Department of Inorganic Chemistry, University of Madras, School of Chemical Sciences, Guindy Maraimalai Campus, Chennai 600 025, India.
Inorg Chem. 2012 May 21;51(10):5580-92. doi: 10.1021/ic202451e. Epub 2012 May 3.
A symmetrical macrocyclic dizinc(II) complex (1) has been synthesized by using the ligand (L(1)) [μ-11,24-dimethyl-4,7,16,19-tetraoxa-3,8,15,20-tetraazatricyclo-[20.3.1.1(10,13)] heptacosa-1(25),2,7,9,11,13(27),14,20,22(26),23-decaene-26,27-diol]. A series of unsymmetrical macrocyclic dizinc(II) complexes (2-6) has been synthesized by Schiff base condensation of bicompartmental mononuclear complex [ZnL] [μ-3,16-dimethyl-8,11-dioxa-7,12-diazadicyclo-[1.1(14,18)] heptacosa-1,3,5(20),6,12,14,16,18(19)-octacaene-19,20-diolato)zinc(II)] with various diamines like 1,2-diamino ethane (L(2)), 1,3-diamino propane (L(3)), 1,4-diamino butane (L(4)), 1,2-diamino benzene (L(5)), and 1,8-diamino naphthalene (L(6)). The ligand L(1) and all the zinc(II) complexes were structurally characterized. To corroborate the consequence of the aromatic moiety in comparison to the aliphatic moiety present in the macrocyclic ring on the phosphate ester hydrolysis, DNA binding and cleavage properties have been studied. The observed first order rate constant values for the hydrolysis of 4-nitrophenyl phosphate ester reaction are in the range from 2.73 × 10(-2) to 9.86 × 10(-2) s(-1).The interactions of complexes 1-6 with calf thymus DNA were studied by spectroscopic techniques, including absorption, fluorescence, and circular dichroism spectroscopy. The DNA binding constant values of the complexes were found in the range from 1.80 × 10(5) to 9.50 × 10(5) M(-1), and the binding affinities are in the following order: 6 > 5 > 1 > 2 > 3 > 4. All the dizinc(II) complexes 1-6 effectively promoted the hydrolytic cleavage of plasmid pBR322 DNA under anaerobic and aerobic conditions. Kinetic data for DNA hydrolysis promoted by 6 under physiological conditions give the observed rate constant (k(obs)) of 4.42 ± 0.2 h(-1), which shows a 10(8)-fold rate acceleration over the uncatalyzed reaction of ds-DNA. The comparison of the dizinc(II) complexes 1-6 with the monozinc(II) complex [ZnL] indicates that the DNA cleavage acceleration promoted by 1-6 are due to the efficient cooperative catalysis of the two close proximate zinc(II) cation centers. The ligand L(1), dizinc(II) complexes 1, 3, and 6 showed cytotoxicity in human hepatoma HepG2 cancer cells, giving IC(50) values of 117, 37.1, 16.5, and 8.32 μM, respectively. The results demonstrated that 6, a dizinc(II) complex with potent antiproliferative activity, is able to induce caspase-dependent apoptosis in human cancer cells. Cytotoxicity of the complexes was further confirmed by the lactate dehydrogenase enzyme level in HepG2 cell lysate and content media.
一种对称的大环二锌（II）配合物（1）已经通过使用配体（L(1)）[μ-11,24-二甲基-4,7,16,19-四氧-3,8,15,20-四氮杂三环[20.3.1.1(10,13)]十七碳-1(25),2,7,9,11,13(27),14,20,22(26),23-二烯-26,27-二醇]合成。通过双隔室单核配合物[ZnL][μ-3,16-二甲基-8,11-二氧-7,12-二氮杂二环[1.1(14,18)]十七碳-1,3,5(20),6,12,14,16,18(19)-辛八碳-19,20-二醇酸根合锌（II）]与各种二胺（如 1,2-二氨基乙烷（L(2)）、1,3-二氨基丙烷（L(3)）、1,4-二氨基丁烷（L(4)）、1,2-二氨基苯（L(5)）和 1,8-二氨基萘（L(6)））的席夫碱缩合，合成了一系列非对称的大环二锌（II）配合物（2-6）。配体 L(1)和所有锌（II）配合物均进行了结构表征。为了证实与大环环中存在的脂肪族部分相比，芳族部分对磷酸酯水解的影响，研究了 DNA 结合和切割特性。4-硝基苯磷酸酯反应水解的一级速率常数值范围为 2.73×10(-2)至 9.86×10(-2)s(-1)。通过吸收、荧光和圆二色光谱等光谱技术研究了配合物 1-6 与小牛胸腺 DNA 的相互作用。复合物的 DNA 结合常数值范围为 1.80×10(5)至 9.50×10(5)M(-1)，结合亲和力的顺序为：6>5>1>2>3>4。所有的二锌（II）配合物 1-6 在厌氧和有氧条件下均能有效促进质粒 pBR322 DNA 的水解断裂。6 在下生理条件下促进 DNA 水解的动力学数据给出了观察到的速率常数（k(obs)）为 4.42±0.2h(-1)，与无催化剂的 ds-DNA 反应相比，表现出 10(8)倍的速率加速。与单核锌（II）配合物[ZnL]的比较表明，1-6 促进的 DNA 切割加速归因于两个紧密接近的锌（II）阳离子中心的有效协同催化。配体 L(1)、二锌（II）配合物 1、3 和 6 对人肝癌 HepG2 癌细胞表现出细胞毒性，IC(50)值分别为 117、37.1、16.5 和 8.32μM。结果表明，具有强大的抗增殖活性的二锌（II）配合物 6 能够诱导人癌细胞中的 caspase 依赖性细胞凋亡。复合物的细胞毒性通过 HepG2 细胞裂解物和介质中的乳酸脱氢酶酶水平进一步得到证实。
