【作者】 王强；

【导师】 毕彩丰； 范玉华；

【作者基本信息】 中国海洋大学 ， 海洋化学工程与技术， 2011， 博士

【摘要】 氨基酸是重要的生理活性物质,是构成生物体内蛋白质、酶等的基本结构单元,在生物体内参与多种生物化学过程。氨基酸希夫碱及其配合物具有抗病毒、抑菌、抗癌等生物活性和较好的载氧、催化性能,在农业、医学、催化、材料、生物科学等领域具有广泛的应用前景,已受到人们的广泛关注。因此,通过反应引入其它不同结构和活性的基团,从而合成出新的氨基酸希夫碱配体及其金属配合物,研究其结构、性质与生物活性,对指导配合物的合成与应用具有重要意义。本文选择活泼羰基化合物与L-蛋氨酸缩合得到了5个系列希夫碱配体,将这些配体与金属离子反应得到了80种新型的的希夫碱配合物,培养了两个希夫碱配合物的单晶。采用元素分析、热分析、核磁共振氢谱等方法对其结构进行了表征,推断出粉末状金属配合物可能的化学结构;采用X-射线单晶衍射测出了单晶的精细结构;对配体及其配合物进行了荧光光谱分析;并对部分配合物与DNA的作用方式进行了研究;研究了铜配合物的抗肿瘤活性。主要工作如下:（1）合成了邻香草醛缩蛋氨酸希夫碱（KHL¹）及其配合物,培养了配位聚合物{[CuL¹（H₂O）₂]·[CuL¹（H₂O）]₃·4H₂O}_n和四核配合物[Cd₄（L¹）₄（H₂O）₂]·3H₂O的单晶。单晶结构分析表明:配合物{[CuL¹（H₂O）₂]·[CuL¹（H₂O）]₃·4H₂O}_n,属三斜晶系,空间点群Pī。晶胞参数为a =5.2027（5）（?）,b = 16.6916（16）（?） ,c = 20.237（2）（?）,α= 88.895（10）°,β= 84.127（1）°,γ=83.577（10）°,V = 1737.2（3）（?）³,F（000） = 848,Dc = 1.561 g/cm³, R₁ = 0.0760,wR₂ = 0.2095。该配合物属于配位聚合物,整个分子包含两个独立单元,且处于不同的配位环境。独立单元一由1个铜离子、2个配位水分子及1个希夫碱配体所组成,Cu（1）离子具有稍畸变的四方锥体配位几何。独立单元二是通过羧基桥连而成的链状聚合物, Cu（2）离子具有扭曲的四方锥体配位几何结构。配合物[Cd₄（L¹）₄（H₂O）₂]·3H₂O,属单斜晶系,空间点群P2（1）/c,晶胞参数为a = 22.035（2） （?）,b = 14.362（6） （?） ,c = 20.237（2）（?）,α= 90°,β=104.8940（10）°,γ=90°,V = 7037（?）³,F（000） = 3416,Dc = 1.605 g/cm³, R₁ = 0.1993, wR₂ = 0.4536。镉配合物分子由4个镉离子、2个配位水分子、4个希夫碱配体和3个未配位水分子所组成四核分子,整个分子通过O–H…O氢键的相互作用形成了二维网状结构。其余8种配合物的可能组成分别为:[ML¹（H₂O）₂]·nH₂O （M=Zn、Co、Ni, n=1; M=Mn, n=2）、[LnL¹ （NO₃）（H₂O）₂]·nH₂O （Ln=La、Pr, n=1; Ln= Sm、Yb, n=2 ）。（2）合成了2-羟基-1萘甲醛缩蛋氨酸希夫碱（KHL²）及其配合物,配合物的可能组成分别为:[ML²（H₂O）₂]·nH₂O （M=Zn, n=0; M= Cu、Mn, n=1; M= Co、Ni, n=2）, [LnL²（NO₃）（H₂O）₂]·nH₂O （Ln=Er、Sm, n=1; Ln=La、Pr, n=2）, [YbL²（NO₃）（H₂O）₂]·2CH₃OH (L² = C₁₆H₁₅NO₃S)。（3）合成了吡啶-2-甲醛缩蛋氨酸希夫碱（KL³）及其配合物,配合物的可能组成分别为:[M（L³）₂]·nH₂O （M= Mn, n=0; M=Ni、Zn, n=1; M= Co、Cu, n=3）, [LnL³（NO₃）₂]·nH₂O （Ln=La、Sm, n=1; Ln=Yb, n=2; Ln=Er、Pr, n=3）, [M（Phen）L³]·Ac·nH₂O （M=Co、Cu, n=1; M=Ni、Zn, n=2; M=Mn, n=3）, [Ln（Phen）（NO₃）L³]·NO₃·nH₂O （Ln=La、Sm, Er, n=2; Ln= Pr、Yb, n=3） (L³ = C₁₁H₁₃N₂O₂S, Phen = 1,10-Phenanthroline, Ac = CH₃COO)。（4）合成了噻吩-2-甲醛缩蛋氨酸希夫碱（KL⁴）及其20种金属配合物,配合物的可能组成分别为:[M（L⁴）₂（H₂O）₂]·nH₂O （M= Co、Cu, n=1; M=Ni, n=2; M=Zn、Mn, n=3）, [LnL⁴（NO₃）₂（H₂O）]·nH₂O （Ln=Er, n=0; Ln=La、Sm, n=2; Ln=Pr, Yb, n=3）, [ML⁴（Phen）（H₂O）]·Ac·nH₂O （M=Co、Cu, Ni, n=2; M=Zn、Mn, n=3）, [LnL⁴（Phen）（NO₃）（H₂O）]·NO₃·nH₂O （Ln=Sm、Pr、Yb, n=1; Ln=La、Er, n=2） (L⁴ = C₁₀H₁₂NO₂S₂, Phen = 1,10-Phenanthroline, Ac = CH₃COO)。（5）合成了2-乙酰基吡啶缩蛋氨酸希夫碱（KL⁵）及其配合物,配合物的可能组成分别为:[M（L⁵）₂]·nH₂O （M= Zn, n=1; M= Cu、Ni、n=2; M= Co、Mn, n=3）, [LnL⁵（NO₃）₂]·nH₂O （Ln=Sm、Yb, n=2; Ln=La、Er、Pr, n=3） , [M（Phen）L⁵]·Ac·nH₂O （M=Cu, n=0; M=Co、Mn, n=2; M=Ni、Zn, n=3）, [Ln（Phen）（NO₃）L⁵]·NO₃·nH₂O （Ln=Pr、Yb, n=1; Ln=La、Sm、Er, n=2） (L⁵ = C₁₂H₁₅N₂O₂S, Phen = 1,10-Phenanthroline, Ac = CH₃COO) (L⁵ = C₁₂H₁₅N₂O₂S, Phen = 1,10-Phenanthroline, Ac = CH₃COO )。