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.     

配体结构对NAMI-A衍生物水解机理、速度的影响

制备并用紫外-可见分光光度法研究了trans-[RuCl₄(DMSO)(N-EtIm)][(N-EtIm)H](N-EtIm=N-乙基咪唑)(化合物1)在pH=7.40及5.00,0.15 mol·L^-1 NaCl,37 ℃溶液中的水解机理及动力学。化合物1在pH=7.40的缓冲溶液中发生两步水解脱氯反应(Ⅰ氯水解及Ⅱ氯水解)(分步反应),最终溶液颜色变深形成聚合物。在pH=5.00缓冲溶液中二甲基亚砜(DMSO)水解。其Ⅰ氯、Ⅱ氯水解及DMSO水解反应皆为零级反应。测定了各水解反应表观速率常数K_obs及半衰期t_1/2。化合物1的Ⅰ氯及Ⅱ氯水解反应与NAMI-A相似,而且各水解速度也相差不大,即将推电子的乙基引入咪唑环,对NAMI-A的Ⅰ氯、Ⅱ氯及DMSO水解反应速度影响较小。化合物在酸性溶液中的稳定性明显高于中性溶液。     

配体结构对含2-甲基咪唑及N-乙基咪唑的NAMI 衍生物水解及溶液稳定性的影响

制备并用UV、循环伏安(CV)和NMR 法研究了NAMI(新抗肿瘤转移抑制剂, trans-[RuCl₄(DMSO)(imidazole)]Na·2DMSO)衍生物trans-[RuCl₄(DMSO)(2-MeIm)]Na·2DMSO (2-MeIm＝2-甲基咪唑, 化合物1)和trans-[RuCl₄(DMSO)-(N-EtIm)]Na·2DMSO (N-EtIm＝N-乙基咪唑, 化合物2)的水解机理-动力学、溶液稳定性和电化学性质. 化合物1 和化合物2 与NAMI 相似, 在pH 7.40 的缓冲溶液中发生两步脱氯水解反应(I 氯水解及II 氯水解) (分步反应); 在酸性溶液(pH 5.00)中脱DMSO 水解. 通过线性拟合得到各水解反应速率常数k_obs 及半衰期t_1/2. 结果表明化合物在酸性溶液中的稳定性相对较高. 在NAMI 衍生物咪唑环的N 位引入乙基比在2 位引入甲基生成的化合物稳定. 含氮配体相同时,NAMI-A(新抗肿瘤转移抑制剂, A: 该系列中的第一个化合物, trans-[RuCl₄(DMSO)(imidazole)][Himidazole])衍生物略比相应的NAMI 衍生物稳定.     

含甲基咪唑的抗肿瘤转移NAMI-A衍生物的水解和电化学性质

合成了trans-[Rucl4 (DMSO) (4-MeIm)][(4-MeIm)H]·HCl(4-MeIm=4-甲基咪唑)(1)和trans-[Rucl4 (DMSO)(N-MeIm)][(N-MeIm)H](N-MeIm=N-甲基咪唑)(2).通过紫外-可见光谱、核磁共振谱和循环伏安法研究了配体结构(4-甲基咪唑,...     

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.     

NAMI-A乙基取代衍生物水解机理的DFT研究

采用密度泛函理论(DFT)方法,并结合导体极化连续模型(CPCM)研究了[(N-EtIm)H][trans-RuⅢCl4(DMSO)(N-EtIm)](N-EtIm=N-乙基咪唑)分别在中性及酸性条件下的水解反应过程.同时,为提高溶剂化能的精确度,在中性条件下水解反应的计算中采用3个水分子的溶剂化模型.计算得到水解反应过程中相应的结构特征和详细的热力学能量及速率常数.首先,在中性条件下,对于第一步水解,液相中配合物的活化能垒为109.9kJ/mol,速率常数为3.3×10-7 s-1,与实验中测得的第一步水解反应的速率常数(4.4×10-7 s-1)一致.对于第二步水解,反应的活化能垒为117.9kJ/mol,这符合实验中观察到的第二步水解比第一步水解反应慢的现象.其次,计算结果表明,酸性条件下,DMSO基团易于水解,Cl-水解困难,这也与实验结果相吻合.     

