Department of Chemistry, Handique Girls' College, Guwahati 781001, Assam, India.
Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560012, Karnataka, India.
Inorg Chem. 2021 May 3;60(9):6649-6662. doi: 10.1021/acs.inorgchem.1c00444. Epub 2021 Apr 15.
The bioessential nature of cobalt and the rich photochemistry of its coordination complexes can be exploited to develop potential next-generation photochemotherapeutics. A series of six novel mixed-ligand cobalt(III) complexes of the formulation [Co(B)(L)]ClO (-), where B is an N,N-donor phenanthroline base, namely, 1,10-phenanthroline (phen in and ), dipyrido[3,2-:2',3'-]quinoxaline (dpq in and ), and dipyrido[3,2-:2',3'-]phenazine (dppz in and ), and L is an O,O-donor dianionic ligand derived from catechol (1,2-dihydroxybenzene, cat, in -) or esculetin (6,7-dihydoxycoumarin, esc, in -), have been prepared and characterized, and their light-triggered cytotoxicity has been studied in cancer cells. The single-crystal X-ray diffraction structures of complexes (as PF salt, ) and show distorted octahedral geometries around the cobalt(III) center formed by the set of NO donor atoms. The low-spin and 1:1 electrolytic complexes - display a d-d transition around 700 nm. Complexes - with a coordinated esc ligand additionally display a π → π* intraligand transition centered at 403 nm. Complexes - possessing a naturally occurring and photoactive esc ligand show high visible-light-triggered cytotoxicity against HeLa and MCF-7 cancer cells, yielding remarkably low micromolar IC values while being much less toxic under dark conditions. Control complexes - possessing the photoinactive cat ligand show significantly less cytotoxicity either in the presence of light or in the dark. The complex-induced cell death is apoptotic in nature caused by the formation of reactive oxygen species via a type 1 photoredox pathway. Fluorescence microscopy of HeLa cells treated with complex reveals mitochondrial localization of the complex. A significant decrease in the dark toxicity of free esculetin and dppz base is observed upon coordination to cobalt(III). Complexes bind to calf-thymus DNA with significant affinity, but binds with the greatest affinity. Complex efficiently photocleaves supercoiled DNA to its nicked circular form when irradiated with visible light via a photoredox type 1 pathway involving hydroxyl radicals (HO). Thus, complex showing remarkable visible-light-triggered cytotoxicity but negligible toxicity in the dark is a good candidate for cancer photochemotherapy applications.
钴的生物必需性和其配位化合物丰富的光化学性质可被利用来开发潜在的下一代光化疗药物。我们合成了一系列六种新型混合配体钴（III）配合物，其分子式为[Co（B）（L）]ClO（-），其中 B 是 N，N-供体菲咯啉碱基，即 1,10-菲咯啉（在 中为 phen）、二吡啶并[3,2-:2',3'-]喹喔啉（在 中为 dpq）和二吡啶并[3,2-:2',3'-]吩嗪（在 中为 dppz），L 是来自儿茶酚（1,2-二羟基苯，在 中为 cat）或秦皮素（6,7-二羟基香豆素，在 中为 esc）的 O，O-供体二阴离子配体。我们对这些配合物进行了制备和表征，并研究了它们在癌细胞中的光触发细胞毒性。配合物 （以 PF 盐形式存在，）和 的单晶 X 射线衍射结构表明，钴（III）中心周围的配位环境为扭曲的八面体，由一组 NO 供体原子组成。低自旋的 1:1 电解质配合物 - 显示出约 700nm 处的 d-d 跃迁。带有配位 esc 配体的配合物 - 另外显示出中心在 403nm 处的π→π* 内配位跃迁。具有天然存在和光活性 esc 配体的配合物 - 对 HeLa 和 MCF-7 癌细胞具有高可见光触发细胞毒性，产生显著的低微摩尔 IC 值，而在黑暗条件下毒性要小得多。具有非光活性 cat 配体的对照配合物 - 无论是在光照下还是在黑暗中，细胞毒性都明显降低。该复合物诱导的细胞死亡是通过 1 型光还原途径形成活性氧而导致的凋亡。用配合物 处理的 HeLa 细胞的荧光显微镜显示复合物的线粒体定位。游离秦皮素和 dppz 碱基的黑暗毒性在与钴（III）配位后显著降低。配合物与小牛胸腺 DNA 具有显著的亲和力，但 与 DNA 的结合能力最强。配合物 在可见光照射下通过涉及羟基自由基（HO）的 1 型光还原途径有效地将超螺旋 DNA 光解为其缺口环状形式。因此，表现出显著的可见光触发细胞毒性但在黑暗中几乎没有毒性的配合物 是癌症光化疗应用的良好候选物。