（6）利用Achar法和Coats-Redfern法,对配合物进行了热分解动力学处理,得出了相关的动力学方程及动力学参数。（7）测定了配合物的荧光光谱,比较了其荧光特性。初步研究结果显示:配合物[ZnL¹（H₂O）₂]·H₂O、[ZnL²（H₂O）₂]、[LaL²（NO₃）（H₂O）₂]·2H₂O、[PrL²（NO₃）（H₂O）₂]·2H₂O、[Zn（L³）₂]·H₂O、[LaL³（NO₃）₂]·H₂O、[Zn（L⁴）₂（H₂O）₂]·3H₂O、[LaL⁴（NO₃）₂（H₂O）]·2H₂O、[Zn（L⁵）₂]·H₂O、[LaL⁵（NO₃）₂]·3H₂O、[SmL⁵（NO₃）₂]·2H₂O、[PrL⁵（NO₃）₂]·3H₂O具有较好的荧光性质,它们与对应的配体相比,配合物的激发峰和发射峰位置均发生了一定程度的兰移或红移,且相对荧光强度明显增强,是配体的2～3倍。（8）研究了Cu（Ⅱ）配合物[CuL²（H₂O）₂]·H₂O、[CuL⁴（Phen）（H₂O）]·Ac·2H₂O ,Zn（Ⅱ）配合物[Zn（L³）₂]·H₂O分别与鱼精DNA之间的作用模式。实验结果显示:配合物[CuL²（H₂O）₂]·H₂O、[CuL⁴（Phen）（H₂O）]·Ac·2H₂O与DNA发生了插入作用,配合物[Zn（L³）₂]·H₂O与DNA发生了静电作用。配合物中配体的共平面性越好、平面面积越大、空间位阻越小,其与DNA作用越显著,越有利于其以插入方式与DNA发生相互作用。（9）对合成的16种铜、锌希夫碱配合物,采用MTT法进行抗肿瘤活性筛选,得到对前列腺癌PC-3细胞增殖具有较好抑制作用的2种铜配合物[CuL²（H₂O）₂]·H₂O、CuL⁴（Phen）（H₂O）]·Ac·2H₂O。对CuL⁴（Phen）（H₂O）]·Ac·2H₂O、CuL²（H₂O）₂]·H₂O的进一步抗肿瘤活性研究发现:这两种配合物对前列腺癌PC-3细胞内的内糜蛋白酶体有较强的抑制作用,其抑制能力与配合物的使用浓度和作用时间正相关;并且前者的抑制效果优于后者。更重要的发现是金属配合物的抗肿瘤活性的差异与金属离子的选择及配体的结构密切相关,对于同一配体,铜配合物的抗肿瘤活性优于锌配合物。此外,共平面性好、空间位阻小、含杂原子的配体所形成的金属配合物抗肿瘤活性效果更佳。更多还原

【Abstract】 Amino acids are important physiological active substance. They are the basic structural unit of the protein and enzyme in many living organisms and involve in various biochemical processes in vivo. Amino acids Schiff base and their metal complexes have been proved having such biological activities as anti-virus, antibacterial, anti-cancer, and they have also good oxygen-carrying and catalytic properties. At the same time they have a wide range of applications such as agriculture, medicine, catalysis, materials, biological science and so on, which have received extensive attention by the people. Therefore, the synthesis of many novel amino acid Schiff bases and their metal complexes through the introduction of some other groups with different structures and activities by the chemical reaction, and the studies such as structures, properties and bioactivities, which is very significant for guiding the synthesis and application of complexs.In this paper, carbonyl compounds with multiple structures have been used to react with L-methionine to synthesize five novel Schiff base ligands, at the same time, eighty coordination compounds of transition ions or rare earth ions with these ligands have been prepared. All these complexes are the first time reported by the author. The