Showing papers on "Aquation published in 2008"

In vitro anticancer activity and biologically relevant metabolization of organometallic ruthenium complexes with carbohydrate-based ligands.

Abstract: The synthesis and in vitro anticancer activity of dihalogenido(eta6-p-cymene)(3,5,6-bicyclophosphite-alpha-D-glucofuranoside)ruthenium(II) complexes are described. The compounds were characterized by NMR spectroscopy and ESI mass spectrometry, and the molecular structures of dichlorido-, dibromido- and diiodido(eta6-p-cymene)(3,5,6-bicyclophosphite-1,2-O-isopropylidene-alpha-D-glucofuranoside)ruthenium(II) were determined by X-ray diffraction analysis. The complexes were shown to undergo aquation of the first halido ligand in aqueous solution, followed by hydrolysis of a P--O bond of the phosphite ligand, and finally formation of dinuclear species. The hydrolysis mechanism was confirmed by DFT calculations. The aquation of the complexes was markedly suppressed in 100 mM NaCl solution, and notably only very slow hydrolysis of the P--O bond was observed. The complexes showed affinity towards albumin and transferrin and monoadduct formation with 9-ethylguanine. In vitro studies revealed that the 3,5,6-bicyclophosphite-1,2-O-cyclohexylidene-alpha-D-glucofuranoside complex is the most cytotoxic compound in human cancer cell lines (IC50 values from 30 to 300 microM depending on the cell line).

The contrasting chemistry and cancer cell cytotoxicity of bipyridine and bipyridinediol ruthenium(II) arene complexes

Abstract: The synthesis and characterization of ruthenium(II) arene complexes [(η6-arene)Ru(N,N)Cl]0/+, where N,N = 2,2′-bipyridine (bipy), 2,2′-bipyridine-3,3′-diol (bipy(OH)2) or deprotonated 2,2′-bipyridine-3,3′-diol (bipy(OH)O) as N,N-chelating ligand, arene = benzene (bz), indan (ind), biphenyl (bip), p-terphenyl (p-terp), tetrahydronaphthalene (thn), tetrahydroanthracene (tha) or dihydroanthracene (dha), are reported, including the X-ray crystal structures of [(η6-tha)Ru(bipy)Cl][PF6] (1), [(η6-tha)Ru(bipy(OH)O)Cl] (2) and [(η6-ind)Ru(bipy(OH)2)Cl][PF6] (8). Complexes 1 and 2 exibit CH (arene)/π (bipy or bipy(OH)O) interactions. In the X-ray structure of protonated complex 8, the pyridine rings are twisted (by 17.31°). In aqueous solution (pH = 2−10), only deprotonated (bipy(OH)O) forms are present. Hydrolysis of the complexes was relatively fast in aqueous solution (t1/2 = 4−15 min, 310 K). When the arene is biphenyl, initial aquation of the complexes is followed by partial arene loss. Complexes with arene =...

Synthesis and Reactivity of the Aquation Product of the Antitumor Complex trans-[RuIIICl4(indazole)2]-

Abstract: Aquation of the investigational anticancer drug trans-[Ru(III)Cl4(Hind)2](-) (1, KP1019) results in the formation of mer,trans-[Ru(III)Cl3(Hind)2(H2O)] (2), which was isolated in high yield (85%) and characterized by spectroscopic methods and X-ray crystallography. Dissolution of 2 in acetone, led to its dimerization into [Ru(III)2(mu-Cl)2Cl4(Hind)4] x 2 (Me)2CO (3) in 79% yield, with release of two water molecules. Complex 2 reacts readily with nucleophilic organic molecules, viz., methanol or dimethyl sulfide, at room temperature by replacement of the aqua ligand to give mer,trans-[Ru(III)Cl3(Hind)2(MeOH)] (4) and mer,trans-[Ru(III)Cl3(Hind)2(Me2S)] (5) in 58 and 64% yield, respectively. By reaction of 2 with DMSO at room temperature or dimethyl sulfide at elevated temperatures trans,trans,trans-[Ru(II)Cl2(Hind)2(Me2S)2] (6) and trans,trans,trans-[Ru(II)Cl2(Hind)2(S-DMSO)2] (7) were prepared in 64 and 75% yield, respectively. Dissolution of 2 in acetonitrile or benzonitrile gave rise to mer,trans-[Ru(III)Cl3(Hind)(HNC(Me)ind)] (8a), mer,trans-[Ru(III)Cl3(Hind)(HNC(Ph)ind)] (8b), and trans,trans-[Ru(III)Cl2(HNC(Me)ind)2]Cl (9) in 67, 50, and 23% yield, respectively, upon metal-assisted iminoacylation of indazole, which is unprecedented for ruthenium(III). Furthermore, complex 2 reacts with the DNA-model bases 9-methyladenine (9-meade) and N6,N6-dimethyladenine (6-me2ade) to yield mer,trans-[Ru(III)Cl3(Hind)2(9-meade)] (10) and mer,trans-[Ru(III)Cl3(Hind)2(6-me2ade)] (11) with the purine bases bound to the Ru(III) center via N7 and N3, respectively. Complex 11 represents the first ruthenium complex in which the coordination of the purine ligand N6,N6-dimethyladenine occurs via N3. In addition, the polymer [Na(EtOAc)2Ru(III)(mu-Cl)4(Hind)2]n (12) was crystallized from ethyl acetate/diethyl ether solutions of Na[trans-Ru(III)Cl4(Hind)2] x 1.5 H2O (1a). The reported complexes were characterized by elemental analysis, IR and UV-vis spectroscopy, ESI mass spectrometry, cyclic voltammetry, and X-ray crystallography. Electrochemical investigations give insight into the mechanistic details of the solvolytic behavior of complex 2. The lability of the aqua ligand in 2 suggests that this complex is a potential active species responsible for the high antitumor activity of trans-[Ru(III)Cl4(Hind)2](-).

