苯并噻唑功能化的金属螯合剂的合成及生物活性

设计、合成了2种苯并噻唑功能化的金属螯合剂:N,N′-双(水杨醛)缩-2,2′-(3-(苯并[d]噻唑-2-基)-1,2-苯基)二氧乙基二胺L1和N,N′-双(水杨醛)缩-2,2′-(4-(苯并[d]噻唑-2-基)-1,2-苯基)二氧乙基二胺L2。并通过比浊度分析、BCA实验、HRP/Amplex Red实验以及MTT实验检测它们的生物活性。发现这2种螯合剂都能有效抑制金属离子(Zn~(2+)、Cu~(2+))诱导的Aβ_(1～40)的聚集,能大幅减少Cu-Aβ加合物产生H_2O_2的量,有效抑制Zn~(2+)、Cu~(2+)诱导Aβ聚集而产生的神经细胞毒性,并大幅提高细胞存活率。作为比较,对非苯并噻唑功能化但螯合部位相同的螯合剂做了相同的生物活性测试,但其生物活性明显比苯并噻唑功能化的金属螯合剂的低。     

Chemoenzymatic Synthesis of Select Intermediates and Natural Products of the Desferrioxamine E Siderophore Pathway

The NIS synthetase family of enzymes responsible for the biosynthesis of siderophores is increasingly associated with bacterial virulence. Proteins in this class represent outstanding potential drug targets, assuming that basic biochemical and structural characterizations can be completed. Towards this goal, we have mated an improved synthesis of the non-commercial amino acid N-hydroxy-N-succinylcadaverine (HSC, 6) with an isothermal titration calorimetry (ITC) assay that profiles the iterative stages of HSC trimerization and macrocyclization by NIS synthetase DesD from Streptomyces coelicolor. HSC synthesis begins with multigram-scale Gabrielle and tert-butyl N-(benzyloxy)carbamate alkylations of 1-bromo-5-chloropentane following prior literature, but the end-game reported herein has two advantages for greater material throughput: (1) hydrogenolysis of benzyl ether and Cbz blocking groups is best accomplished with Pearlman’s catalyst at 40 psi of H₂ and (2) purification of neutral (zwitterionic) HSC is effected by simple flash chromatography over silica gel in MeOH. HSC is subsequently shown to be a substrate for NIS synthetase DesD, which catalyzes three successive amide bond syntheses via adenyl monophosphate ester intermediates. We quantify and present the iterative and overall enzyme kinetic constants associated with formation of the cyclotrimeric siderophore desferrioxamine E (dfoE, 1).     

Syntheses and crystal structures of neutral oxorhenium(V) complexes of N2O2-donor tripodal ligands

The neutral distorted octahedral complexes [ReOCl(L)] {H₂L = N,N-bis(2-hydroxybenzyl)-2-(2-aminoethyl)dimethylamine (H₂had); N,N-bis(2-hydroxybenzyl)-aminomethylpyridine (H₂hap); N,N-bis(2-hydroxybenzyl)-2-(2-aminoethyl)pyridine (H₂hae)} were prepared by the reaction of trans-[ReOCl₃(PPh₃)₂] with a twofold molar excess of H₂L in ethanol. X-ray structure determinations of [ReOCl(had)] (1) and [ReOCl(hap)] (2) were performed, and the structures compared. In both complexes the choride is coordinated trans to the tripodal tertiary amino nitrogen, with a phenolate oxygen trans to the oxo oxygen.     

Efficient and tunable synthesis of new polydentate bifunctional chelating agents using click chemistry

Two novel bifunctional chelating agents, which are bistriazole-based polyaminocarboxylic acids, have been designed and synthesised in high yields. An elegant synthetic approach using the Cu-catalysed azide-alkyne cycloaddition has been developed. This convenient route could be employed for the synthesis of a variety of polydentate bifunctional chelators.     

4,7,10-三(叔丁氧碳酰甲基)-1,4,7,10-四氮杂环十二烷-1-乙酰肼的微波合成

以轮环藤宁为起始原料,依次与溴乙酸叔丁酯,溴乙酸乙酯和水合肼反应合成了一种核磁共振对比剂螯合前体--4,7,10-三(叔丁氧碳酰甲基)-1,4,7,10-四氮杂环十二烷-1-乙酰肼（4）,其结构经¹H NMR, ¹³C NMR, FT-IR和MS(ESI)表征。研究了溶剂、水合肼用量、微波功率和反应时间对4收率的影响。结果表明：乙醇为溶剂,水合肼10 eq.,于400 W微波反应10 min, 4（粉末固体）收率90%。     

Some new Schiff base ligands giving a NNOS coordination sphere and their nickel(II) complexes: Synthesis,characterization and complex formation