取代锰卟啉的轴向配位反应及平衡常数的测定

研究了4种具有不同取代基的锰卟啉在三氯甲烷溶剂中与咪唑(Im)、4-甲基咪唑(4-MeIm)、吡啶(Py)、4-甲基吡啶(4-MePy)等4种客体小分子的轴向配位反应,并采用微量紫外-可见光谱滴定法测定了反应的平衡常数。结果表明:每种锰卟啉均可以与咪唑及吡啶类客体分子发生轴向配位反应,轴向配合物的形成能力和稳定性与锰卟啉所含有的取代基有关,在β位上含有强吸电子硝基取代基的锰卟啉与客体分子能够形成更稳定的配合物;客体分子的性质对轴向配合物的形成也有显著的影响,锰卟啉与吡啶以物质的量之比为1∶1反应生成五元配位化合物;每一种锰卟啉与其他3种客体分子均以物质的量之比为1∶2反应生成六元配位化合物。客体的轴向配位反应能力由大到小依次为Im、4-MeIm、4-MePy、Py。     

氮杂环卡宾的合成及在氢转移反应中的应用

利用氯甲基吡啶与咪唑反应制备了一系列含吡啶取代咪唑L1～L5,考察了所得咪唑衍生物与钌化合物在碱性条件下原位形成的氮杂卡宾钌络合物对苯胺与醇氢转移反应的催化活性.研究了碱的种类、钌前体、温度等对反应的影响,结果表明RuCl3 H2O/1-(2-吡啶甲基)-3-甲基碘化咪唑(L3)/KOH催化体系在185℃时对苯胺与乙二醇反应的催化活性较高,选择性生成N-羟乙基苯胺,TON(单位活性转化的底物分数)可达2130.此外,还考察了RuCl3 H2O/L3/KOH催化体系对苯胺与丁醇、环己醇、异丙醇、苯甲醇反应的催化性能.在催化剂作用下,醇与苯胺可形成亚胺及仲胺,伯醇可以自氢转移反应形成酯,反应产物的结构及选择性取决于醇的结构及反应条件.     

新型吡啶基修饰的尾式卟啉的合成及性质

报道了一种新型尾式锌卟啉(o-PyOC₆H₁₂OTPPZn)的合成及表征, 采用紫外-可见光谱滴定法对该化合物与5种吡啶类小分子间的轴向配位反应的热力学性质进行了研究. 轴配体系的热力学数据显示, 5种吡啶类配体的平衡常数按K(4-MePy)>K(Py)>K(3-MePy)>K(2,4,6-triMePy)>K(2-MePy)依次减小, 吡啶类小分子对主体的配位能力按4-MePy>Py>3-MePy>2,4,6-triMePy>2-MePy依次减弱, 同时分子模拟的理论研究得到了与实验完全一致的结果. 通过Z-扫描实验对该化合物的非线性光学性质的研究表明, 该样品具有较强的反饱和吸收特征.     

含C16长碳链1，2－邻二萘醌－2－肟钌（Ⅱ）配合物的合成

通过三种构型的1，2－邻二萘醌－2－肟（2－nqo)钌（Ⅱ）羰基配合物trans, cis－（Ru(2-nqo)2(CO)2](1){(trans-NO,cis-O},cis-,trans-[Ru(2-nqo)2(CO)2] (2){cis-NO,trans-O}及cis,-cis-[Ru(2-nqo)2(CO)2](3){(cis-NO,cis-O)}的去羰 基取代反应，合成了含C16长碳链2-nqo钌（Ⅱ）配合物trans-,cis-[Ru(2-nqo)2 (CO)(spy)](4),cis-,trans-(Ru(2-nqo)2(CO)(spy)(5),cis-,cis-[Ru(2-nqo)2 (CO)(spy)](6)及trans-,trans-(Ru(2-nqo)2(spy)2](7){(trans-NO,trans-O)}。 对其进行了红外、紫外－可见质谱及核磁人振测试，并利用^1H-^1H偶合二维核磁 技术对核磁共振峰进行了指认。     

