Showing papers on "Aquation published in 2009"

Maltol‐Derived Ruthenium–Cymene Complexes with Tumor Inhibiting Properties: The Impact of Ligand–Metal Bond Stability on Anticancer Activity In Vitro

Abstract: Organometallic rutheniumarene compounds bearing a maltol ligand have been shown to be nearly inactive in in vitro anticancer assays, presumably due to the formation of dimeric Ru-II species in aqueous solutions. In an attempt to stabilize such complexes, [Ru(eta(6)-p-cymene)(XY)Cl] (XY=pyrones or thiopyrones) complexes with different substitution pattern of the (thio)pyrone ligands have been synthesized, their structures characterized spectroscopically, and their aquation behavior investigated as well as their tumor-inhibiting potency. The aquation behavior of pyrone systems with electron-donating substituents and of thiopyrone complexes was found to be significantly different from that of the maltol-type complex reported previously. However, the formation of the dimer call be excluded as the primary reason for the inactivity of the complex because some of the stable compounds are not active in cancer cell lines either. In contrast, studies of their reactivity towards amino acids demonstrate different reactivities of the pyrone and thiopyrone complexes, and the higher stability of the latter probably renders them active against human tumor cells.

Influence of amine ligands on the aquation and cytotoxicity of trans-diamine platinum(II) anticancer complexes

Abstract: Three (15)N-labelled trans-Pt(ii) amine complexes with isopropylamine ((15)N-ipa), methylamine ((15)N-ma) and dimethylamine ((15)N-dma) have been prepared and characterized. 2D [(1)H,(15)N] HSQC NMR spectroscopy was used to obtain the rate and equilibrium constants for the aquation of trans-[PtCl(2)((15)N-ipa)((15)N-ma)] ((15)N-1), trans-[PtCl(2)((15)N-dma)((15)N-ma)] ((15)N-2) and trans-[PtCl(2)((15)N-dma)((15)N-ipa)] ((15)N-) in 100 mM NaClO(4) solutions at 298 K. New (15)N shift ranges for H(2)N-Pt(II)-N and HN-Pt(II)-N groups are reported. Formation of the diaqua complex was not observed for and accounted for <2% of the species at equilibrium for 1 and 2 . The first aquation step is significantly faster for 2 (k(1) = 14 x 10(-5) s(-1)) than for the two complexes with the bulkier ipa ligand (k(1) = 5.5 x 10(-5) s(-1) (), 6.1 x 10(-5) s(-1) (3)), but 2 is the least aquated of the three complexes at equilibrium. The pK(a) values for the monoaqua adducts of 1-3 are similar (5.98, 5.85 and 5.91, respectively) and 0.4 pH units lower than the related cis complex cis-[PtCl(2)(dma)(2)], indicating a smaller proportion of more reactive aqua species will exist at physiological pH. The pK(a) values for the diaqua adduct of 2 (4.59 and 7.98) are 0.3-0.6 pH units higher than those of 1(4.31 and 7.30) and 3 (4.28 and 7.29), which have very similar values. The speciation profiles of 1-3 , calculated on the basis of the calculated equilibrium and dissociation constants, indicate that <1% hydrolyzed species will exist under physiological conditions in cancer cells. The cytotoxicity of 1-3 (non-(15)N-labelled) was assessed in three cancer lines (SF268, MCF-7 and NCI-H460). The new trans-Pt(ii) diamine complex 2 is more active than 1 and 3 in all cases and is more potent than cisplatin in the MCF-7 adenocarcinoma cell line.

