The hydrolysis process of the anticancer complex [ImH][trans-RuCl4(Im)2]: a theoretical study

A hydrolysis process of the anticancer drug [ImH][trans-RuCl4(Im)2] (ICR, Im=imidazole) has been investigated using density functional theory (DFT), and the aqueous solution effect has been considered and calculated by the conductor-like polarizable calculation model (CPCM). The stationary points on the potential energy surfaces for the first and second hydrolysis steps (including two different paths) were fully optimized and characterized. The results show that the computed values of free energy barriers DeltaG degrees (aq) and rate constants (k) in aqueous solution, in particular for the first hydrolysis step, are in excellent agreement with the experimental results. The analysis of electronic characteristics of species in the hydrolysis process suggests that the nucleophilic attack abilities (A) of hydrolysis products by biomolecular targets is in the sequence of A()相似文献   

The hydrolysis mechanism of the anticancer ruthenium drugs NAMI-A and ICR investigated by DFT-PCM calculations

(ImH)[trans-RuCl(4)(DMSO-S)(Im)], (Im = imidazole, DMSO-S = S-bonded dimethylsulfoxide), NAMI-A, is the first anticancer ruthenium compound that successfully completed Phase I clinical trials. NAMI-A shows a remarkable activity against lung metastases of solid tumors, but is not effective in the reduction of primary cancer. The structurally similar (ImH)[trans-RuCl(4)(Im)(2)], ICR (or KP418), and its indazole analog (KP1019) are promising candidate drugs in the treatment of colorectal cancers, but have no antimetastatic activity. Despite the pharmacological relevance of these compounds, no rationale has been furnished to explain their markedly different activity. While the nature of the chemical species responsible for their antimetastatic/anticancer activity has not been determined, it has been suggested that the difference between reduction potentials of NAMI-A and ICR may be the key to the different biological responses they induce. In this work, Density Functional Theory calculations were performed to investigate the hydrolysis of NAMI-A and ICR in both Ru(III) and Ru(II) oxidation states, up to the third aquation. In line with experimental findings, our calculations provide a picture of the hydrolysis of NAMI-A and ICR mainly as a stepwise loss of chloride ligands. While dissociation of Im is unlikely under neutral conditions, that of DMSO becomes competitive with the loss of chloride ions as the hydrolysis proceeds. Redox properties of NAMI-A and ICR and of their most relevant hydrolytic intermediates were also studied in order to monitor the effects of biological reductants on the mechanism of action. Our findings may contribute to the identification of the active compounds that interact with biological targets, and to explain the different biological activity of NAMI-A and ICR.     

Hydrolysis Mechanism of the NAMI-A-type Antitumor Complex (HL)[trans-RuCl4L(dmso-S)] (L=1-methyl-1,2,4-triazole)

The hydrolysis process of Ru(III) complex (HL)[trans-RuCl₄L(dmso-S)] (L=1-methyl-1,2,4-triazole and dmso-S=S-dimethyl sulfoxide) (1), a potential antitumor complex similar to the well-known antitumor agent (Him)[trans-RuCl₄L(dmso-S)(im)] (NAMI-A, im=imidazole), was investigated using density functional theory combined with the conductor-like polarizable continuum model approach. The structural characteristics and the detailed energy profiles for the hydrolysis processes of this complex were obtained. For the first hydrolysis step, complex 1 has slightly higher barrier energies than the reported anticancer drug NAMI-A, and the result is in accordance with the experimental evidence indicating larger half-life for complex 1. For the second hydrolysis step, the formation of cis-diaqua species is thermodynamic preferred to that of trans isomers. In addition, on the basis of the analysis of electronic characteristics of species in the hydrolysis process, the trend in nucleophilic attack abilities of hydrolysis products by pertinent biomolecules is revealed and predicted.     

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

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, I(d), 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.     

