Cyclometalated Ruthenium(II) Complexes Derived from α-Oligothiophenes as Highly Selective Cytotoxic or Photocytotoxic Agents.
Cyclometalated Ruthenium(II) Complexes Derived from α-Oligothiophenes as Highly Selective Cytotoxic or Photocytotoxic Agents.
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DOI：
10.1021/acs.inorgchem.8b00689
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发表时间：
2018-07-02
影响因子：
4.6
通讯作者：
McFarland SA
中科院分区：
文献类型：
--
作者：
Ghosh G;Colón KL;Fuller A;Sainuddin T;Bradner E;McCain J;Monro SMA;Yin H;Hetu MW;Cameron CG;McFarland SA
研究了一类新的含π扩展的苯并[h]咪唑并[4，5-f]喹啉(IBQ)环金属配体(C^N)的环金属化Ru(II)化合物(n=1-4，化合物1-4)的光物理和光生物学性质。它们的辛醇-水分配系数(logPo/w)均为正值，且随n的增加而增大。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发生了显著的红移。它们表现出C^N基对齐(IL)荧光和三重态激发态吸收随n的增加而向更长波长移动，以及N^N基的金属-配体电荷转移(MLCT)磷光，它们的发光寿命(τem)分别为4-10 ns和12-18 ns。化合物4在355 nm激发下的瞬时吸收寿命(τTA)为5-8μS，属于3IL态，在532 nm激发(1-3，τTA=16-17 ns)下1-3不可达；化合物4的3IL只能在较低能量激发下获得，τTA=3.8μS。化合物1和2在黑暗中对黑色素瘤细胞具有选择性，其亚微摩尔电势(EC50=350-500 nm)和选择性因子(SFs)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具有显著的光疗指数(PI)(3，43；4，>；1,100)。化合物1和2的较大细胞毒性归因于细胞摄取和核积累的增加，并可能与所有四种化合物的DNA聚集特性有关，如无细胞凝胶迁移率-位移分析所证明的那样。综上所述，这些结果显示了一类新的含噻吩环金属Ru(II)化合物，它既包含高选择性的化疗药物，也包含极强的光细胞毒剂。TOC图描述：基于苯并[h]咪唑并[4，5-f]喹诺酮配体和1-4个噻吩基，合成了一类新的环金属化Ru(II)配合物。其中一种化合物(n=4)作为一种有效的光毒剂，而其他化合物(n=1-3)作为传统的化疗药物，对黑色素瘤细胞比非癌皮肤成纤维细胞具有选择性。
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 Po/w) 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 (τem) ranged from 4–10 ns for 1IL states and 12–18 ns for 3MLCT states. Transient absorption lifetimes (τTA) were 5–8 μs with 355-nm excitation, ascribed to 3IL states that became inaccessible for 1–3 with 532-nm excitation (1–3, τTA=16–17 ns); the 3IL of 4 only was accessible by lower energy excitation, τTA=3.8 μs. Complex 4 was nontoxic (EC50 >300 μM) to SK-MEL-28 melanoma cells and CCD1064-Sk normal skin fibroblasts in the dark, while 3 was selectively cytotoxic to melanoma (EC50= 5.1 μM) only. Compounds 1 and 2 were selective for melanoma cells in the dark, with submicromolar potencies (EC50=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, >1,100). 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. Description of TOC graphic: A new family of cyclometalated Ru(II) complexes was prepared based on a benzo[h]imidazo[4,5-f]quinolone ligand appended with 1-4 thiophene units. One of the complexes (n=4) acted as a potent phototoxic agent, while others (n=1-3) acted as traditional chemotherapeutics with selectivity toward melanoma cells over noncancerous skin fibroblasts.
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影响因子：
2.3
作者：
Koizumi, T;Tomon, T;Tanaka, K
通讯作者：
Tanaka, K
影响因子：
15
作者：
Bessho, Takeru;Yoneda, Eiji;Graetzel, Michael
通讯作者：
Graetzel, Michael
影响因子：
4.6
作者：
JURIS, A;CAMPAGNA, S;VONZELEWSKY, A
通讯作者：
VONZELEWSKY, A
影响因子：
20.6
作者：
Knoll JD;Turro C
通讯作者：
Turro C
影响因子：
4
作者：
Fetzer, Ludivine;Boff, Bastien;Pfeffer, Michel
通讯作者：
Pfeffer, Michel