Interactions of the “piano‐stool” [ruthenium(II) (η6‐arene)(en)CL]+ complexes with water and nucleobases; ab initio and DFT study

Abstract: Piano stool ruthenium complexes of the composition [Ru(II)(η6-arene)(en)Cl]+/2+ (en = ethylenediamine) represent an emerging class of cisplatin-analogue anticancer drug candidates. In this study, we use computational quantum chemistry to characterize the structure, stability and reactivity of these compounds. All these structures were optimized at DFT(B3LYP)/6-31G(d) level and their single point properties were determined by the MP2/6-31++G(2df,2pd) method. Thermodynamic parameters and rate constants were determined for the aquation process, as a replacement of the initial chloro ligand by water and subsequent exchange reaction of aqua ligand by nucleobases. The computations were carried out at several levels of DFT and ab initio theories (B3LYP, MP2 and CCSD) utilizing a range of bases sets (from 6-31G(d) to aug-cc-pVQZ). Excellent agreement with experimental results for aquation process was obtained at the CCSD level and reasonable match was achieved also with the B3LYP/6-31++G(2df,2pd) method. This level was used also for nucleobase-water exchange reaction where a smaller rate constant for guanine exchange was found in comparison with adenine. Although adenine follows a simple replacement mechanism, guanine complex passes by a two-step mechanism. At first, Ru-O6(G) adduct is formed, which is transformed through a chelate TS2 to the Ru-N7(G) final complex. In case of guanine, the exchange reaction is more favorable thermodynamically (releasing in total by about 8 kcal/mol) but according to our results, the rate constant for guanine substitution is slightly smaller than the analogous constant in adenine case when reaction course from local minimum is considered. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009

Iron(III) complexes of fluorescent hydroxamate ligands: preparation, properties, and cellular processing

Abstract: Iron(III) complexes containing hydroxamic acid fluorophores were investigated as models of hypoxia selective prodrugs in vitro. Two complexes were synthesised, [Fe(c343haH)3] and [Fe(salen)(c343haH)]. The fluorescence of the hydroxamate coumarin fluorophore was almost completely quenched on coordination to the iron(III) centre in [Fe(c343haH)3]. However, quenching was minimal for [Fe(c343haH)(salen)] in aqueous media and we propose that the fluorescence results from structural rearrangements that occur because of the inherent strain in the iron-salen structure. Fluorescence was also measured in the presence of the cellular reductants ascorbic acid and cysteine. Fluorescence intensity increased over time, with the most rapid return of fluorescence occurring over a two hr period. The rapid fluorescence return indicates that the complexes undergo ligand release, either via reduction followed by aquation, or via direct ligand exchange with the reductants. Electrochemical studies demonstrated that both complexes have very negative reduction potentials. Furthermore, [Fe(c343haH)(salen)] was shown to exhibit quasi-reversibility of reduction. The distribution of the free hydroxamate ligand and the complexes were monitored in A2780 cells. The free ligand displayed non-specific distribution, which differed from the nucleolar distribution of [Fe(c343haH)3] and the lysosomal accumulation of [Fe(c343haH)(salen)] over time. Thus the results of the present study show that iron(III) complexes present a viable model for monitoring hydroxamate fluorophore displacement in vitro to determine the fate of prodrugs.

Synthesis, characterization, and reaction pathways for the formation of a GMP adduct of a cytotoxic thiocyanato ruthenium arene complex.

Abstract: The organoruthenium complex [(η6-hmb)Ru(en)(Cl)][PF6] (hmb is hexamethylbenzene, en is ethylenediamine) undergoes facile aquation and then reacts with KSCN in unbuffered solution to give the S-coordinated thiocyanato product [(η6-hmb)Ru(en)(S-SCN)]+ which slowly converts to the thermodynamically favored N-bound complex [(η6-hmb)Ru(en)(N-NCS)]+ (1+). Complex 1 was synthesized and characterized by X-ray crystallography and mass spectrometry. Despite its lack of hydrolysis over 24 h, complex 1 exhibits moderate cytotoxicity (IC50 24 μM) towards the human ovarian cancer cell line A2780, comparable with that of the chlorido analogue which is thought to be activated (towards potential target DNA) via a rapid aquation (Wang et. al. in Proc Natl Acad Sci USA 102:18269–18274, 2005). Detailed kinetic studies suggest that complex 1 binds to guanosine 5′-monophosphate (GMP) through direct N7 substitution of the N-bound SCN ligand. In the presence of a high concentration of chloride (104 mM), however, complex 1 may bind partly to GMP via Cl substitution.

