Differential anti-proliferative properties of novel hydroxydicarboxylatoplatinum(II) complexes with high or low reactivity with thiols

We have examined the anti-proliferative effect of 13 recently synthesised platinum dicarboxylate complexes, very similar in their chemical, structural and kinetic properties to carboplatin. We used the L5178Y model: two murine lymphoma sublines, which differ in nucleotide excision repair ability and hence, in sensitivity to those platinum complexes that react with DNA. The anti-proliferative effect of the examined compounds mainly depends on the kind of amine ligand. Complexes with the primary amine (ethylenediamine) are more effective than complexes containing the tertiary amine (1-alkylimidazole). The ethylenediaminemalatoplatinum(II) complexes show a differential in vitro anti-proliferative activity in the L5178Y model; hence, it may be expected that they inflict DNA lesions that are repaired by the nucleotide excision system. The cytotoxicity of these complexes is directly correlated with reactivity with glutathione (GSH). The 1-alkylimidazole complexes are of low toxicity and moderate to low reactivity with GSH; in contrast to the ethylenediaminemalatoplatinum(II) complexes, their cytotoxicity is inversely correlated with reactivity with GSH. Two of the 1-alkylimidazole complexes, bis(1-ethylimidazole)(L-malato)platinum(II) and bis(1-propylimidazole (L-malato)platinum(II), show a considerable ability to arrest cells in G2 phase. We expect that the properties of these two groups of platinum complexes may be exploited in combined platinum complex treatment and irradiation.     

Inhibition of peroxidase, trypsin, and alpha-chymotrypsin by platinum (II) and platinum (IV) complexes

Effects of various complexes of platinum (II) and platinum (IV) on activities of trypsin, alpha-chymotrypsin, and peroxidase were compared. The platinum (II) complexes were found to inhibit these enzymes, though with variable efficiency. The platinum (IV) complexes at concentrations < or = 0.2 mM efficiently inhibited peroxidase but had no effect on the proteases. An enzymatic assay was developed to measure the most effective peroxidase inhibitor (cisplatin) at concentrations of 5-50 microM in the presence of fivefold excess of its isomer (transplatin).     

Cis-platinum(II) complexes of carboxymethyl-dextran as potential antitumor agents. I. Preparation and characterization

Cis-diamminedichloro platinum (II) (cis-DDP) and cis-diamminediaquo platinum (II) nitrate (cis-aq) were demonstrated to form complexes with dextran (dex) substituted with carboxymethyl (CM) groups at an average substitution ratio of 1 mole CM per 2 mole glucose units of dextran. The complexes were formed by reacting each of the two platinum (II) derivatives with carboxymethyl-dextran (CM-dex) at room temperature (RT) or at 37 degrees C in an aqueous solution. The complexing rate depended on temperature, ratio of platinum (II) compounds to CM-dex in the reaction mixture, and time of reaction. Experiments were performed with two CM-dex preparations, derived from dex T-10 (Mr-10,000) and from dex T-40 (Mr-40,000). Soluble cis-DDP and cis-aq complexes formed with CM-dex T-10 and CM-dex T-40 could carry up to 15 mole or 60 mole of the platinum (II) compounds per 1 mole CM-dex, respectively but higher complexing ratios resulted in complex precipitation. Reactivity of cis-aq with CM-dex was higher than that of cis-DDP. NaCl interfered with complex formation, but did not cause dissociation of already formed complexes. The binding of cis-DDP and cis-aq to CM-dex is, however, reversible since the drugs could be exchanged by other acceptors of higher affinity to platinum (II) such as O-phyenlenediamine, or DNA.     