含吡啶的抗肿瘤转移NAMI-A衍生物的制备和水解机理动力学

目的研究配体结构对NAMI-A衍生物水解机理、电化学性质的影响。方法制备了trans-[RuCl4(DMSO)(3-MePy)][(3-MePy)H](3-MePy=3-甲基吡啶,化合物1)和trans-[RuCl4(DMSO)(4-MePy)][(4-MePy)H](4-MePy=4-甲基吡啶,化合物2)。用UV、NMR、CV法研究化合物1、化合物2的水解机理-动力学、溶液稳定性及电化学性质。结果化合物1和化合物2与NAMI-A相似,在pH7.40的缓冲液中发生脱氯水解反应(Ⅰ氯水解及Ⅱ氯水解)(分步反应);在pH 5.00缓冲液中DMSO(二甲亚砜)及少量吡啶水解。测定各水解反应表观速率常数及半衰期、溶液稳定性及氧化还原电位。结论化合物1、化合物2的Ⅰ氯、Ⅱ氯及DMSO水解反应机理与NAMI-A相似,而且各水解速率与NAMI-A相差不大,即用甲基吡啶取代咪唑环,对NAMI-A衍生物的Ⅰ氯、Ⅱ氯及DMSO水解反应速率影响较小。化合物在酸性溶液中的稳定性明显高于中性溶液。     

Hydrolysis process of the second generation platinum-based anticancer drug cis-amminedichlorocyclohexylamineplatinum(II)

The hydrolysis process of the anticancer drug cis-amminedichlorocyclohexylamineplatinum(II) (JM118 or cis-[PtCl2(NH3)cyclohexylamine]) and the influence of solvent models therein have been studied using hybrid density functional theory (B3LYP). The aquation reactions leading to the activated drug forms a key step for the reaction with the target DNA. In this study, the stepwise hydrolysis, cis-[PtCl2(NH3)cyclohexylamine] + 2 H2O --> cis-[Pt(NH3)cyclohexylamine(OH2)2]2+ + 2 Cl- was explored, using three different models. Implicit solvent effects were incorporated through polarized continuum models. The stationary points on the potential energy surfaces for the first and second hydrolysis steps, proceeding via a general S(N)2 pathway, were fully optimized and characterized. It was found that the explicit solvent effects originating from the inclusion of extra water molecules into the system are significantly stronger than those arising from the bulk aqueous medium, especially for the second aquation step, emphasizing the use of appropriate models for these types of problems. In comparison with previous work on the parent compound cisplatin, a slower rate of hydrolysis is determined for the first (rate determining) reaction. The results furthermore imply that the doubly aquated form of JM118 will be the main DNA binding form of the drug. The results provide detailed energy profiles for the mechanism of hydrolysis of JM118, which may assist in understanding the reaction mechanism of the drug with the DNA target and in the design of novel Pt-containing anticancer drugs.     

Appraisal of the redox behaviour of the antimetastatic ruthenium(III) complex [ImH][RuCl(4)(DMSO)(Im)], NAMI-A

The imidazolium trans-tetrachloro(dimethylsulfoxide)imidazoleruthenate(III) complex [ImH][Ru(III)Cl(4)(DMSO)(Im)], NAMI-A, has shown an interesting antimetastatic activity. Since Ru(III) complexes are coordinatively more inert than the corresponding Ru(II) derivatives, an "activation by reduction" mechanism has been proposed to explain the biological activity of NAMI-A, thus acting as a pro-drug. We report here an electrochemical study on NAMI-A in aqueous solutions which emphasizes the structural and chemical consequences accompanying the easy Ru(III)/Ru(II) electron transfer (e.g., axial imidazole/water exchange in acidic solution in the short timescale of cyclic voltammetry followed by equatorial chloride/water exchange in the longer timescale of macroelectrolysis).     

杂环反铂(Ⅱ)抗癌药物水解反应机理的DFT研究

用DFT-B3LYP方法和IEF-PCM溶剂化模型研究了反铂抗癌药物trans-[PtCl2(piperidine)(Am)](Am=2-picoline(1),3-picoline(2),4-picoline(3)),trans-[PtCl2(piperidine)(piperazine)](4),trans-[PtCl2(pipera-zine)2](5)and trans-[PtCl2(iminoether)2](6)的水解过程.水解反应是药物与DNA靶分子作用的关键活化步骤.全优化和表征了一水解和二水解反应经由一般的SN2路径过程所有物种的势能面稳定点.结果发现反应过程遵循已经建立的平面正方形配合物的配体取代反应理论,即取代反应通常通过一个三角双锥过渡态结构的铂配体交换反应发生.得到的过渡态结构与以前的相关工作一致,所有反应都是吸热反应;所有体系的二水解能垒都高于一水解.与顺铂相比,这些配合物都有更快的水解反应速率;并与以前类似的反铂配合物的研究做了比较.研究结果提供了这些配合物水解反应过程的详细能量变化,对理解药物与DNA靶分子的作用机理和新型反铂抗癌药物的设计有帮助.     

