Transferring the Concept of Multinuclearity to Ruthenium Complexes for Improvement of Anticancer Activity.
作者
Mendoza-Ferri, Maria G.;Hartinger, Christian G.;Mendoza, Marco A.;Groessl, Michael;Egger, Alexander E.;Eichinger, Rene E.;Mangrum, John B.;Farrell, Nicholas P.;Maruszak, Magdalena;Bednarski, Patrick J.;Klein, Franz;Jakupec, Michael A.;Nazarov, Alexey A.;S
[摘要]：Multinuclear platinum anticancer complexes are a proven option to overcome resistance of established anticancer compds. Transferring this concept to ruthenium complexes led to the synthesis of dinuclear Ru(II)-arene compds. contg. a bis(pyridinone)alkane ligand linker. A pronounced influence of the spacer length on the in vitro anticancer activity was found, which is correlated to the lipophilicity of the complexes. IC50 values in the same dimension as for established platinum drugs were found in human tumor cell lines. No cross-resistance to oxoplatin, a cisplatin prodrug, was obsd. for the most active complex in three resistant cell lines; in fact, a 10-fold reversal of sensitivity in two of the oxoplatin-resistant lines was found. (Bio)anal. characterization of the representative examples showed that the ruthenium complexes hydrolyze rapidly, forming predominantly diaqua species that exhibit affinity toward transferrin and DNA, indicating that both proteins and nucleobases are potential targets.