single crystals of two coordination compounds have been also obtained. These ligands and complexes were characterized by elemental analysis, TG-DTG analysis, 1HNMR, and so on. The suggested structures of the powder of metal complexes were concluded. The fine structures of two single crystals were detected by X-ray crystal diffraction. Fluorescence properties of Schiff base ligands and their complexes have been studied. The mode of interaction between part complexes and DNA has been tested, too. The inhibition and inducing apoptosis of the amino acid Schiff base copper complexes on tumor cells have been also studied by targeting the cellular proteasome. The main works of the article are as follows:（1） Ten metal complexes with Schiff base ligand （KHL¹） derived from O-vanillin and methionine were synthesized. The single crystals of coordination polymer {[CuL¹（H₂O）₂]·[CuL¹（H₂O）]₃·4H₂O}_n and tetranuclear coordination complex [Cd₄（L¹）₄（H₂O）₂]·3H₂O have been also obtained. Crystal structure showed that:The crystal of [CuL¹（H₂O）₂]·[CuL¹（H₂O）]₃·4H₂O}_n belongs to the triclinic crystal system, space group Pīwith the cell parameter a =5.2027（5）（?）, b = 16.6916（16）（?）, c = 20.237（2）（?）,α= 88.895（10）°,β= 84.127（1）°,γ=83.577（10）°, V = 1737.2（3）（?）³, F（000） = 848, Dc = 1.561 g/cm³, R₁ = 0.0760, wR₂ = 0.2095. The title copper （Ⅱ） complex is a kind of coordination polymer, which contains two independent units with different coordination environments. The independent unit 1 consists of one copper ion, two uncoordinated water molecules and one Schiff base ligand and the Cu （1） has a slightly distorted square pyramidal coordination geometry. On the other hand, the independent unit 2 is a one-dimensional chain coordination polymer bridged by carboxyl, and the Cu （2） possess coordination geometry as similar as the Cu （1）. The crystal of [Cd₄（L¹）₄（H₂O）₂]·3H₂O belongs to the monoclinic crystal system, space group P2（1）/c with the cell parameter a = 22.035（2） （?）, b = 14.362（6） （?）, c = 20.237（2）（?）,α= 90（?）,β=104.8940（10）°,γ=90°, V = 7037（?）³, F（000） = 3416, Dc = 1.605 g/cm³, R₁ = 0.1993, wR₂ = 0.4536. The [Cd₄（L¹）₄（H₂O）₂]·3H₂O is a tetranuclear coordination complex consisting of four Cd （Ⅱ） ions, two coordinated water molecules, four Schiff base ligands, and three uncoordinated water molecules. A two-dimensional network of molecule is formed by the interaction of the intramolecular and intermolecular hydrogen bonds （O-H…O）.The possible chemical compositions of the remaining eight metal complexes are confirmed to be: [ML¹（H₂O）₂]·nH₂O （M=Zn,Co,Ni, n=1; M=Mn, n=2）, [LnL¹ （NO₃）（H₂O）₂]·nH₂O （Ln=La,Pr, n=1; Ln= Sm,Yb, n=2 ） （where L¹ = C13H15NO4S）.