SYNTHESIS,ELECTROCHEMICAL CHARACTERIZATION AND POTENTIOMETRIC TITRATION of trans-[RuCl2(L)4] COMPLEXES (L ˭ PYRIDINE DERIVED LIGANDS: 3-PYRIDINECARBOXYLIC ACID AND 4-PYRIDINECARBOXYLIC ACID)

Abstract

In this work we report the synthesis, spectroscopic characterization, potentiometric titration and electrochemical studies performed on trans-[RuCl₂(nic)₄] (1) and trans-[RuCl₂(i-nic)₄] (II) complexes, where nic = 3-pyridinecarboxylic acid and i-nic = 4-pyridinecarboxylic acid. The complexes were synthesized using a ruthenium blue solution as a precursor in the synthetic route, and characterized by electronic spectroscopy, vibrational FT-IR spectroscopy, and ¹H and ¹³C NMR. The results indicated a trans geometry. Cyclic voltammetry performed in water/ acetone (1:1) solution revealed a quasi-reversible process centered on the Ru(II) species and a dependence of the redox potential, E _1/2, on the pH. The electronic spectra showed that the MLCT bands were also affected by the pH, undergoing a hypsochromic shift (blue shift) as the pH increased. The spectroelectrochemical analysis indicated that the bands in the visible region progressively faded as new UV bands emerged during the oxidation process. The equilibrium constants for trans-[RuCl₂(nic)₄] and trans-[RuCl₂(i-nic)₄] were determined by potentiometric titration, indicating that protonic species dominated at pH values lower than 2.6, whereas non-protonic species dominated at pH values higher than 5.0.     

Cobalt(II) complexes with pyridine and 5-[(E)-2-(aryl)-1-diazenyl]-quinolin-8-olates: synthesis,electrochemistry and X-ray structural characterization

Abstract

Nine new cobalt(II) compounds, trans-[Co(L^PAQ)₂(Py)₂] (1), trans-[Co(L^PAQ)₂(3-MePy)₂] (2), trans-[Co(L^MeAQ)₂(Py)₂] (3), trans-[Co(L^OMeAQ)₂(Py)₂] (4), trans-[Co(L^OEtAQ)₂(Py)₂]·2(H₂O) (5), trans-[Co(L^CAQ)₂(Py)₂] (6), trans-[Co(L^BAQ)₂(Py)₂] (7), cis-[Co(L^BAQ)₂(3-MePy)₂] (8a) and trans-[Co(L^BAQ)₂(3-MePy)₂]·2(3-MePy) (8b) (primary ligand: L^XAQ?=?substituted 5-[(E)-2-(aryl)-1-diazenyl]quinolin-8-olate; secondary ligands: Py?=?pyridine, 3-MePy = 3-methylpyridine), have been synthesized and characterized by elemental analysis, IR and UV-vis spectroscopy. Magnetic measurements of the cobalt compounds were performed in solution by ¹H NMR spectroscopy using the Evans’ method while their redox properties were studied by cyclic voltammetry. Single-crystal X-ray diffraction analysis of the compounds revealed their octahedral geometries and trans configuration, except for 8a, which has a cis configuration. Intermolecular noncovalent interactions were detected, π···π interactions in 5, C?–?H···π interactions in 2 and C?–?H···π edge-to-face (T-shaped) arrangements in 3, 4, 6, and 7.     

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.     