Synthesis and in vitro cytotoxicity of novel hydrophilic chiral 2-alkoxy-1,4-butanediamine platinum (II) complexes

Twenty-six new hydrophilic chiral 2-alkoxy-1,4-butanediamine platinum (II) complexes having a seven-membered ring structure between a bidentate carrier ligand and a platinum atom have been synthesized and most of them were evaluated for their in vitro cytotoxicity toward A549 human non-small cell lung carcinoma and HCT-116 human colon cancer cell lines. The cytotoxicities of platinum complexes are related to the nature of the carrier ligand and leaving group. Complex 5'b, viz. cis-dichloro[(2R)-ethoxy-1,4-butanediamine] platinum (II), exhibits the greatest potency among those 21 tested platinum complexes in both cell lines.     

cis-Platinum(II) amine complexes: Some structure-activity relationships for immunosuppressive,nephrotoxic and gastrointestinal (side) effects in rats

A local graft-versus-host reaction was established to elicit lymphoid hypertrophy in F₁ hybrid PVG × Lew rats. cis-Di(amine)platinum(II) complexes were given i.p. on days 1–4 in divided doses. Overnight proteinuria and measurements of renal hypertrophy on day 5 reflected the nephrotoxicity of the test compound. Stomach weights indicated the peculiar effect on pyloric stasis causing gastric distension. Weights of thymus' and spleens together with lymph-nodes showed the lymphodepressant/immunosuppressive properties of platinum compounds.Structure activity relationships for immunosuppressant, nephrotoxic and gastric-distending activities were investigated with: (a) cis-diaquo-, cis-hydroxyaquo- and cis-dichlorodi(amine)platinum(II) complexes; (b) dinuclear μ-dihydroxo-bridged di(amine)platinum(II) complexes; (c) carboxylatodi(amine)platinum(II) complexes. Nephrotoxicity was minimised (with retention of immunosuppressant activity) by (a) the use of certain N-substituted amines e.g. Dach, Me₄en; (b) co-administration of selected adjuncts e.g. citrate, salicylate; (c) auxiliary treatment with a penicillin mixture (Triplopen^®). In vitro effects of some platinum(II) compounds on isolated rat kidney tubules were also investigated.     

Methyl iodide reactions on the surface of mechanically pre-activated platinum(II) salt in the heterogeneous system: K2PtCl4 powder–MeI vapor

Mechanically pre-activated K₂PtCl₄ salt consumes methyl iodide producing methyl chloride at room temperature. The reaction mechanism includes the following steps sequence: oxidative addition of methyl iodide to platinum(II) complexes with intermediate formation of methyl platinum(IV) complexes and further decomposition of the latter in the course of innersphere reductive elimination yielding methyl chloride. The first step of the reaction proceeds owing to the assistance of active centers regenerated in the course of each event of MeI into MeCl transformation taking part in the chain halogen substitution process. It could be assumed that the role of active centers is played by coordinatively unsaturated platinum(II) complexes located on the surface. These species bearing a positive efficient charge can render electrophilic assistance for the nucleophilic substitution. The chain termination can be caused by recombination of coordinatively unsaturated platinum(II) complexes and interstitial chloride ions forming an inactive K₂PtCl₄ complex.     

Examination of the effects of oxidation and ring closure on the cytotoxicities of the platinum complexes of N-(2-hydroxyethyl)ethane-1,2-diamine and ethane-1,2-diamine-N,N'-diacetic acid

The crystal structures, electrochemical properties and cytotoxicities of platinum(II) and platinum(IV) complexes of the multidentate ligands N-(2-hydroxyethyl)ethane-1,2-diamine (NNOH) and ethane-1,2-diamine-N,N'-diacetic acid (H(2)enda) are reported. In the platinum(II) state the NNOH and H(2)enda ligands act as bidentate ligands, coordinating through the two amine groups with the hydroxyethyl and carboxylate groups remaining uncoordinated. Oxidation with hydrogen peroxide followed by refluxing yields the ring closed Pt(IV) complexes in which the NNOH and H(2)enda ligands are deprotonated and coordinate via the two amine groups and either the deprotonated alcohol group in the case of NNO or both carboxylato groups in the case of enda. The platinum(IV) complex of NNO is 2- to 5-fold more active against a panel of cisplatin sensitive and resistant human tumour cell lines than is the platinum(II) complex, whereas in the case of enda, the reverse is true. Ring closure to occupy both axial sites apparently leads to deactivation of platinum(IV) complexes, but a single closure does not necessarily do so.     

