Transferring the concept of multinuclearity to ruthenium complexes for improvement of anticancer activity.
Multinuclear platinum anticancer complexes are a proven option to overcome resistance of established anticancer compounds. Transferring this concept to ruthenium complexes led to the synthesis of dinuclear Ru(II)-arene compounds containing 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. IC(50) 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 observed 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)analytical 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.
Mendoza-Ferri
Maria G
MG
University of Vienna, Institute of Inorganic Chemistry, Austria.
Hartinger
Christian G
CG
Mendoza
Marco A
MA
Groessl
Michael
M
Egger
Alexander E
AE
Eichinger
Rene E
RE
Mangrum
John B
JB
Farrell
Nicholas P
NP
Maruszak
Magdalena
M
Bednarski
Patrick J
PJ
Klein
Franz
F
Jakupec
Michael A
MA
Nazarov
Alexey A
AA
Severin
Kay
K
Keppler
Bernhard K
BK
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D006868:Hydrolysis; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008024:Ligands; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017671:Platinum Compounds / Q000494:pharmacology; D012428:Ruthenium / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014168:Transferrin / Q000378:metabolism
D000970:Antineoplastic Agents; D008024:Ligands; D009942:Organometallic Compounds; D017671:Platinum Compounds; D014168:Transferrin; D012428:Ruthenium; D004247:DNA