Dicopper(II) and Dizinc(II) Complexes with Nonsymmetric Dinucleating Ligands Based on Indolo[3,2‑<i>c</i>]quinolines: Synthesis, Structure, Cytotoxicity, and Intracellular Distribution

Dicopper­(II) and dizinc­(II) complexes [Cu2(MeOOCLCOO)­(CH3COO)2] (1) and [Zn2(MeOOCLCOO)­(CH3COO)2] (2) were synthesized by reaction of Cu­(CH3COO)2·H2O and Zn­(CH3COO)2·2H2O with a new nonsymmetric dinucleating ligand EtOOCHLCOOEt prepared by condensation of 6-hydrazinyl-11H-indolo­[3,2-c]­quinoline with diethyl-2,2′-((3-formyl-2-hydroxy-5-methylbenzyl)­azanediyl)­diacetate. The design and synthesis of this elaborate ligand was performed with the aim of increasing the aqueous solubility of indolo­[3,2-c]­quinolines, known as biologically active compounds, and investigating the antiproliferative activity in human cancer cell lines and the cellular distribution by exploring the intrinsic fluorescence of the indoloquinoline scaffold. The compounds have been comprehensively characterized by elemental analysis, spectroscopic methods (IR, UV–vis, 1H and 13C NMR spectroscopy), ESI mass spectrometry, magnetic susceptibility measurements, and UV–vis complex formation studies (for 1) as well as by X-ray crystallography (1 and 2). The antiproliferative activity of EtOOCHLCOOEt, 1, and 2 was determined by the MTT assay in three human cancer cell lines, namely, A549 (nonsmall cell lung carcinoma), CH1 (ovarian carcinoma), and SW480 (colon adenocarcinoma), yielding IC50 values in the micromolar concentration range and showing dependence on the cell line. The effect of metal coordination on cytotoxicity of EtOOCHLCOOEt is also discussed. The subcellular distribution of EtOOCHLCOOEt and 2 was investigated by fluorescence microscopy, revealing similar localization for both compounds in cytoplasmic structures.双核铜(II)与双核锌(II)配合物[Cu₂(MeOOCLCOO)(CH₃COO)₂]（1）和[Zn₂(MeOOCLCOO)(CH₃COO)₂]（2），由Cu(CH₃COO)₂·H₂O、Zn(CH₃COO)₂·2H₂O与新型非对称双核配体EtOOCHLCOOEt通过反应合成；该配体通过6-肼基-11H-吲哚并[3,2-c]喹啉与二乙基-2,2′-((3-甲酰基-2-羟基-5-甲基苄基)亚氨基)二乙酸酯的缩合反应制备得到。 本研究设计并合成该结构精巧的配体，意在提升吲哚并[3,2-c]喹啉类生物活性化合物的水溶性，同时探究其在人类癌细胞系中的抗增殖活性，并借助吲哚喹啉骨架的固有荧光特性研究其细胞内分布情况。 上述化合物已通过多种手段完成全面表征：元素分析、光谱学方法（红外光谱、紫外-可见光谱、¹H及¹³C核磁共振波谱）、电喷雾电离（ESI）质谱、磁敏感性测量，针对配合物1的紫外-可见配位结合研究，以及配合物1和2的X射线晶体学（X-ray crystallography）结构解析。 采用MTT比色法，在三种人类癌细胞系——A549（非小细胞肺癌）、CH1（卵巢癌）与SW480（结肠腺癌）——中测定了配体EtOOCHLCOOEt、配合物1和2的抗增殖活性，结果显示其半数抑制浓度（IC₅₀）处于微摩尔浓度范围，且活性存在细胞系依赖性。 本文还探讨了金属配位对配体EtOOCHLCOOEt细胞毒性的影响。 通过荧光显微镜术研究了配体EtOOCHLCOOEt与配合物2的亚细胞分布，结果表明二者在细胞质结构中的定位模式高度相似。