（2） Ten metal complexes with Schiff base ligand （KHL²） derived from 2-hydroxy-1-naphthaldehyde and methionine were synthesized. The possible chemical compositions of these complexes are confirmed to be: [ML²（H₂O）₂]·nH₂O （M=Zn, n=0; M=Cu, Mn, n=1; M=Co, Ni, n=2）, [LnL²（NO₃）（H₂O）₂]·nH₂O （Ln=Er, Sm, n=1; Ln=La, Pr, n=2）, [YbL²（NO₃）（H₂O）₂]·2CH₃OH (where L² = C₁₆H₁₅NO₃S).（3） Twenty metal ions complexes with Schiff base ligand （KL³） derived from pyridine-2-formaldehyde and methionine were synthesized. The possible chemical compositions of these complexes are confirmed to be: [M（L³）₂]·nH₂O （M= Mn, n=0; M=Ni, Zn, n=1; M= Co, Cu, n=3）, [LnL³（NO₃）₂]·nH₂O （Ln=La, Sm, n=1; Ln=Yb, n=2; Ln=Er, Pr, n=3）, [M（Phen）L³]·Ac·nH₂O （M=Co, Cu, n=1; M=Ni, Zn, n=2; M=Mn, n=3）, [Ln（Phen）（NO₃）L³]·NO₃·nH₂O （Ln=La, Sm, Er, n=2; Ln= Pr, Yb, n=3） (where L³ = C₁₁H₁₃N₂O₂S, Phen = 1,10-Phenanthroline, Ac = CH₃COO).（4） Twenty metal complexes with Schiff base ligand （KL⁴） derived from thiophene-2-formaldehyde and methionine were synthesized. The possible chemical compositions of these complexes are confirmed to be: [M（L⁴）₂（H₂O）₂]·nH₂O （M= Co, Cu, n=1; M=Ni, n=2; M=Zn, Mn, n=3）, [LnL⁴（NO₃）₂（H₂O）]·nH₂O （Ln=Er, n=0; Ln=La, Sm, n=2; Ln=Pr, Yb, n=3）, [ML⁴（Phen）（H₂O）]·Ac·nH₂O （M=Co, Cu, Ni, n=2; M=Zn, Mn, n=3）, [LnL⁴（Phen）（NO₃）（H₂O）]·NO₃·nH₂O （Ln=Sm, Pr, Yb, n=1; Ln=La, Er, n=2） (where L⁴ = C₁₀H₁₂NO₂S₂, Phen = 1,10-Phenanthroline, Ac = CH₃COO).（5） Twenty metal complexes with Schiff base ligand （KL⁵） derived from 2-acetyl pyridine and methionine were synthesized. The possible chemical compositions of these complexes are confirmed to be: [M（L⁵）₂]·nH₂O （M= Zn, n=1; M= Cu, Ni, n=2; M= Co, Mn, n=3）, [LnL⁵（NO₃）₂]·nH₂O （Ln=Sm, Yb, n=2; Ln=La, Er, Pr, n=3） , [M（Phen）L⁵]·Ac·nH₂O （M=Cu, n=0; M=Co, Mn, n=2; M=Ni, Zn, n=3）, [Ln（Phen）（NO₃）L⁵]·NO₃·nH₂O （Ln=Pr, Yb, n=1; Ln=La, Sm, Er, n=2） (where L⁵ = C₁₂H₁₅N₂O₂S, Phen = 1,10-Phenanthroline, Ac = CH₃COO ).（6） Combinating Achar differential and Coats-Redfern integral method were used to process non-isothermal decomposition kinetics of part of the complexes. The kinetic equations and kinetic parameters of thermal decomposition of the complex in some step were obtained.