Exploiting soft and hard X-ray absorption spectroscopy to characterize metallodrug/protein interactions: the binding of [trans-RuCl4(Im)(dimethylsulfoxide)][ImH] (Im = imidazole) to bovine serum albumin

The reaction of bovine serum albumin (BSA) with [ trans-RuCl 4(Im)(dimethylsulfoxide)][ImH] (Im = imidazole) (NAMI-A), an experimental ruthenium(III) anticancer drug, and the formation of the respective NAMI-A/BSA adduct were investigated by X-ray absorption spectroscopy (XAS) at the sulfur and chlorine K-edges and at the ruthenium K- and L 3-edges. Ruthenium K and L 3-edge spectra proved unambiguously that the ruthenium center remains in the oxidation state +3 after protein binding. Comparative analysis of the chlorine K-edge XAS spectra of NAMI-A and NAMI-A/BSA, revealed that the chlorine environment is greatly perturbed upon protein binding. Only modest changes were observed in the sulfur K-edge spectra that are dominated by several protein sulfur groups. Overall, valuable information on the nature of this metallodrug/protein adduct and on the mechanism of its formation was gained; XAS spectroscopy turns out to be a very suitable method for the characterization of this kind of systems.     

Reaction mechanism of NO with hydrolysates of NAMI-A: an MD simulation by combining the QM/MM(ABEEM) with the MD-FEP method

Nitrosylation reaction mechanisms of the hydrolysates of NAMI-A and hydrolysis reactions of ruthenium nitrosyl complexes were investigated in the triplet state and the singlet state. Activation free energies were calculated by combining the QM/MM(ABEEM) method with free energy perturbation theory, and the explicit solvent environment was simulated by an ABEEMσπ polarizable force field. Our results demonstrate that nitrosylation reactions of the hydrolysates of NAMI-A occur in both the triplet and the singlet states. The Ru-N-O angle of the triplet ruthenium nitrosyl complexes is in the range of 132.0°–138.2°. However, all the ruthenium nitrosyl complexes at the singlet state show an almost linear Ru-N-O angle. The nitrosylation reaction happens prior to the hydrolysis reaction for the first-step hydrolysates. The activation free energies of the nitrosylation reactions show that the H₂O-NO exchange reaction of [RuCl₄(Im)(H₂O)] in the singlet spin sate is the most likely one. Comparing with the activation free energies of the hydrolysis reactions of the ruthenium nitrosyl complexes, the results indicate that the rate of the DMSO–H₂O exchange reaction of [RuCl₃(NO)(Im)(DMSO)] is faster than that of [RuCl₃(H₂O)(Im)(DMSO)] in both the triplet spin state and the singlet spin state. © 2018 Wiley Periodicals, Inc.     

Combined therapy of the antimetastatic compound NAMI-A and electroporation on B16F1 tumour cells in vitro

Ruthenium complex NAMI-A [ImH][trans-RuCl(4)(DMSO-S)Im] (Im = imidazole) is a potential chemotherapeutic drug in cancer treatment. Electroporation can be used to facilitate delivery of NAMI-A into cells. Suspension of B16F1 tumour cells from mouse melanoma in NAMI-A solution was exposed to a train of electric pulses. The effect of NAMI-A was determined by examining cell viability in clonogenic test. Our results show that electroporation increases the otherwise scarce in vitro effects of NAMI-A, i.e. reduces cell viability. At the conditions chosen for experiments 90% of cells survived in the presence of 1 microM NAMI-A, whereas in a combined treatment with 1 microM NAMI-A and electroporation only about 10% of cells survived.     

Hydrolysis of New Transplatin Analogue Containing One Aliphatic and One Planar Heterocyclic Amine Ligand: A Density Functional Theory Study

