Studies on the manganese and copper complexes derived from chiral Schiff base: synthesis, structure, cytotoxicity and DNA/BSA interaction

Three new manganese and copper complexes, [Mn(ONO-(S)L¹)₂] (<b>1</b>), [Cu(ONO-(R)L²)]₄·2CH₃OH (<b>2</b>), and [Mn₃(ONO-(S)L³)₄(OAc)₄(H₂O)₂] (<b>3</b>), {[H₂L¹ = (<i>S</i>)-2-phenyl-2-(2-hydroxy-5-chlorobenzylideneamino)ethane-1-ol], H₂L² = (<i>R</i>)-2-(2-hydroxy-5-chlorobenzylideneamino)butane-1-ol] and H₂L³ = (<i>S</i>)-2-phenyl-2-(2-hydroxy-3-methoxybenzylideneamino)ethane-1-ol]}, have been synthesized. The crystal structures of <b>1</b>–<b>3</b> were determined through single-crystal X-ray diffraction. The structure of mononuclear <b>1</b> shows a six-coordinate octahedral geometry around the manganese ion. Complex <b>2</b> is a five-coordinate tetranuclear copper complex with the central Cu atoms adopting distorted square pyramidal geometry. Complex <b>3</b> shows a trinuclear structure with the six-coordinate Mn ions surrounded by four L³ ligands and acetate ions. The <i>in vitro</i> cytotoxicity screening revealed that the <b>1–3</b> had substantial cytotoxicity against three cancer cell lines (HepG2, MDA-MB-231, and A549), even higher than that of <i>cisplatin</i>. Inspiringly, <b>2</b> derived from (<i>R</i>)-Schiff base ligand H₂L² was more potent against MDA-MB-231 cells. Interaction of <b>1</b>–<b>3</b> with calf-thymus DNA (CT-DNA) has been investigated using UV-vis, viscosity and thermal denaturation experiments. It was found that <b>1</b> binds with DNA through intercalation while <b>2</b> and <b>3</b> interact with DNA probably through groove-binding and electrostatic mode. In addition, the capability of the complexes to bind with bovine serum albumin was monitored using some spectral techniques. The metal ions, chiral and nuclearity have significant influences on the properties of the title compounds.

本研究成功合成了三种新型锰、铜配合物：[Mn(ONO-(S)L¹)₂]（配合物1）、[Cu(ONO-(R)L²)]₄·2CH₃OH（配合物2）与[Mn₃(ONO-(S)L³)₄(OAc)₄(H₂O)₂]（配合物3）。其中配体H₂L¹为(S)-2-苯基-2-(2-羟基-5-氯苯亚甲基氨基)乙烷-1-醇，H₂L²为(R)-2-(2-羟基-5-氯苯亚甲基氨基)丁烷-1-醇，H₂L³为(S)-2-苯基-2-(2-羟基-3-甲氧基苯亚甲基氨基)乙烷-1-醇。通过单晶X射线衍射技术解析了配合物1~3的晶体结构。单核配合物1的锰离子中心为六配位八面体几何构型。配合物2为五配位四核铜配合物，其铜中心原子呈现畸变四方锥配位构型。配合物3为三核结构，六配位的锰离子被四个L³配体与乙酸根离子配位包裹。体外（in vitro）细胞毒性筛选结果表明，配合物1~3对三种癌细胞系（HepG2、MDA-MB-231及A549）均具有显著的细胞毒性，其活性甚至优于顺铂（cisplatin）。值得关注的是，由(R)型席夫碱（Schiff base）配体H₂L²衍生得到的配合物2对MDA-MB-231细胞的抑制活性更强。通过紫外-可见光谱、黏度法及热变性实验，研究了配合物1~3与小牛胸腺DNA（CT-DNA）的相互作用。研究发现，配合物1通过嵌入结合方式与DNA结合，而配合物2和3则可能通过沟槽结合与静电作用模式与DNA相互作用。此外，通过多种光谱技术考察了三种配合物与牛血清白蛋白的结合能力。金属离子种类、手性特征及核数对目标配合物的性能具有显著影响。