binding, as well as anticancer activity of 1–3 follows the order 2>3>1. The implications of these findings are discussed.
Three Pd(II) and Pt(II) complexes with chelating mono(imidazolin-2-imine) and bis(imidazolin-2-imine) ligands are evaluated as potential anticancer agents. Interactions with DNA and protein models were explored through absorption and fluorescence techniques and through ESI-MS spectrometry. Display omitted
•Studied complexes: Pd(II) and Pt(II) compounds bearing one or two imidazolin-2-imine moiety•The activity of Pd(II)/Pt(II) complexes was tested in liquid and solid tumor cell lines.•Pd(II) complex shows high cytotoxicity against liquid tumor cell lines.•These complexes displace Ethidium bromide (EtBr) from EtBr-DNA complex interacting with DNA.•ESI-MS provides evidence for the formation of Pd(II)-protein/oligodeoxynucleotide adducts.
A series of novel Pd(ii) complexes with chelating mono(imidazolin-2-imine) and bis(imidazolin-2-imine) ligands were synthesized. The crystal structures of Pd(DMEAIm(iPr))Cl2 and Pd(DPENIm(iPr))Cl2 ...were determined by X-ray diffraction analysis. The reactivity of the six Pd(ii) complexes, namely, Pd(en)Cl2, Pd(EAIm(iPr))Cl2, Pd(DMEAIm(iPr))Cl2, Pd(DPENIm(iPr))Cl2, Pd(BL(iPr))Cl2 and Pd(DACH(Im(iPr))2)Cl2, were investigated. Spectrophotometric acid-base titrations were performed to determine the pKa values of the coordinated water molecules in Pd(en)(H2O)2(2+), Pd(EAIm(iPr))(H2O)2(2+), Pd(DMEAIm(iPr))(H2O)2(2+), Pd(DPENIm(iPr))(H2O)2(2+), Pd(BL(iPr))(H2O)2(2+) and Pd(DACH(Im(iPr))2)(H2O)2(2+). The substitution of the chloride ligands in these complexes by TU, l-Met, l-His and Gly was studied under pseudo-first-order conditions as a function of the nucleophile concentration and temperature using stopped-flow techniques; the sulfur-donor nucleophiles have shown better reactivity than nitrogen-donor nucleophiles. The obtained results indicate that there is a clear correlation between the nature of the imidazolin-2-imine ligands and the acid-base characteristics and reactivity of the resulting Pd(ii) complexes; the order of reactivity of the investigated Pd(ii) complexes is: Pd(en)Cl2 > Pd(EAIm(iPr))Cl2 > Pd(DMEAIm(iPr))Cl2 > Pd(DPENIm(iPr))Cl2 > Pd(BL(iPr))Cl2 > Pd(DACH(Im(iPr))2)Cl2. The solubility measurements revealed good solubility of the studied imidazolin-2-imine complexes in water, despite the fact that these Pd(ii) complexes are neutral complexes. Based on the performed studies, three unusual features of the novel imidazolin-2-imine Pd(ii) complexes are observed, that is, good solubility in water, very low reactivity and high pKa values. The coordination geometries around the palladium atoms are distorted square-planar; the Pd(DMEAIm(iPr))Cl2 complex displays Pd-N distances of 2.013(2) and 2.076(2) Å, while the Pd(DPENIm(iPr))Cl2 complex displays similar Pd-N distances of 2.034(4) and 2.038(3) Å. The studied systems are of interest because little is known about the substitution behavior of imidazolin-2-imine Pd(ii) complexes with bio-molecules under physiological conditions.
•An overview of the research in the field of kinetics and mechanisms of substitution reactions of Pd(II) complexes with sulfur and nitrogen donor bio-molecules, is presented.•The structure-reactivity ...relationship of Pd(II) complexes is discussed.•To improve the understanding of the mechanism of action of Pd(II) complexes as analogues to Pt(II) complexes that are potential anti-tumor drugs in the human body.•Interactions of Pd(II) complexes with sulphur and nitrogen bio-molecules are covered in detail.
