Department of Chemistry , Acadia University , Wolfville , Nova Scotia B4P 2R6 , Canada.
Department of Chemistry and Biochemistry , The University of North Carolina at Greensboro , Greensboro , North Carolina 27402 , United States.
Inorg Chem. 2018 Jul 2;57(13):7694-7712. doi: 10.1021/acs.inorgchem.8b00689. Epub 2018 Jun 21.
The photophysical and photobiological properties of a new class of cyclometalated ruthenium(II) compounds incorporating π-extended benzo[ h]imidazo[4,5- f]quinoline (IBQ) cyclometalating ligands (C^N) bearing thienyl rings ( n = 1-4, compounds 1-4) were investigated. Their octanol-water partition coefficients (log P) were positive and increased with n. Their absorption and emission energies were red-shifted substantially compared to the analogous Ru(II) diimine (N^N) complexes. They displayed C^N-based intraligand (IL) fluorescence and triplet excited-state absorption that shifted to longer wavelengths with increasing n and N^N-based metal-to-ligand charge transfer (MLCT) phosphorescence that was independent of n. Their photoluminescence lifetimes (τ) ranged from 4-10 ns for IL states and 12-18 ns for MLCT states. Transient absorption lifetimes (τ) were 5-8 μs with 355 nm excitation, ascribed to IL states that became inaccessible for 1-3 with 532 nm excitation (1-3, τ = 16-17 ns); the IL of 4 only was accessible by lower energy excitation, τ = 3.8 μs. Complex 4 was nontoxic (EC > 300 μM) to SK-MEL-28 melanoma cells and CCD1064-Sk normal skin fibroblasts in the dark, while 3 was selectively cytotoxic to melanoma (EC= 5.1 μM) only. Compounds 1 and 2 were selective for melanoma cells in the dark, with submicromolar potencies (EC = 350-500 nM) and selectivity factors (SFs) around 50. The photocytotoxicities of compounds 1-4 toward melanoma cells were similar, but only compounds 3 and 4 displayed significant phototherapeutic indices (PIs; 3, 43; 4, >1100). The larger cytotoxicities for compounds 1 and 2 were attributed to increased cellular uptake and nuclear accumulation, and possibly related to the DNA-aggregating properties of all four compounds as demonstrated by cell-free gel mobility-shift assays. Together, these results demonstrate a new class of thiophene-containing Ru(II) cyclometalated compounds that contain both highly selective chemotherapeutic agents and extremely potent photocytotoxic agents.
研究了一类新型的环金属钌（II）化合物，这些化合物包含π-扩展的苯并[h]咪唑[4,5-f]喹啉（IBQ）环金属配体（C^N），带有噻吩环（n=1-4，化合物 1-4）。它们的辛醇-水分配系数（log P）为正，且随 n 的增加而增加。与类似的 Ru(II)二亚胺（N^N）配合物相比，它们的吸收和发射能量有很大的红移。它们显示出基于 C^N 的内配位体（IL）荧光和三重态激发态吸收，随着 n 的增加而移向更长的波长，而基于 N^N 的金属-配体电荷转移（MLCT）磷光则与 n 无关。它们的光致发光寿命（τ）在 IL 态下为 4-10 ns，在 MLCT 态下为 12-18 ns。用 355 nm 激发时，瞬态吸收寿命（τ）为 5-8 μs，归因于 IL 态，用 532 nm 激发时 1-3 不可用（1-3，τ=16-17 ns）；4 的 IL 仅可通过较低能量的激发来获得，τ=3.8 μs。在黑暗中，化合物 4 对 SK-MEL-28 黑色素瘤细胞和 CCD1064-Sk 正常皮肤成纤维细胞无毒性（EC>300 μM），而 3 仅对黑色素瘤具有选择性细胞毒性（EC=5.1 μM）。化合物 1 和 2 在黑暗中对黑色素瘤细胞具有选择性，具有亚微摩尔效力（EC=350-500 nM）和选择性因子（SF）约为 50。化合物 1-4 对黑色素瘤细胞的光细胞毒性相似，但只有化合物 3 和 4 显示出显著的光治疗指数（PI；3，43；4，>1100）。化合物 1 和 2 的细胞毒性增加归因于细胞摄取和核积累的增加，并且可能与所有四种化合物的 DNA 聚集特性有关，这通过无细胞凝胶迁移率变动测定得到证明。总的来说，这些结果表明了一类新型的含有噻吩的 Ru(II)环金属化合物，它们既包含高度选择性的化疗药物，又包含非常有效的光细胞毒性药物。