Chromium(III) complexes with lutidinic acid: kinetic studies in HClO4 and NaOH solutions

Abstract: Chromium(III)-lutidinato complexes of general formula [Cr(lutH) n (H2O)6−2n ]3−n (where lutH− is N,O-bonded lutidinic acid anion) were obtained and characterized in solution. Acid-catalysed aquation of [Cr(lutH)3]0 leads to only one ligand dissociation, whereas base hydrolysis produces chromates(III) as a result of subsequent ligand liberation steps. The kinetics of the first ligand dissociation were studied spectrophotometrically, within the 0.1–1.0 M HClO4 and 0.4–1.0 M NaOH range. In acidic media, two reaction stages, the chelate-ring opening and the ligand dissociation, were characterized. The dependencies of pseudo-first-order rate constants on [H+] are as follows: k obs1 = k 1 + k −1/K 1[H+] and k obs2 = k 2 K 2[H+]/(1 + K 2[H+]), where k 1 and k 2 are the rate constants for the chelate-ring opening and the ligand dissociation, respectively, k −1 is the rate constant for the chelate-ring closure, and K 1 and K 2 are the protonation constants of the pyridine nitrogen atom and coordinated 2-carboxylate group in the one-end bonded intermediate, respectively. In alkaline media, the rate constant for the first ligand dissociation depends on [OH−]: k obs1 = k OH(1) + k O[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 K 2 is an equilibrium constant between these two protolytic forms. Kinetic parameters were determined and a mechanism for the first ligand dissociation is proposed. The kinetics of the ligand liberation from [Cr(lut)(OH)4]3− were also studied and the values of the pseudo-first-order rate constants are [OH−] independent.

Mixed chromium(III) complexes with pyridinedicarboxylato and oxalato ligands: kinetic studies in HClO4 solutions

Abstract: Three chromium(III) complexes of general formula [Cr(ox)2(pdaH)]2− (where ox = C2O4 2− and pdaH− is N,O-bonded 2,3-, 2,4- or 2,5-pyridinedicarboxylic acid anion) were obtained and characterized in solution. Acid-catalysed aquation of [Cr(ox)2(pdaH)]2− gave two products: [Cr(ox)(pdaH)(H2O)2]0 (P1) and cis-[Cr(ox)2(H2O)2]2− (P2). The kinetics of these reactions were studied spectrophotometrically, within the 0.1–1.0 M HClO4 range, and the pseudo-first-order rate constants for the oxalato (k obs1) and pdaH− (k obs2) ligands dissociation were calculated based on the determined pseudo-first-order rate constants (k obs) and P1:P2 molar ratio. The dependencies of the pseudo-first-order rate constants on [H+] are as follows: k obs1 = b 1[H+] and k obs2 = b 2[H+], where b 1 and b 2 are the second-order rate constants for the oxalato and pdaH− ligands dissociation, respectively. Kinetic parameters were determined and the mechanism of the pdaH− ligand dissociation is proposed.

Ruthenium Azo Complexes: Synthesis, Spectra, and Electrochemistry of Dithiocyanato-Bis{1-(Alkyl)- 2-(Arylazo)imidazole}ruthenium(II)*

Abstract: Silver-assisted aquation of blue cis-trans-cis-RuCl2(RAaiR’)2 (I) leads to the synthesis of solvento species, blue-violet cis-trans-cis-[Ru(OH2)2(RAaiR’)2](ClO4)2 (II), where RAaiR’ = p-R-C6H4-N=N-C3H2-NN, abbreviated as N,N′ chelator (N(imidazole) and N(azo) represent N and N′, respectively); R = H (a), p-Me (b), p-Cl(c); R′ = Me (III), Et (IV), Bz (V), that reacted with NCS− in warm EtOH resulting in red-violet dithiocyanato complexes of the type [Ru(NCS)2(RAaiR)2] (IIIa–Vn). These complexes were studied by elemental analysis, UV-Vis, IR, and 1H NMR spectroscopy and cyclic voltammetry. The solution structure and stereoretentive transformation in each step have been established from 1H NMR results. All the complexes exhibit strong MLCT transitions in the visible region. They are redox active and display one metal-centered oxidation and successive ligand-based reductions. Linkage isomerisation was studied by changing the solvent and then by UV-Vis spectral analysis.

