Strategy to Optimize the Biological Activity of Arene Ruthenium Metalla-Assemblies

Three new dinuclear arene ruthenium metalla-clips of the general formula [(p-cymene)2­Ru2Cl2­(μ-L)] have been prepared from [(p-cymene)2­Ru2Cl2­(μ-Cl)2] and H2L organic linkers (H2La = diethyl-1,2-diazenedicarboxylate, H2Lb = N,N′-bis­(2-hydroxy­ethyl)­oxamide, H2Lc = N,N′-bis­{2-(2-hydroxy­ethoxy)­ethyl}­ethanediamide). The bis-chelating bridging-linkers possess two functional groups that can be synthetically modified for physico-chemical optimizations. Reaction of these three dinuclear metalla-clips with 4,4′-bipyridine, 1,2-bis­(4-pyridyl)­ethylene, and 4,4′-azopyridine affords, in the presence of AgCF3SO3, nine tetracationic tetranuclear metalla-rectangles. Similarly, the tridentate ligands 2,4,6-tris­(4-pyridyl)-1,3,5-triazine and 1,3,5-tris­{2-(4-pyridyl)­vinyl}­benzene were used to generate six hexacationic hexanuclear metalla-prisms. All metalla-assemblies and the dinuclear complexes were evaluated as anticancer agents against cancerous (A2780) and noncancerous (HEK293) cell lines, showing an excellent selectivity for cancer cells. The IC50 values of the cationic metalla-assemblies were typically 50 values were >100 μM.

本研究以二(对伞花烃(p-cymene))二钌(II)桥连二氯化物[(p-cymene)₂Ru₂Cl₂(μ-Cl)₂]与双齿有机桥连配体H₂L（其中H₂Lᵃ为偶氮二甲酸二乙酯，H₂Lᵇ为N,N'-双(2-羟乙基)草酰胺，H₂Lᶜ为N,N'-双{2-(2-羟基乙氧基)乙基}乙二酰胺）为原料，合成了三个通式为[(p-cymene)₂Ru₂Cl₂(μ-L)]的新型双核芳烃钌金属钳形构件。该类双螯合桥连配体含有两个可通过合成修饰以优化其物理化学性能的官能团。将上述三个双核金属钳形构件分别与4,4'-联吡啶、1,2-双(4-吡啶基)乙烯、4,4'-偶氮吡啶在三氟甲磺酸银(AgCF3SO3)存在下反应，得到九种四阳离子四核金属矩形配合物。类似地，以三齿配体2,4,6-三(4-吡啶基)-1,3,5-三嗪与1,3,5-三{2-(4-吡啶基)乙烯基}苯为原料，合成了六种六阳离子六核金属三棱柱配合物。对所有金属组装体及双核配合物，分别针对癌细胞系A2780与正常细胞系HEK293开展抗癌活性评价，结果显示其对癌细胞具有优异的选择性。该类阳离子金属组装体的半最大抑制浓度(IC50)通常小于1 μM，而对正常细胞的IC50值均大于100 μM。