Synthesis and cytotoxic activities of estrone and estradiol cis-dichloroplatinum(II) complexes

Sixteen platinum(II) complexes of estrone and estradiol were synthesized in this work to evaluate their cytotoxic activity against several cancer cell lines including estrogen dependent and independent ones. The synthesis of all the complexes was done in three steps. The reaction of steroids with dibromoalkanes was followed by a reaction of the bromoalkyl steroids with 2-(aminomethyl)pyridine or 2-(2-aminoethyl)pyridine. The last step was a reaction of steroidal diamino ligands with potassium tetrachloroplatinate to obtain the desired platinum(II) complexes. Cytotoxicity assays showed that most of the complexes prepared are active against the cancer cell lines used—CEM, U-2 OS, MCF7, MCF7 AL, MDA-MB-468, BT-474, BT-549, and BJ fibroblasts. The six-membered platinum complexes are more active than five-membered ones.     

2-Deoxyglucose conjugated platinum (II) complexes for targeted therapy: design,synthesis, and antitumor activity

Malignant neoplasms exhibit an elevated rate of glycolysis over normal cells. To target the Warburg effect, we designed a new series of 2-deoxyglucose (2-DG) conjugated platinum (II) complexes for glucose transporter 1 (GLUT1)-mediated anticancer drug delivery. The potential GLUT1 transportability of the complexes was investigated through a comparative molecular docking analysis utilizing the latest GLUT1 protein crystal structure. The key binding site for 2-DG as GLUT1’s substrate was identified with molecular dynamics simulation, and the docking study demonstrated that the 2-DG conjugated platinum (II) complexes can be recognized by the same binding site as potential GLUT1 substrate. The conjugates were synthesized and evaluated for in vitro cytotoxicity study with seven human cancer cell lines. The results of this study revealed that 2-DG conjugated platinum (II) complexes are GLUT1 transportable substrates and exhibit improved cytotoxicities in cancer cell lines that over express GLUT1 when compared to the clinical drug, Oxaliplatin. The correlation between GLUT1 expression and antitumor effects are also confirmed. The study provides fundamental information supporting the potential of the 2-DG conjugated platinum (II) complexes as lead compounds for further pharmaceutical R&D.     

Synthesis and evaluation of bi-functional 7-hydroxycoumarin platinum(IV) complexes as antitumor agents

A series of bi-functional 7-hydroxycoumarin platinum(IV) complexes were synthesized, characterized, and evaluated for antitumor activities. The 7-hydroxycoumarin platinum(IV) complexes display moderate to effective antitumor activities toward the tested cell lines and show much potential in overcoming drug resistance of platinum(II) drugs. In reducing microenvironment, the title compounds could be reduced to platinum(II) complex accompanied with two equivalents of coumarin units. By a unique mechanism, the 7-hydroxycoumarin platinum(IV) complex attacks DNA via the released platinum(II) compound, meanwhile it also inhibits the activities of cyclooxygenase by coumarin fragment. This action mechanism might be of much benefit for reducing tumor-related inflammation in the progress of inhibiting tumor proliferation and overcoming cisplatin resistance. The incorporation of 7-hydroxycoumarin leads to significantly enhanced platinum accumulation in both whole tumor cells and DNA. The HSA interaction investigation reveals that the tested coumarin platinum(IV) compound could effectively combine with HSA via van der Waals force and hydrogen bond.     