α-Synuclein as a Target for Metallo-Anti-Neurodegenerative Agents

The unique thermodynamic and kinetic coordination chemistry of ruthenium allows it to modulate key adverse aggregation and membrane interactions of α-synuclein (α-syn) associated with Parkinson's disease. We show that the low-toxic Ru^III complex trans-[ImH][RuCl₄(Me₂SO)(Im)] (NAMI-A) has dual inhibitory effects on both aggregation and membrane interactions of α-syn with submicromolar affinity, and disassembles pre-formed fibrils. NAMI-A abolishes the cytotoxicity of α-syn towards neuronal cells and mitigates neurodegeneration and motor impairments in a rat model of Parkinson's. Multinuclear NMR and MS analyses show that NAMI-A binds to residues involved in protein aggregation and membrane binding. NMR studies reveal the key steps in pro-drug activation and the effect of activated NAMI-A species on protein folding. Our findings provide a new basis for designing ruthenium complexes which could mitigate α-syn-induced Parkinson's pathology differently from organic agents.     

Synthesis and DFT calculations of new ruthenium(II) nitrosyl complexes using cis-fac-dichlorotetrakis(dimethylsulfoxide)ruthenium(II) precursor and different oximes as sources of nitrosyl ligand

Abstract

Three NO⁺-ruthenium(II) complexes were prepared by using cis-[RuCl₂(DMSO)₄] as precursor, P, and the compounds benzohydroxamic acid (BHA), 1′, anti-diphenylglyoxime (H₂dpg), 2′, and dimethylglyoxime (H₂dmg), 3′, as sources of NO moiety. The three complexes [RuCl₂(DMSO)₃(NO)]⁺(BA)^?, 1, [RuCl₂(DMSO)₃(NO)]⁺(Hdpg)^?, 2, and [RuCl₂(DMSO)₃(NO)]⁺(Hdmg)^?, 3, were characterized by (FT-IR, NMR, UV-Vis) spectroscopy, thermogravimetry, and microanalysis. From FT-IR spectral data, two modes of coordination of DMSO to Ru atom through both S and O atoms were detected for 1 and 2. For 3, only S coordination was reported. Computational studies on the [RuCl₂(DMSO)₃(NO)]⁺ cationic parts, 1″, 2″ and 3″, of the investigated complexes 1, 2 and 3 were carried out by DFT. The molecular geometry and mode of attachment of Ru(II) with DMSO were performed with the B3LYP/LANL2DZ level of theory and basis set. Theoretical to the experimental agreement was achieved for analysis of IR data of the investigated complexes. Additional information about binding between the ruthenium atom and the DMSO ligand has been obtained by NBO analysis.     

Driving forces in substitution reactions of octahedral complexes: The influence of the competitive effect

The reaction of cis-[RuCl₂(P–P)(N–N)] type complexes (P–P = 1,4-bis(diphenylphosphino)butane or (1,1′-diphenylphosphino)ferrocene; N–N = 2,2′-bipyridine or 1,10-phenantroline) with monodentate ligands (L), such as 4-methylpyridine, 4-phenylpyridine and benzonitrile forms [RuCl(L)(P–P)(N–N)]⁺ species. Upon characterization of the isolated compounds by elemental analysis, ³¹P{¹H} NMR and X-ray crystallography it was found out that the type of the L ligand determines its position in relation to the phosphorus atom. While pyridine derivatives like 4-methylpyridine and 4-phenylpyridine coordinate trans to the phosphorus atom, the benzonitrile ligand (bzCN), a good π acceptor, coordinates trans to the nitrogen atom. A ³¹P{¹H} NMR experiment following the reaction of the precursor cis-[RuCl₂(dppb)(phen)] with the benzonitrile ligand shows that the final position of the entering ligand in the complex is better defined as a consequence of the competitive effect between the phosphorus atom and the cyano-group from the benzonitrile moiety and not by the trans effect. In this case, the benzonitrile group is stabilized trans to one of the nitrogen atoms of the N–N ligand. A differential pulse voltammetry experiment confirms this statement. In both experiments the [RuCl(bzCN)(dppb)(phen)]PF₆ species with the bzCN ligand positioned trans to a phosphorus atom of the dppb ligand was detected as an intermediate complex.