[1H, 15N] Heteronuclear Single Quantum Coherence NMR Study of the Mechanism of Aquation of Platinum(IV) Ammine Complexes

Abstract: The aquation and hydrolysis of a series of platinum(IV) complexes of the general form cis, trans, cis-[PtCl2(X)2(15NH3)2] (X = Cl−, O2CCH3−, OH−) have been followed by [1H,15N] Heteronuclear Single Quantum Coherence NMR spectroscopy. Negligible aquation (<5%) is observed for the complexes where X = O2CCH3− or OH− over 3−4 weeks. Aquation of cis-[PtCl4(15NH3)2] (1) is observed, and the rate of aquation increases with increasing pH and upon the addition of 0.01 mol equiv of the platinum(II) complex cis-[PtCl2(15NH3)2] (cisplatin). The first aquated species formed from cis-[PtCl4(NH3)2] has one of the axial chloro groups (relative to the equatorial NH3 ligands) replaced by an aqua/hydroxo ligand. The second observed substitution occurs in an equatorial position. Peaks that are consistent with five of the eight possible aquation species were observed in the NMR spectra.

Aquation of the ruthenium-based anticancer drug NAMI-A: a density functional study.

Abstract: We carried out density functional theory (DFT) calculations to investigate the thermodynamics and the kinetics of the double aquation reaction of the anticancer drug NAMI-A. Three explicit water molecules were included in the calculations to improve the PB solvation energies. Our calculations show that the chloride substitution reactions on the considered Ru(III) octahedral complex follow a dissociative interchange mechanism, Id, passing through a loose heptacoordinate transition state. We calculated an activation enthalpy and free energy for the first aquation step of 101.5 and 103.7 kJ mol-1, respectively, values that are in good agreement with the available experimental results. The activation enthalpy and free energy for the second aquation step were found significantly higher, 118.7 and 125.0 kJ mol-1, again in agreement with the experimental evidence indicating a slower rate for the second aquation.

Synthesis, X-ray crystallographic, and NMR characterizations of platinum(II) and platinum(IV) pyrophosphato complexes.

Abstract: A series of mononuclear cis-diamineplatinum(II) pyrophosphato complexes containing ammine (am), trans-1,2-cyclohexanediamine (dach), and 1,2-ethanediamine (en) as the amine ligands were synthesized and characterized by 31P and 195Pt NMR spectroscopy. Chemical shifts of 31P NMR resonances of these completely deprotonated complexes appear at 2.12, 1.78, and 1.93 ppm, indicating a coordination chemical shift of at least 8 ppm. The 195Pt NMR chemical shifts for the am and dach complexes were observed at −1503 and −1729 ppm. The complexes are highly stable at neutral pH; no aquation due to the release of either phosphate or amine ligands was observed within 48 h. Furthermore, no partial deligation of the pyrophosphate ligand was detected within several days at neutral pH. At lower pH, however, release of a pyrophosphate ion was observed with concomitant formation of a bridged pyrophosphatoplatinum(II) dinuclear complex. The extended crystal structure containing the dach ligand revealed a zigzag chain stacked i...