Herein we give a theoretical study of the hydrolysis processes of a novel anticancer drug trans-PtCl2(3-pico)(ipa) (3-pico=3-methylpyridine, ipa=isopropylamine). Two different models, model 1 relative to isolated reactant/product (R/P, wherein R=platinum complex+H2O, P=platinum complex+Cl-) and model 2 relative to reactant complex/product complex (RC/PC, wherein RC=(platinum complex)(H2O),PC=(platinum complex)(Cl-) are employed and the geometric structures are optimized at the B3LYP level of DFT method. It is found that the processes of the reactions follow the established theory for ligand substitution in square planar complexes; the geometries of the transition states (TS) agree with the previous related work and all of the reactions are endothermic. The effects originating from the inclusion of the attacking water/released chloride into the second coordination shell of platinum in RC/PC play an important role in the thermodynamic and kinetic profiles of the reactions, that is, the barrier heights of the reactions of model 2 are increased by ~6.3 and ~23.8 kJ/mol for step1 and step2 respectively, and the endother-micity is considerably decreased by ~420.5 and ~771.2 kJ/mol compared to model 1 in the gas phase. Theconsideration of the bulk solvation effects increase the barrier heights for both steps of model 1 by ~27.6 and ~6.7 kJ/mol respectively, whereas it reduces the barrier heights by ~7.9 and ~29.3 kJ/mol for model 2.The reaction energies are all decreased, especially for model 1, indicating more stable complexes solvated in the bulk aqueous solution than in the gas phase. Additionally, to get an accurate energy picture of the title complex, the relative free energies derived from the DFT-SCRF (density functional theory self-consistent field) calculations are compared with the relative total energies. The results are that activation energies rise for the first hydrolysis and fall for the second hydrolysis for all the systems, and for all the systems,the barrier height of the second hydrolysis is always higher than that of the first step. The rate constants indicate that transplatin analogue is kinetically comparable to cisplatin and its analogue in the hydrolysis process     

Development of NAMI-A-loaded PLGA-mPEG Nanoparticles: Physicochemical Characterization,in vitro Drug Release and in vivo Antitumor Efficacy

NAMI-A has showed extraordinary activities against metastatic tumors. However, the hydrolysis of DMSO from NAMI-A could reduce anti-metastatic activity. To enhance the circulation time and the anti-metastatic effect of NAMI-A, we first synthesized the NAMI-A-loaded nanoparticles. NAMI-A-loaded nanoparticles were prepared by the double emulsion method and characterized by scanning electron microscopy for surface morphology, laser light scattering for size and zeta potential for surface charge. Controlled release of NAMI-A was observed in a sustained manner. Compared with free NAMI-A, NAMI-A -loaded nanoparticles exhibited superior antitumor effect by delaying tumor growth in T739 mice. PLGA-mPEG nanoparticles are promising for further studies as drug delivery carriers.     

Theoretical study on the hydrolysis mechanism of N,N-dimethyl-N'-(2-oxo-1, 2-dihydro-pyrimidinyl)formamidine: water-assisted mechanism and cluster-continuum model

The hydrolysis reaction of N,N-dimethyl-N'-(2-oxo-1, 2-dihydro-pyrimidinyl)formamidine (DMPFA), a model compound of the antivirus drug amidine-3TC (3TC = 2', 3'-dideoxy-3'-thiacytidine), is investigated by the hybrid density functional theory B3LYP/6-31+G (d,p) method. The hydrolysis reaction of the title compound is predicted to undergo via two pathways, each of which is a stepwise process. Path A is the addition of H2O to the C=N double bond in the amidine group to form a tetrahedral structure in its first step, and then the transfer of the H atom of hydroxyl leads to the corresponding products via four possible channels. Path B simultaneously involves the nucleophilic attack of H2O to the C atom of the C=N bond and the proton transfer to the N atom of amino group leading to the cleavage of the C-N single bond in the amidine group. The results indicate that path A is more favorable than path B in the gas phase. Moreover, to simulate the title reaction in aqueous solution, water-assisted mechanism and the cluster-continuum model, based on the SCRF/CPCM model, are taken into account in our work. The results indicate that it is rational for two water molecules served as a bridge to assist in the first step of path A and that cytosine rather than the cytosine-substituted formamide should be released from the tetrahedral intermediate via s six-membered cycle transition state (channel 2). Our calculations exhibit that the process toward the tetrahedral intermediate is the rate-determining step both in the gas phase and in aqueous solution.     

A DFT study on the hydrolysis mechanism of NH‐tautomeric antitumors of [HL][trans‐RuCl4L(dmso‐S)]