An overview of the research in the field of kinetics and mechanisms of substitution reactions of Pd(II) complexes with sulfur and nitrogen donor bio-molecules is presented here. Pd(II) complexes are often used in research projects as a model for Pt(II) complexes since their behavior in solution is very similar. The most important difference is that Pd(II) complexes react 103–105 times faster than the corresponding Pt(II) complexes. The goal of this review is to correlate kinetic, thermodynamic and structural properties of Pd(II) complexes throughout their interaction with biologically relevant molecules. The first part of this review describes the synthesis and structure of some Pd(II) complexes. In addition, the results obtained for substitution reactions of Pd(II) complexes with different sulfur and nitrogen donor bio-molecules under various experimental conditions (pH, ionic strength, temperature, pressure, micelles, ionic liquids) are presented. Furthermore, over the past few decades the anti-tumor activity of some Pd(II) complexes has been demonstrated, which has increased the interest in understanding the mechanism of interaction of Pd(II) complexes with bio-relevant molecules. These studies can contribute to a better understanding of the behavior of these complexes in biological systems and to improve their anti-tumor activity.
The reduction of the Pt(IV) complexes PtCl4(bipy), PtCl4(dach) and PtCl4(en) by glutathione (GSH), L-cysteine (L-Cys) and L-methionine (L-Met) was investigated by stopped-flow spectrophotometry at pH ...2.0 (in 0.01 M perchloric acid) and at pH 7.2 (in 25 mM Hepes buffer). Kinetic measurements were performed under pseudo-first order conditions with an excess of the reducing agent. The order of the reactivity of the studied complexes was PtCl4(bipy) > PtCl4(dach) > PtCl4(en), and reactivity of investigated reducing agents followed the order GSH > L-Cys > L-Met. All the reactions between the selected Pt(IV) complexes and the sulfur donor biomolecules proceeded by a reductive elimination process that included nucleophilic attack by the reducing agent on one of the mutually trans-coordinated chloride ligands, which led to a two-electron transfer process. The final products of the redox reactions were the corresponding reduced Pt(II) complexes and the oxidized form of the reducing agents.
The influence of tridentate, nitrogen donor ligands, on the stability of gold(III) complexes under physiological conditions was investigated. The interaction of Au(terpy)Cl(2+) (terpy = 2,2':6'2'' ...terpyridine), Au(bpma)Cl(2+) (bpma = bis(pyridyl-methyl)amine), Au(dien)Cl(2+) (dien = diethylenetriamine) and AuCl4(-) with the biologically relevant thiols, L-cysteine (L-Cys) and glutathione (GSH), and thioether, L-methionine (L-Met), was studied using UV-Vis spectroscopy, cyclic voltammetry, (1)H NMR spectroscopy and ESI-MS. In this study, the rate constants for substitution reactions between monofunctional gold(III) complexes and sulfur donor ligands in aqueous solution were determined at different initial concentrations of reactants, chloride ions, pH and constant ionic strength. The obtained second-order rate constants for the reaction with L-methionine in the absence of added chloride at pH 2.5 and 25 °C follow the sequence (7.5 ± 0.4) × 10(3) > (4.5 ± 0.1) × 10(2) > 88.3 ± 0.8 M(-1) s(-1) for the terpy, bpma and dien complexes, respectively, demonstrating that the substitution step could be detected prior to the reduction step. This behavior was expected due to the influence of a decreasing π-donor ability of the chelate ligands, which slows down the substitution reactions along the series of complexes studied. In order to throw more light on the mechanism of biological activity of gold(iii) compounds, such a systematic study was performed for all the mentioned thiols and thioether.
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•This review focusses on the stability and reactivity of Au(I,II,III) compounds.•Special attention is given to the thermodynamic stability and kinetic reactivity of these ...compounds.•Organometallic Au(I) complexes and their applications in medicinal chemistry are covered.•The rich coordination chemistry of Au(III) is covered and their applications are high-lighted.•Mechanistic details form an essential part of the review.
This review summarizes the chemistry of gold(0/I/II/III) compounds and outlines progress made towards obtaining more stable coordination compounds in order to improve their application in industry and the medicinal treatment of several diseases. Special attention is given to the kinetic reactivity and thermodynamic stability of such compounds, and to their mechanisms of interaction with biological relevant molecules. Also highlighted in this paper is the rich chemistry of coordinating ligands which play a key role in the stability and reactivity of gold(I/III) complexes.
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