Comparison of the electronic properties, and thermodynamic and kinetic parameters of the aquation of selected platinum(II) derivatives with their anticancer IC50 indexes

Abstract: Three potential anticancer agents {trans-[PtCl2(NH3)(thiazole)], cis-[PtCl2(NH3)(piperidine)], and PtCl2(NH3)(cyclohexylamine) (JM118)} were explored and compared with cisplatin and the inactive [PtCl(dien)]+ complex Basic electronic properties, bonding and stabilization energies were determined, and thermodynamic and kinetic parameters for the aquation reaction were estimated at the B3LYP/6-311++G(2df,2pd) level of theory Since the aquation process represents activation of these agents, the obtained rate constants were compared with the experimental IC50 values for several tumor cells Despite the fact that the processes in which these drugs are involved and the way in which they affect cells are very complex, some correlations can be deduced

Synthesis and kinetic studies in aqueous solution on chromium(III) complexes with isocinchomeronic acid—potential new biochromium sources

Abstract: The chromium(III) complexes with a new potential chromium transporting ligand—2,5-pyridinedicarboxylic acid (isocinchomeronic acid, icaH2):[Cr(icaH)3]0, [Cr(icaH)2 (H2O)2]+ and [Cr(icaH)(H2O)4]2+ (where icaH = N,O-bonded isocinchomeronic acid anion), have been obtained and characterized in solution. The [Cr(icaH)3]0 complex undergoes aquation in acidic media to the diaqua-product. Kinetics of this process was studied spectrophotometrically in the 0.1–1.0 M HClO4 range, at I = 1.0 M. The first aquation stage, the chelate-ring opening at the Cr–N bond, is a much faster than the second one. The rate laws are of the form: k obs = k 1 + k −1/Q 1[H+] and k obs = k 2 Q 2[H+]/(1 + Q 2[H+]), where k 1 and k 2 are the rate constants for the chelate-ring opening and the ligand liberation, respectively, k −1 is the rate constant of the chelate-ring closure, Q 1 and Q 2 are the protonation constants of the pyridine nitrogen and 5-carboxylate group in the one-end bonded intermediate, respectively. The results are discussed in terms of potential pharmaceutical application of the complex.

Effects of geometric isomerism and anions on the kinetics and mechanism of the stepwise formation of long-range DNA interstrand cross-links by dinuclear platinum antitumor complexes.

Abstract: Reported herein is a detailed study of the kinetics and mechanism of formation of a 1,4-GG interstrand cross-link by the dinuclear platinum anticancer compound [ 15 N][{cis-Ptcl-(NH 3 ) 2 } 2 (μ-NH 2 (CH 2 ) 6 NH 2 }] 2+ + (1,1/c,c (1)). The reaction of [ 15 N]1 with 5'-{d(ATATGTACATAT)2} (I) has been studied by [ 1 H, 15 N] HSQC NMR spectroscopy in the presence of different concentrations of phosphate. In contrast with the geometric trans isomer (1,1/t,t), there was no evidence for an electrostatic preassociation of 1,1/c,c with the polyanionic DNA surface, and the pseudo-first-order rate constant for the aquation of [ 15 N]1was actually slightly higher (rather than lower) than that in the absence of DNA. When phosphate is absent, the overall rate of formation of the cross-link is quite similar for the two geometric isomers, occurring slightly faster for 1,1/t,t. A major difference in the DNA binding pathways is the observation of phosphate-bound intermediates only in the case of 1,1/c,c. 15 mM phosphate causes a dramatic slowing in the overall rate of formation of DNA interstrand cross-links due to both the slow formation and slow closure of the phosphate-bound monofunctional adduct. A comparison of the molecular models of the bifunctional adducts of the two isomers shows that helical distortion is minimal and globally the structures of the 1,4 interstrand cross-links are quite similar. The effect of carrier ligand was investigated by similar studies of the ethylenediamine derivative [ 15 N]1-en. A pK a value of 5.43 was determined for the [ 15 N]1,1/c,c-en diaquated species. The rate of reaction of [ 15 N]1-en with duplex I is similar to that of 1,1/c,c and the overall conformation of the final adduct appears to be similar. The significance of these results to the development of "second-generation" polynuclear platinum clinical candidates based on the 1,1/c,c chelate (dach) series is discussed.

Pt(II) uptake by dendrimer outer pockets: 1. Solventless ligand exchange reaction.