The hydrolysis process of Ru (III) complex [Htrz][trans‐RuCl₄(1‐H‐1,2,4‐triazole)(dmso‐S)] 1 , a potential antitumor complex similar to the well‐known anticancer agent [ImH][trans‐RuCl₄(Im)(dmso‐S)] (NAMI‐A), has been investigated by using density functional theory (DFT) method, and the solvent effect was also considered and calculated by conductor‐like polarizable calculation model (CPCM). Meanwhile, the hydrolysis process of the NH‐tautomeric isomer, [Htrz][trans‐RuCl₄(4‐H‐1,2,4‐triazole)(dmso‐S)] 2 , was also modeled and predicted by the same methods. The structural characteristics and the detailed energy profiles for the hydrolysis processes of two isomers have been obtained. The analysis of thermodynamic and kinetic characteristics of hydrolysis reaction suggests the following: for the first hydrolysis step, the Complex 1 has lower hydrolysis rate than the reported anticancer drug NAMI‐A, and the result is in accordance with experimental one. However, Complex 1 has obviously higher hydrolysis rate than its isomer Complex 2 , and the result was reasonably explained in theory. For the second hydrolysis step, the formation of cis‐diaqua species is thermodynamic preferred to that of trans isomers. In addition, the trend in nucleophilic attack abilities (A) of hydrolysis products by pertinent biomolecules was revealed and predicted. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2010     

含有一个非平面杂环胺配体的新型反铂抗癌药物的水解机理

用B3LYP杂化泛函和等电子聚焦极化连续模型(IEF-PCM)研究了trans-[PtCl2(NH3)(Am)](Am: 非平面哌啶或哌嗪)新型反铂抗癌药物的水解反应机理. 对经由一般的SN2机理的第一步和第二步水解反应势能面上的稳定点进行了全优化和表征. 在水解中, 最显著的结构变化发生在反应过渡态和中间体的五配位三角双锥的赤道面上. 与经典顺铂(cisplatin)比较, 反式[PtCl2(NH3)(piperazine)]的第一步和第二步水解活化能均低于顺铂, 而反式[PtCl2(NH3)(piperidine)]的第一步水解活化能稍高于顺铂, 第二步水解活化能稍低于顺铂. 计算表明, 这些含有非平面杂环胺反铂的配合物减小了赤道面上的立体效应和水解势垒.     

Hydrolysis Process of the Anticancer Agents Novel Non-classical trans-Platinum(Ⅱ) with Aliphatic Amines

The hydrolysis process of the anticancer agents novel non-classical trans- platinum(Ⅱ ) with aliphatic amines and the influence of solvent models therein have been studied by using hybrid density functional theory (B3LYP). In this study, the stepwise hydrolysis, trans- [PtCl2(Am)(isopropylamine)] + 2H2O → trans-[Pt(Am)(isopropylamine)(OH2)2]2+ + 2Cl-, was explored. Implicit solvent effects were incorporated through polarized continuum models. The stationary points on the potential energy surfaces for the first and second hydrolysis steps, proceeding via a general SN2 pathway, were fully optimized and characterized. It was found that the first hydrolysis reaction is easier than the second one and the hydrolysis of trans-[PtCl2- (isopropylamine)2] is the easiest in our studying systems. The result can assist in under-tanding the hydrolysis mechanism of trans-[PtCl2(Am)(isopropylamine)] and designing novel Pt-based anticancer drugs.     

Osmium NAMI-A analogues: synthesis, structural and spectroscopic characterization, and antiproliferative properties

The osmium(III) complex [(DMSO)2H][trans-OsIIICl4(DMSO)2] (1) has been prepared via stepwise reduction of OsO4 in concentrated HCl using N2H(4).2HCl and SnCl(2).2H2O in DMSO. 1 reacts with a number of azole ligands, namely, indazole (Hind), pyrazole (Hpz), benzimidazole (Hbzim), imidazole (Him), and 1H-1,2,4-triazole (Htrz), in organic solvents, affording novel complexes (H2ind)[OsIIICl4(Hind)(DMSO)] (2), (H2pz)[OsIIICl4(Hpz)(DMSO)] (3), (H2bzim)[OsIIICl4(Hbzim)(DMSO)] (4), (H2im)[OsIIICl4(Him)(DMSO)] (6), and (H2trz)[OsIIICl4(Htrz)(DMSO)] (7), which are close analogues of the antimetastatic complex NAMI-A. Metathesis reaction of 4 with benzyltriphenylphosphonium chloride in methanol led to the formation of (Ph3PCH2Ph)[OsIIICl4(Hbzim)(DMSO)] (5). The complexes were characterized by IR, UV-vis, ESI mass spectrometry, 1H NMR spectroscopy, cyclic voltammetry, and X-ray crystallography. In contrast to NAMI-A, 2-4, 6, and 7 are kinetically stable in aqueous solution and resistant to hydrolysis. Surprisingly, they show reasonable antiproliferative activity in vitro in two human cell lines, HT-29 (colon carcinoma) and SK-BR-3 (mammary carcinoma), when compared with analogous ruthenium compounds. Structure-activity relationships and the potential of the prepared complexes for further development are discussed.     