（7） Fluorescence spectra of all ligands and part of their metal ions complexes were detected. Meanwhile, the related fluorescence properties were studied. The experimental results show that these complexes such as [ZnL¹（H₂O）₂]·H₂O, [ZnL²（H₂O）₂], [LaL²（NO₃）（H₂O）₂]·2H₂O, [PrL²（NO₃）（H₂O）₂]·2H₂O, [Zn（L³）₂]·H₂O, [LaL³（NO₃）₂]·H₂O, [Zn（L⁴）₂（H₂O）₂]·3H₂O, [LaL⁴（NO₃）₂（H₂O）]·2H₂, [Zn（L⁵）₂]·H₂O, [LaL⁵（NO₃）₂]·3H₂O, [SmL⁵（NO₃）₂]·2H₂O, [PrL⁵（NO₃）₂]·3H₂O have good fluorescence effects. Compared with the corresponding ligand, the excitation and emission peaks of these complexes have shifted to some range. Besides, their fluorescence intensity enhanced significantly, which are two or three times as strong as that of the ligand.（8） The interaction between complexes [CuL²（H₂O）₂]·H₂O, [Zn（L³）₂]·H₂O and [CuL⁴（Phen）（H₂O）]·Ac·2H₂O with Sperm DNA was studied. The experimental results suggest that the interaction modes of [CuL²（H₂O）₂]·H₂O and [CuL⁴（Phen）（H₂O）]·Ac·2H₂O with deoxyribonucleic acid are intercalation. However, the interaction of [Zn（L³）₂]·H₂O with deoxyribonucleic acid belongs to static electricity attraction mode. It has been demonstrated that when ligand has more co-planar, wider flat area and smaller steric hindrance, its interaction with DNA is more significant, simultaneously, ligand is more favorable to interact with DNA in the way of insertion.（9） The antiproliferaion activities of sixteen Schiff base copper（Ⅱ）, zinc（Ⅱ） complexes were studied by 3-[4,5-dimethyltiazol-2-yl]-2,5-diphenyl-tetrazolium bromide （MTT method） in prostate cancer PC-3 cells. It was found that [CuL²（H₂O）₂]·H₂O and CuL⁴（Phen）（H₂O）]·Ac·2H₂O showed the higher antiproliferation activities than other complexes. So CuL²（H₂O）₂]·H₂O and CuL⁴（Phen）（H₂O）]·Ac·2H₂O were chosen for further anticancer studies and it turned out to be that they could inhibit proteasome activity and induce apoptosis in prostate cancer PC-3 cells in a concentration- and time-dependent manner. In addition, antiproliferation activity of CuL⁴（Phen）（H₂O）]·Ac·2H₂O for prostate cancer PC-3 cells is higher than that of [CuL²（H₂O）₂]·H₂O. More importantly, anti-tumor activity of metal complexes is closely related to selected metal ions and the structure of the ligands. For the same ligand, anti-tumor activity of copper（Ⅱ） complex is better than that of zinc（Ⅱ） complex. Besides, It was found that the complexe formed by the ligand containing better coplanarity, smaller steric hindrance and heteroatom have much higher anti-tumor activities than that formed by other ligands.更多还原