The mechanism of action of platinum(IV) complexes in ovarian cancer cell lines

The reduction potentials, lipophilicities, cellular uptake and cytotoxicity have been examined for two series of platinum(IV) complexes that yield common platinum(II) complexes on reduction: cis-[PtCl(4)(NH(3))(2)], cis,trans,cis-[PtCl(2)(OAc)(2)(NH(3))(2)], cis,trans,cis-[PtCl(2)(OH)(2)(NH(3))(2)], [PtCl(4)(en)], cis,trans-[PtCl(2)(OAc)(2)(en)] and cis,trans-[PtCl(2)(OH)(2)(en)] (en=ethane-1,2-diamine, OAc=acetate). As previously reported, the reduction occurs most readily when the axial ligand is chloride and least readily when it is hydroxide. The en series of complexes are marginally more lipophilic than their ammine analogues. The presence of axial chloride or acetate ligands results in a slighter higher lipophilicity compared with the platinum(II) analogue whereas hydroxide ligands lead to a substantially lower lipophilicity. The cellular uptake is similar for the platinum(II) species and their analogous tetrachloro complexes, but is substantially lower for the acetato and hydroxo complexes, resulting in a correlation with the reduction potential. The activities are also correlated with the reduction potentials with the tetrachloro complexes being the most active of the platinum(IV) series and the hydroxo being the least active. These results are interpreted in terms of reduction, followed by aquation reducing the amount of efflux from the cells resulting in an increase in net uptake.     

Synthesis and characterization of palladium(II) and platinum(II) complexes with Schiff bases derivatives of 2-pyridincarboxyaldehyde. Study of their interaction with DNA

Several Schiff bases ligand derivatives of 2-pyridincarboxyaldehyde and different amines, together with their palladium(II) and platinum(II) complexes have been synthesised and characterised. The aim of this study is to probe the influence of substituents beared on the pyridyl/toulene ring at different position to their possible antitumor activity. The amines used were o-, m-, p-toluidine and 4-hydroxyaniline. All the compounds were characterised by elemental analysis, FT-IR spectroscopy, 1H and 195Pt NMR spectroscopy and matrix assisted laser desorption/ionization time-of-flight mass spectroscopy. The formation of DNA adducts were analysed by circular dichroism and electrophoretic mobility. Atomic force microscopy images of the compounds with plasmid DNA pBR322 were also obtained. In all cases changes in the second and tertiary structure of DNA could be observed as a consequence of the covalent interaction of the palladium(II) or platinum(II) ions with the N of the nucleobases. However, there are not significant differences in the behavior of the complexes related to the position of the methyl groups or the presence of the OH group. Values of IC50 were also calculated for the platinum(II) complexes for several pairs of ovarian tumor cell lines which were either sensitive or resistant to cisplatin. Finally in vitro apoptosis studies for platinum(II) complexes with ovarian tumor cell lines A2780/A2780cisR were carried out. The results indicated interesting antiproliferative activity and significant apoptosis induction.     

Interaction of platinum and palladium 5-sulfo-8-mercaptoquinoline complexes with sarcoplasmic reticulum Ca2+-dependent ATPase]

5-Sulfo-8-mercaptoquinoline complexes of platinum and palladium (complexes I and II) effectively inhibit Ca2+-dependent ATPase from sarcoplasmic reticulum. However, in contrast to K2PtCl4, K2PdCl4 and other previously investigated platinum and palladium complexes, they do not interact with the thiol groups of the enzyme. The inhibiting effects of complexes I and II are reversible and competitive with respect to ATP. In aqueous solutions complexes I and II decrease the fluorescence of tryptophane with a simultaneous shift in fluorescence towards the long-wave region. The same effect is exerted by the complexes on the fluorescence of tryptophane residues in Ca2+-dependent ATPase preparations. An addition of tryptophane to the enzyme preparations preincubated with complexes I and II partly restores the enzyme activity. It is assumed that the inhibiting effect of complexes I and II is due to their non-covalent interactions with the trytophane residues vicinal to the ATPase center.     

