JBIC Journal of Biological Inorganic Chemistry ( IF 3 ) Pub Date : 2021-08-10 , DOI: 10.1007/s00775-021-01882-8 Anja Busemann 1 , Ingrid Flaspohler 1 , Xue-Quan Zhou 1 , Claudia Schmidt 2 , Sina K Goetzfried 1 , Vincent H S van Rixel 1 , Ingo Ott 2 , Maxime A Siegler 3 , Sylvestre Bonnet 1
The known ruthenium complex [Ru(tpy)(bpy)(Hmte)](PF6)2 ([1](PF6)2, where tpy = 2,2’:6’,2″-terpyridine, bpy = 2,2’-bipyridine, Hmte = 2-(methylthio)ethanol) is photosubstitutionally active but non-toxic to cancer cells even upon light irradiation. In this work, the two analogs complexes [Ru(tpy)(NN)(Hmte)](PF6)2, where NN = 3,3'-biisoquinoline (i-biq, [2](PF6)2) and di(isoquinolin-3-yl)amine (i-Hdiqa, [3](PF6)2), were synthesized and their photochemistry and phototoxicity evaluated to assess their suitability as photoactivated chemotherapy (PACT) agents. The increase of the aromatic surface of [2](PF6)2 and [3](PF6)2, compared to [1](PF6)2, leads to higher lipophilicity and higher cellular uptake for the former complexes. Such improved uptake is directly correlated to the cytotoxicity of these compounds in the dark: while [2](PF6)2 and [3](PF6)2 showed low EC50 values in human cancer cells, [1](PF6)2 is not cytotoxic due to poor cellular uptake. While stable in the dark, all complexes substituted the protecting thioether ligand upon light irradiation (520 nm), with the highest photosubstitution quantum yield found for [3](PF6)2 (Φ[3] = 0.070). Compounds [2](PF6)2 and [3](PF6)2 were found both more cytotoxic after light activation than in the dark, with a photo index of 4. Considering the very low singlet oxygen quantum yields of these compounds, and the lack of cytotoxicity of the photoreleased Hmte thioether ligand, it can be concluded that the toxicity observed after light activation is due to the photoreleased aqua complexes [Ru(tpy)(NN)(OH2)]2+, and thus that [2](PF6)2 and [3](PF6)2 are promising PACT candidates.
Graphic abstract
中文翻译:
基于双喹啉螯合物的钌 PACT 试剂:合成、光化学和细胞毒性
已知的钌络合物[Ru(tpy)(bpy)(Hmte)](PF 6 ) 2 ([ 1 ](PF 6 ) 2,其中tpy = 2,2':6',2″-三联吡啶,bpy = 2 ,2'-联吡啶,Hmte = 2-(甲硫基)乙醇) 具有光取代活性,但即使在光照射下也对癌细胞无毒。在这项工作中,两种类似物配合物 [Ru(tpy)(NN)(Hmte)](PF 6 ) 2,其中 NN = 3,3'-二异喹啉 (i-biq, [ 2 ](PF 6 ) 2 ) 和二(isoquinolin-3-yl)amine (i-Hdiqa, [ 3 ](PF 6 ) 2) 被合成并评估它们的光化学和光毒性以评估它们作为光活化化学疗法 (PACT) 剂的适用性。与[ 1 ] (PF 6 ) 2相比, [ 2 ](PF 6 ) 2和[ 3 ](PF 6 ) 2芳香表面的增加导致前者复合物具有更高的亲脂性和更高的细胞吸收。这种提高的吸收与这些化合物在黑暗中的细胞毒性直接相关:而 [ 2 ](PF 6 ) 2和 [ 3 ](PF 6 ) 2显示出低 EC在人类癌细胞中的50值,[ 1 ](PF 6 ) 2由于细胞吸收不良而没有细胞毒性。虽然在黑暗中稳定,但所有配合物在光照射 (520 nm) 时都取代了保护性硫醚配体,发现 [ 3 ](PF 6 ) 2 (Φ [ 3 ] = 0.070) 的光取代量子产率最高。化合物 [ 2 ](PF 6 ) 2和 [ 3 ](PF 6 ) 2发现在光激活后比在黑暗中更具细胞毒性,光指数为 4。考虑到这些化合物的单线态氧量子产率非常低,以及光释放的 Hmte 硫醚配体缺乏细胞毒性,可以得出结论:光活化后观察到的毒性是由于光释放水络合物[Ru(tpy)(NN)(OH 2 )] 2+,因此[ 2 ](PF 6 ) 2和[ 3 ](PF 6 ) 2是有希望的PACT 候选人。