Abstract: Density functional theory is used to elucidate molecular-level details of the complexation of Pt(II) metal compounds with PAMAM dendrimers. Particular attention is given to the ligand exchange reaction (LER). Binding of Pt(II) complexes to one dendrimer atom site (monodentate binding) is found to be thermodynamically feasible. Tertiary amine nitrogen (N3) is found to be the most favorable binding site in agreement with previous experimental work. Comparing the binding of Pt(II) species to atom sites in simple molecules with those to similar sites in dendrimer outer pockets allowed us to assess the impact of dendrimer branches on the binding. The impact of branches is manifested in more complex reaction profiles for complexation of Pt(II) species, because of the numerous ways in which a single molecule could be hosted by an outer dendrimer pocket. It is found that branches slightly improve the binding strength to all sites, particularly to N3. However, they could also be responsible for the increase of the activation energy for direct LER of PtCl 4 2- and PtCl 3 (H 2 O) - at the N3 site. Considering the thermodynamics of both complexation steps, namely noncovalent binding (NCB) and LER, it is found that to have a PtCl 3 - moiety bound to N3, as a result of NCB + LER operating on PtCl 4 2- , is more likely than to have any other ion hosted in the outer pockets. However, the activation energy for direct LER of PtCl 4 2- at the N3 site is found to be the largest among all Pt(II) metal complexes and even larger than the barrier to its own aquation yielding PtCl 3 (H 2 O) - .

Chromium(III)-isocinchomeronato and quinolinato complexes: kinetic studies in NaOH solutions and effect on 3T3 fibroblast proliferation

Abstract: The aquation of chromium(III)-isocinchomeronato and quinolinato complexes, mer-[Cr(icaH)3]0 and mer-[Cr(quinH)3]0 (where icaH− and quinH− are N,O-bonded isocinchomeronic and quinolinic acid anion, respectively) was studied in NaOH solutions. The process leads to successive ligand liberation in the fully deprotonated species. The kinetics of the first ligand liberation were studied spectrophotometrically in the visible region. A mechanism is proposed in which the rate of the chelate-ring opening at the Cr–N bond is much faster than the rate of the Cr–O bond breaking. The rate-determining step is described by the rate law: k obs1 = k OH(1) + k O Q 2 [OH−], where k OH(1) and k O are rate constants of the first ligand liberation from the hydroxo- and oxo-forms of the intermediate, respectively, and Q 2 is an equilibrium constant between these two protolytic forms. The first pseudo-first-order rate constants (k obs1) were calculated using SPECFIT software for an A → B → C reaction pattern. The results are compared with those determined in acidic medium. Kinetics of the second and third ligand liberation were also studied and values of successive pseudo-first-order rate constants (k obs2, k obs3) are [OH−] independent. Effect of chromium(III)-quinolinato and isocinchomeronato complexes on 3T3 fibroblast proliferation was evaluated. Cytotoxicity of these complexes is low, suggesting they may be promising candidates as novel dietary supplements.

Pt(II) uptake by dendrimer outer pockets: 2. Solvent-mediated complexation.

Abstract: We study the effect of the solvent (water) on the ligand exchange reaction (LER) step of Pt(II) complexation to PAMAM dendrimers. The results suggest that aquation of tetrachloroplatinate anion (PtCl(4)(2-)) inside PAMAM outer pockets occurs prior to its reaction with dendrimer atom binding sites. Thus, the active involvement of water opens up several pathways by which Pt(II) can bind to tertiary amine sites (N3). Monodentate binding pathways by which a PtCl(3)(-) moiety is obtained as a final product rather than PtCl(2)(H(2)O) are considered to be the predominant routes due to their smaller degree of complexity, including aspects such as less number of intermediates and lower energy barriers. Monodentate binding of Pt(II) to the secondary amide site (N2) is found to be feasible, in agreement with previous NMR experiments, once aquation of the tetrachloroplatinate anion has occurred. For this type of binding to occur, the dendrimer branch amide group configuration would have to switch from its equilibrium position (trans) to a cis position. It is also found that outer pockets aid Pt(II) complexation with the dendrimer mainly by making the noncovalent binding (NCB) step more favorable than that in branchless environments. Finally, our results predict that competitive monodentate binding of Pt(II) to either N3 or N2 is thermodynamically rather than kinetically driven.