Some new tetradentate ligands with a NNOS coordination sphere were prepared and their corresponding nickel(II) complexes were synthesized and characterized by elemental analysis, IR, ¹H NMR, UV–Vis and mass spectrophotometry. The thermodynamic formation constants of the complexes were measured spectrophotometrically, at a constant ionic strength of 0.1 M (NaClO₄) at 25 °C in DMF solvent. The trend of the complex formation for nickel is as follows:     

Synthesis and Antimalarial Activities of New Hybrid Atokel Molecules

The currently spreading resistance of the malaria parasite Plasmodium falciparum to artemisinin-based combination therapies makes an urgent need for new efficient drugs. Aiming to kill artemisinin-resistant Plasmodium, a series of novel hybrid drugs named Atokels were synthesized and characterized. Atokels are based on an 8-amino- or 8-hydroxyquinoline entity covalently bound to a 1,4-naphthoquinone through a polyamine linker. These drugs have been designed to target the parasite mitochondrion by their naphthoquinone moiety reminiscent of the antimalarial drug atovaquone, and to trigger a damaging oxidative stress due to their ability to chelate metal ions in order to generate redox active complexes in situ. The most effective Atokel drug shown a promising antimalarial activity (IC₅₀=622 nm on an artemisinin-resistant P. falciparum strain) and no cytotoxicity at 50 μm indicating a specific antiplasmodial mode of action.     

螯合剂对结合在人血清白蛋白(HSA)上的铜离子活动化能力的研究

用凝胶色谱法研究了螯合剂使结合在人血清白蛋白上的铜(Ⅱ)活动化的能力,若用在螯合剂存在时和无螯合剂存在时蛋白部分结合金属量之比作为表征活动化能力的参数,有如下顺序:Trien>DTPA>EDTA>EGTA>NTA>IDA除Trien和DTPA外,其他几种螯合剂的活动化能力的对数值与其相应的条件稳定常数的对数值之间有一线性关系.Trien和DTPA的反常被认为与复杂的反应历程有关,这可能涉及三元配合物的形成。     

Anion directed templated synthesis of mono- and di-Schiff base complexes of Ni(II)

Two sets of Schiff base ligands, set-1 and set-2 have been prepared by mixing the respective diamine (1,2-propanediamine or 1,3-propanediamine) and carbonyl compounds (2-acetylpyridine or pyridine-2-carboxaldehyde) in 1:1 and 1:2 ratios, respectively and employed for the synthesis of complexes with Ni(II) perchlorate and Ni(II) thiocyanate. Ni(II) perchlorate yields the complexes having general formula [NiL₂](ClO₄)₂ (L = L¹ [N¹-(1-pyridin-2-yl-ethylidine)-propane-1,3-diamine] for complex 1, L² [N¹-pyridine-2-ylmethylene-propane-1,3-diamine] for complex 2 or L³ [N¹-(1-pyridine-2-yl-ethylidine)-propane-1,2-diamine] for complex 3) in which the Schiff bases are mono-condensed terdentate whereas Ni(II) thiocyanate results in the formation of tetradentate Schiff base complexes, [NiL](SCN)₂ (L = L⁴ [N,N′-bis-(1-pyridine-2-yl-ethylidine)-propane-1,3-diamine] for complex 4, L⁵ [N,N′-bis(pyridine-2-ylmethyline)-propane-1,3-diamine] for complex 5 or L⁶ [N,N′-bis-(1-pyridine-2-yl-ethylidine)-propane-1,2-diamine] for complex 6) irrespective of the sets of ligands used. Formation of the complexes has been explained by anion modulation of cation templating effect. All the complexes have been characterized by elemental analyses, spectral and electrochemical results. Single crystal X-ray diffraction studies confirm the structures of four representative members, 1, 3, 4 and 5; all of them have distorted octahedral geometry around Ni(II). The bis-complexes of terdentate ligands, 1 and 3 are the mer isomers and the complexes of tetradentate ligands, 4 and 5 possess trans geometry.     

利用钴-氨基硫脲类配合物作为氧化还原催化剂光分解水制备氢气

通过将磷配体与氨基硫脲结合进一步增加螯合配体的配位能力,并引入磺酸根增强其水溶性,合成了一个钴配合物Co-NSP(配体HNSP:4-[2-(2-二苯基膦-苯烯基)-氨基硫脲腙]苯甲酸),利用其氧化还原特性开展均相体系的光驱动从水中制备氢气的研究。新的NSP三齿配体能够稳定低价的金属中心,有助于提升催化剂的催化性能。利用其与荧光素所构筑的光催化体系,在电子牺牲剂三乙胺存在下显示出良好的性能,光照6h其TON(turnover number)可达2000molH₂每摩尔催化剂。为了研究和比较其性能特点,对这一光催化体系的荧光滴定和氧化还原性能也进行了较细致的研究。