Platinum complexes with anticancer potential and their evaluation by a colorimetric lambda prophage induction assay

A simple biochemical phage induction assay (BIA) showed significant activity with 90% of the antitumor platinum compounds tested and lack of activity for all Pd(II) compounds and Pt(II) cationic complexes, compounds that are expected to be inactive. Structure-activity relationships for a large number of chemicals can be studied simultaneously by this simple, rapid, inexpensive and quantitative biochemical assay. Fifty-three platinum complexes were tested, including a number of ethylenediamines synthesized for this work. The magnitude of inducing activity varied over a 25-fold range; differences among analogs reflected structural differences in a chemically consistent manner. Seven platinum complexes showed greater activity than that of cis-diamminedichloroplatinum(II) (cisplatin, cis-DDP), while other compounds appeared to be substantially less toxic. The assay was predictive for most compounds with very high or very low activity in vivo against L1210. For compounds with intermediate levels of activity, no correlation between inducing and antitumor activity was observed.     

The cellular distribution and oxidation state of platinum(II) and platinum(IV) antitumour complexes in cancer cells

The cellular distribution of platinum in A2780 ovarian cancer cells treated with cisplatin and platinum(IV) complexes with a range of reduction potentials has been examined using elemental analysis (synchrotron radiation-induced X-ray emission). The cellular distribution of platinum(IV) drugs after 24 h is similar to that of cisplatin, consistent with the majority of administered platinum(IV) drugs being reduced. Micro-X-ray absorption near-edge spectra of cells treated with cisplatin and platinum(IV) complexes confirmed the reduction of platinum(IV) to platinum(II). In cells treated, the most difficult to reduce complex, cis,trans,cis-[PtCl₂(OH)₂(NH₃)₂], platinum(IV) was detected in the cells along with platinum(II). The observations are in accordance with the relative ease of reduction of the platinum(IV) complexes used and support the requirement of reduction for activation of platinum(IV) complexes.Abbreviations en ethane-1,2-diamine - GM growth medium - PBS phosphate buffered saline - RPMI Roswell Park Memorial Institute - SRIXE synchrotron radiation-induced X-ray emission - XAFS X-ray absorption fine structure - XANES X-ray absorption near-edge spectroscopy     

Enantiopure platinum(II) complexes with chiral diphosphine and diphosphinite ligands derived from 2,2-biphosphole: Synthesis, crystal structure and catalysis

Enantiopure platinum(II) complexes have been synthetized with chiral stereodynamic diphosphine and diphosphinite ligands derived from 2,2-biphosphole through a dynamic chirality control upon coordination. Catalytic performances of these platinum complexes have been explored in asymmetric hydroformylation. All complexes proved to be effective catalysts with respect to chemoselectivity and regioselectivity but induced only low enantioselectivities.     

Interaction of binuclear xylylthiolato(2,2',2"-terpyridine)platinum(II) complexes with DNA

The new binuclear platinum(II) complexes, (1,3-benzenedimethanethiolate-S)di(2,2',2"-terpyridine)diplatinum(II) chloride tetrahydrate, 5, and (1,4-benzenedimethanethiolate-S)di(2,2',2"-terpyridine)diplatinum(II) chloride tetrahydrate, 6, were synthesized in order to investigate the binding of platinum(II) complex with calf thymus DNA, which was examined by UV and CD spectroscopies. Complex 5 interacted strongly with DNA by intercalation compared to 6.     

Platinum(II) catalysis and radical intervention in reductions of platinum(IV) antitumor drugs by ascorbic acid

