Santos Jayson C Dos, Neto João G de Oliveira, Moreira Ana B N, da Silva Luzeli M, Ayala Alejandro P, Lage Mateus R, Lang Rossano, de Sousa Francisco F, Mendes Fernando, Dos Santos Adenilson O
Center for Sciences of Imperatriz, Federal University of Maranhão-UFMA, Imperatriz 65900-410, MA, Brazil.
Department of Physics, Federal University of Ceará-UFC, Fortaleza 65455-900, CE, Brazil.
Molecules. 2025 Jul 6;30(13):2873. doi: 10.3390/molecules30132873.
This study presents the synthesis, physicochemical characterization, and biological evaluation of a novel ternary nickel(II) complex with isoleucine and 1,10-phenanthroline ligands, [Ni(Phen)(Ile)]∙6HO, designed as a potential antitumor agent. Single-crystal X-ray diffraction revealed a monoclinic structure (C2-space group) with an octahedral Ni(II) coordination involving Phen and Ile ligands. A Hirshfeld surface analysis highlighted intermolecular interactions stabilizing the crystal lattice, with hydrogen bonds (H···H and O···H/H···O) dominating (99.1% of contacts). Density functional theory (DFT) calculations, including solvation effects (in water and methanol), demonstrated strong agreement with the experimental geometric parameters and revealed higher affinity to the water solvent. The electronic properties of the complex, such as HOMO-LUMO gaps (3.20-4.26 eV) and electrophilicity (4.54-5.88 eV), indicated a charge-transfer potential suitable for biological applications through interactions with biomolecules. Raman and infrared spectroscopic studies showed vibrational modes associated with Ni-N/O bonds and ligand-specific deformations, with solvation-induced shifts observed. A study using ultraviolet-visible-near-infrared absorption spectroscopy demonstrated that the complex remains stable in solution. In vitro cytotoxicity assays against MCF-7 (breast adenocarcinoma) and HCT-116 (colorectal carcinoma) cells showed dose-dependent activity, achieving 47.6% and 65.3% viability reduction at 100 μM (48 h), respectively, with lower toxicity to non-tumor lung fibroblasts (GM07492A, 39.8%). Supporting the experimental data, we performed computational modeling to examine the pharmacokinetic profile, with particular focus on the absorption, distribution, metabolism, and excretion properties and drug-likeness potential.
本研究介绍了一种新型三元镍（II）配合物[Ni(Phen)(Ile)]∙6H₂O的合成、物理化学表征及生物学评价，该配合物由异亮氨酸和1,10-菲咯啉配体构成，被设计为一种潜在的抗肿瘤药物。单晶X射线衍射揭示了其单斜结构（C2空间群），八面体镍（II）通过Phen和Ile配体进行配位。 Hirshfeld表面分析突出了稳定晶格的分子间相互作用，其中氢键（H···H和O···H/H···O）占主导（99.1%的接触）。密度泛函理论（DFT）计算，包括溶剂化效应（在水和甲醇中），与实验几何参数显示出高度一致性，并揭示了对水溶剂的更高亲和力。该配合物的电子性质，如最高占据分子轨道-最低未占据分子轨道能隙（3.20 - 4.26 eV）和亲电性（4.54 - 5.88 eV），表明其具有通过与生物分子相互作用适用于生物应用的电荷转移潜力。拉曼光谱和红外光谱研究显示了与Ni-N/O键及配体特异性变形相关的振动模式，并观察到了溶剂化诱导的位移。使用紫外-可见-近红外吸收光谱的研究表明该配合物在溶液中保持稳定。针对MCF-7（乳腺腺癌）和HCT-116（结肠直肠癌）细胞的体外细胞毒性试验显示出剂量依赖性活性，在100 μM（48小时）时分别使细胞活力降低47.6%和65.3%，对非肿瘤性肺成纤维细胞（GM07492A）的毒性较低（39.8%）。为支持实验数据，我们进行了计算建模以研究药代动力学特征，特别关注吸收、分布、代谢和排泄特性以及药物相似性潜力。