THE HYDROLYSIS MECHANISM OF THE ANTICANCER AGENT trans-DICHLORO(AMMINE)(QUINOLINE)PLATINUM COMPLEX: A THEORETICAL STUDY

Abstract: Hydrolysis of trans-dichloro(ammine)(quinoline)platinum, a novel potential anticancer drug, is believed to be the key activation step before the drug reaches its intracellular target DNA. To obtain an accurate hydrolysis mechanism for this nonclassical class of square-planar Pt(II) complex, five different models were used at the experimental temperature with the solvent effect B3LYP/PCM using hybrid density functional theory. The stationary points on the potential energy surfaces for the first and second hydrolysis steps, proceeding via a five-coordinate trigonal-bipyramidal (TBP)-like structure of transition state, were fully optimized and characterized. The most remarkable structural variations in the hydrolysis process were found to occur in the equatorial plane of the TBP-like structures of the intermediates and transition states. It was found that the explicit solvent effect originating from the inclusion of extra water molecules into the system is significantly stronger than those arising from the bulk aqueous medium, especially for the first aquation step, which emphasizes the use of appropriate models for these types of problems. The results give detailed energy profiles for the mechanism of hydrolysis of trans-dichloro(ammine)(quinoline)platinum, which may assist in understanding the reaction mechanism of the drug with DNA target and in the design of novel platinum-based anticancer drugs with trans geometries.

A study of solid-state rhodium(III) sulfates

Abstract: Solid-state rhodium(III) sulfates and their aqueous solutions were examined by IR and electronic absorption spectroscopy, thermogravimetry, X-ray powder diffraction analysis, and 103Rh and 17O NMR spectroscopy. A study of the spontaneous aquation of freshly prepared solutions showed that this process results in an equilibrium between the subsystems of monomeric and oligomeric complexes. It was found that solid-state rhodium(III) sulfates vary in phase composition, basically consisting of dimeric and trimeric complexes.

The Aquation of Po(IV): A Quantum Chemical Study.

Abstract: The aim of this work is to present theoretical results of the hydration of the Po(IV) in solution. Particular attention is paid to the level of calculation needed to properly describe the system under study: Po(IV) coordination number in the first hydration shell and the nature of the polonium‐water bonding. The hydration number of the Po(IV) is found to be in solution between 8 and 9 and the solvation free energy around −1450 kcal/mol. The Po‐H2O bonding is dominated by the strong electrostatic contribution although the peculiar geometry adopted by the different hydrates is due to covalent contributions. This involves the empty 6p orbital of the polonium ion and one lone pair on the oxygen atom of the water molecule. No role of the 6s orbital of the polonium ion is detected.

Pulse radiolytic studies on cis-dichlorobis-(2,2'-bipyridine)cobalt(III) and cis-dichlorobis-(1,10-phenanthroline)cobalt(III) complexes

Abstract: The reactions of hydrated electron (C - aq )with Co(lll) polypyridyl complexes of the type [Co(NN) 2 Cl 2 ]Cl where NN = 2,2'-bipyridine (bpy), and 1.10-phenanthroline (phen) have been studied by pulse radiolysis. The rate constants for the reactions at 300 K have been evaluated to he (7.6±0.2)x10 10 , and (6.9±0.2)x10 10 dm 3 mol -1 S -1 respectively. Time resolved transient absorption spectra show two broad peaks at 360 and 610 nm for the bpy complex and a single broad peak at 420 nm for the phen complex at I μs. Comparison with reported transient spectra ol' the anion radicals of ligands indicates that the electron is located on the complex as a whole. The anion radicals of both the complexes initially produced, decay in the lime scale of ∼80 μs. Steady state absorption spectra on irradiation point out to breakdown of the phen complex, and the bpy-Co(lll) complex is reduced to Co(II) complex. Conductance of the solution substantially increases on irradiation for both the complexes and can he attributed to aquation/de-ligation of the phen complex. The phen complex anion radical undergoes aquation/de-ligation by intramolecular electron transfer leading to dissociation of the complex. For bpy complex the conductance increases due to the release of chloride ions and reduction to Co(ll) complex species is observed.

Kinetics and Mechanism of Formation and Acid–Catalyzed Decomposition of the [Co(NH3)4CO3]+ Complex Cation in Aqueous Solution

Abstract: It has been found that the kinetics of acid-catalyzed hydrolysis of the [Co(NH3)4CO3]+ cation follows the rate law –d ln [complex]/d t = k1K[H+]/(1+K[H+]) (5 °C < T < 25 °C; 0.0543M < [HClO4] < 2.7M and I = 1.0M (NaClO4). The reaction course consists of a rapid pre-equlibrium protonation followed by a rate determining ring opening process and the subsequent fast release of monodentate carbonato ligand. The changes of the absorbance for the acidic aqueous solution of the [Co(NH3)4CO3]+ complex ion proceeded at relevant wavelength in the UV-Vis region and time course of these changes were analysed according to a programme “Glint” for the consecutive first – order reaction with two experimental rate constants kfast and kslow. Finally, the aquation mechanism has been proposed and the effect of ligand coordination mode (bidentate carbonato anion) on complex reactivity has been discussed.