Reductions of four platinum(IV) amine complexes, cis-diamminetetrachloroplatinum(IV), tetraammine-cis-dichloroplatinum(IV), cis,cis,trans-diamminedichlorodihydroxoplatinum(IV), and cis,trans,cis-dichloro-dihydroxo-bis(isopropylamine)platinum(IV) by ascorbic acid were catalyzed by platinum(II) at pH 7.3 and 22 degrees C. Except for the first mentioned compound, initial slow uncatalyzed reductions yielded platinum(II) products which served as catalyst as revealed by the presence of induction periods and their disappearance by the addition of the platinum(II) products. The platinum(II) catalysis generated ascorbate bound platinum(IV) intermediates. An internal electron transfer process within these intermediates led to the formation of platinum(II) complexes. Although the rate constants for the uncatalyzed reductions vary greatly depending on the nature of the ligands and their spatial arrangements, the magnitudes of the platinum(II) catalyzed rate constants fall in the narrow range, 100 to 300 M(-2) s(-1). The values of the uncatalyzed reductions lie in the range 5 x 10(-2) to 15 M(-1) s(-1), the tetrachloroplatinum(IV) complex suffered the faster reduction. The reduction of iproplatin with two hydroxide ligands in trans configuration was the slowest. The internal electron transfer rate constants span two orders of magnitude, from 0.15 to 4 x 10(-3) s(-1). These reactions were accompanied by the formation of the ascorbate radical which persists throughout the entire reaction. Although the tetrachloro species exhibited simple second order reduction, first order in each of the reactants, the rate of reduction was also accelerated by the addition of cis-diamminedichoroplatinum(II) indicating the presence of catalysis in this reaction as well.     

Platinum(II) complexes with l-methionylglycine and l-methionyl-l-leucine ligands: synthesis, characterization and in vitro antitumoral activity

Four dipeptide complexes of the type [PtX(2)(dipeptide)] x H(2)O (X=Cl, I, dipeptide=l-methionylglycine, l-methionyl-l-leucine) were prepared. The complexes were characterized by (1)H, (13)C, (195)Pt NMR and infrared spectroscopy, DTG and elemental analysis. From the infrared, (1)H and (13)C NMR spectroscopy it was concluded that dipeptides coordinate bidentately via sulfur and amine nitrogen donor atoms. Confirmed with (13)C and (195)Pt NMR spectroscopy, each of the complexes exists in two diastereoisomeric forms, which are related by inversion of configuration at the sulfur atom. The (1)H NMR spectrum for the platinum(II) complex with l-methionylglycine and chloro ligands exhibited reversible, intramolecular inversion of configuration at the S atom; DeltaG( not equal)=72 kJ mol(-1) at coalescence temperature 349 K was calculated. In vitro cytotoxicity studies using the human tumor cell lines liposarcoma, lung carcinoma A549 and melanoma 518A2 revealed considerable activity of the platinum(II) complex with l-methionylglycine and chloro ligands. Further in vitro cytotoxic evaluation using human testicular germ cell tumor cell lines 1411HP and H12.1 and colon carcinoma cell line DLD-1 showed moderate cytotoxic activity for all platinum(II) complexes only in the cisplatin-sensitive cell line H12.1. Platinum uptake studies using atomic absorption spectroscopy indicated no relationship between uptake and activity. Potential antitumoral activity of this class of platinum(II) complexes is dependent on the kind of ligands as well as on tumor cell type.     

Terpyridine platinum(II) complexes inhibit cysteine proteases by binding to active-site cysteine

Platinum(II) complexes have been demonstrated to form covalent bonds with sulfur-donating ligands (in glutathione, metallothionein and other sulfur-containing biomolecules) or coordination bonds with nitrogen-donating ligands (such as histidine and guanine). To investigate how these compounds interact with cysteine proteases, we chose terpyridine platinum(II) (TP-Pt(II)) complexes as a model system. By using X-ray crystallography, we demonstrated that TP-Pt(II) formed a covalent bond with the catalytic cysteine residue in pyroglutamyl peptidase I. Moreover, by using MALDI (matrix-assisted laser desorption/ionization) and TOF-TOF (time of flight) mass spectrometry, we elucidated that the TP-Pt(II) complex formed a covalent bond with the active-site cysteine residue in two other types of cysteine protease. Taken together, the results unequivocally showed that TP-Pt(II) complexes can selectively bind to the active site of most cysteine proteases. Our findings here can be useful in the design of new anti-cancer, anti-parasite or anti-virus platinum(II) compounds.