Solvent tuning of the substitution behavior of a seven-coordinate iron(III) complex

A detailed kinetic study of the substitution behavior of the seven-coordinate [Fe(dapsox)(L)2]ClO4 complex (H(2)dapsox = 2,6-diacetylpyridine-bis(semioxamazide), L = solvent or its deprotonated form) with thiocyanate as a function of the thiocyanate concentration, temperature, and pressure was undertaken in protic (EtOH and acidified EtOH and MeOH) and aprotic (DMSO) organic solvents. The lability and substitution mechanism depend strongly on the selected solvent (i.e., on solvolytic and protolytic processes). In the case of alcoholic solutions, substitution of both solvent molecules by thiocyanate could be observed, whereas in DMSO only one substitution step occurred. For both substitution steps, [Fe(dapsox)(L)2]ClO4 shows similar mechanistic behavior in methanol and ethanol, which is best reflected by the values of the activation volumes (MeOH DeltaV(I) = +15.0 +/- 0.3 cm(3) mol(-1), DeltaV(II) = +12.0 +/- 0.2 cm(3) mol(-1); EtOH DeltaV(I) = +15.8 +/- 0.7 cm(3) mol(-1), DeltaV(II) = +11.1 +/- 0.5 cm(3) mol(-1)). On the basis of the reported activation parameters, a dissociative (D) mechanism for the first substitution step and a D or dissociative interchange (I(d)) mechanism for the second substitution step are suggested for the reaction in MeOH and EtOH. This is consistent with the predominant existence of alcoxo [Fe(dapsox)(ROH)(OR)] species in alcoholic solutions. In comparison, the activation parameters for the substitution of the aqua-hydroxo [Fe(dapsox)(H2O)(OH)] complex by thiocyanate at pH 5.1 in MES were determined to be DeltaH = 72 +/- 3 kJ mol(-1), DeltaS = +38 +/- 11 J K(-1) mol(-1), and DeltaV = -3.0 +/- 0.1 cm(3) mol(-1), and the operation of a dissociative interchange mechanism was suggested, taking the effect of pressure on the employed buffer into account. The addition of triflic acid to the alcoholic solutions ([HOTf] = 10(-3) and 10(-2) M to MeOH and EtOH, respectively) resulted in a drastic changeover in mechanism for the first substitution step, for which an associative interchange (Ia) mechanism is suggested, on the basis of the activation parameters obtained for both the forward and reverse reactions and the corresponding volume profile. The second substitution step remained to proceed through an I(d) or D mechanism (acidified MeOH DeltaV(II) = +9.2 +/- 0.2 cm(3) mol(-1); acidified EtOH DeltaV(II) = +10.2 +/- 0.2 cm(3) mol(-1)). The first substitution reaction in DMSO was found to be slowed by several orders of magnitude and to follow an associative interchange mechanism (DeltaS = -50 +/- 9 J K(-1) mol(-1), DeltaV(I) = -1.0 +/- 0.5 cm(3) mol(-1)), making DMSO a suitable solvent for monitoring substitution processes that are extremely fast in aqueous solution.     

含4-乙基吡啶的抗转移NAMI、NAMI-A衍生物的水解动力学及稳定性研究

制备了trans-[RuCl4(DMSO)(4-EtPy)]Na·2DMSO(4-EtPy=4-乙基吡啶)(化合物1)和trans-[RuCl4(DMSO)(4-EtPy)][(4-EtPy)H](化合物2).用UV、NMR研究了化合物在pH 7.40及5.00(0.15 mol·L-1 NaCl,37℃)缓冲液中的水解机理-动力学和溶液稳定性.测得各水解反应表观速率常数、半衰期.研究结果表明:两个化合物的Ⅰ氯、Ⅱ氯及DMSO水解反应机理均与NAMI-A相似,但其各级水解速率比NAMI-A略快,即用4-EtPy取代咪唑环,可加快NAMI-A衍生物的Ⅰ氯、Ⅱ氯及DMSO水解反应速率.在含氮配体相同时,NAMI-A衍生物比相应NAMI衍生物的稳定性稍好.化合物在酸性溶液中的稳定性高于中性溶液.提供了用核磁法定量测定NAMI-A衍生物的水解机理-动力学.