Catalytic Spectrophotometry for the Determination of Trace Zinc

Abstract: A new catalytic spectrophotomery for the Determination of trace Zinc has been studied based on the catalytic effect of Zinc on oxidizing decoloration rection of Calcein and potassium periodate and on the sensitive effect of Polyacrylicacidsodiumsalt(PAAS).Beer,s law is obeyed in the range of 0.040 to 2.00μg/L and the linear regression aquation is ΔA=0.04982+0.06828CZn2+(μg/L)(r=0.9992),the detection limit is 1.9×10-11g/mL.The method has been applied to the determination of trace Zinc in water and human hair samples with satisfactory results.

Synthesis, crystal structure and properties of three different derivatives of bis[di(2-pyridyl)methanediol]copper(II), [Cu(bpmd)2]2+ ¶

Abstract: In an attempt to obtain ternary copper(II) [Cu(II)] complexes where bis(2-pyridyl) ketone (bpk) could induce the fac-O2 + N(apical) conformation in the HL2− form of two different nitrilotriacetates (HNTA2− and HDNTA2−), we obtained [Cu(bpmd)2][Cu(HNTA)2] · 2H2O (1) and [Cu(bpmd)2](H2DNTA)2 · 4H2O (2) where bpmd is di(2-pyridyl)methanediol. On this basis, the salt [Cu(bpmd)2][Cu(IDA)2] · 6H2O (3) [iminodiacetate (IDA) ligand] was also obtained. The crystallographic studies of these compounds revealed that the common cation of these salts results from aquation of bpk in the aqueous media. The aquation of bpk is unexpectedly fast in the case of 1 because crystals appeared on the same day of the synthesis. ¶This article is dedicated to Professor Alfredo Mederos for his contribution to the coordination chemistry.

Kinetics and Mechanism of Base Hydrolysis of Some (Aminomonocarboxylato)(tetraethylenepentamine) Cobalt(III) Complexes in Aqueous Medium

Abstract: Base hydrolysis of some (aminomonocarboxylato)(tetraethylenepentamine)cobalt(III) complexes were studied in aqueous medium. The pseudo-first order rate constant fitted the relationship. k obs = k OH [OH - ] T at 0.005 ≤ [OH - ] mol dm -3 ≤ 0.10 at 293.15 K-313.15 K, (I = 0.1 mol dm -3 ), where k OH denotes the second order base hydrolysis rate constant. The αβR isomer of the α-alaninato complex reacted approximately 8 times faster than its apS analogue at 298.15 K. Also the reactivity difference k OH (pyridine-2-carboxylato)/k OH (β-alaninato)≈ 3 for the (αβS) isomer is indicative of the relative electron displacement property of the pyridine ring and the aliphatic chain attached to the bound carboxylate function which influences partly the Co-O bond strength. The D cb mechanism is valid for all these substrates. The ionic strength dependence of k OH in the range 0.01 ≤ I, mol dm -3 ≤ 0.1 for glycinato and p-alaninato complex also confirmed the relationship log k OH = log k 0 OH + S 1 [I 1/2 /(1 +I 1/2 ) + CI], where C is an adjustible parameter S 1 = 2bZ A Z B , with b = 0.509 at 298.15 K, Z A and Z B denote charges of the reactant species. The acid catalyzed aquation indicated that αβR-[(tetren)CoO 2 C-(CH 3 )NH 3 ] 3+ aquates via spontaneous (ko) and acid catalyzed (k aq ) path. However, these reactions are extremely slow (k o = (1.74±0.17)× 10 -5 s -1 , k aq = (2.72+0.05)×10 -5 dm 3 mol -1 s -1 at 333.15 K and I = 1.0 mol dm -3 ).