Cytotoxic Rhodium(III) and Iridium(III) Polypyridyl Complexes: Structure–Activity Relationships, Antileukemic Activity, and Apoptosis Induction

Abstract Whereas the cytostatic agents mer ‐[RhX 3 (DMSO)(pp)] (X=Cl, Br; pp=phen, dpq) are considerably more potent than their facial isomers, this order is reversed for the analogous kinetically more inert Ir III polypyridyl complexes. The complexes induce specific apoptotic cell death in leukemia and lymphoma cells via the intrinsic mitochondrial pathway and cause negligible necrotic damage. magnified image Meridional rhodium(III) polypyridyl complexes of the type mer ‐[RhX 3 (DMSO)(pp)] (X=Cl, pp=phen 1 , dpq 2 , dppz 3 ; X=Br, pp=phen 4 ) represent a promising class of potent cytostatic agents for the treatment of lymphoma and leukemia. Exposure of their DMSO solutions to light leads to slow isomerization to mixtures of the mer and the generally less active fac isomers. As a result, the IC 50 values of 1 and 2 toward HT‐29 cells increase from 0.19 and 0.069 μ M on immediate use in the dark to 0.66 and 0.312 μ M , respectively, after exposure of their DMSO stock solutions to light for 7 days. In striking contrast, the complexes mer ‐[IrX 3 (DMSO)(phen)] (X=Cl 7 , Br 8 ) are significantly less cytotoxic than their facial Ir III polypyridyl counterparts: IC 50 =20.3 μ M for 7 and 4.6 μ M for fac ‐[IrCl 3 (DMSO)(phen)] 5 toward MCF‐7 cells. The IC 50 values for the complexes fac ‐[IrX 3 (L)(pp)] 9 – 13 decrease in the orders: a) Cl>Br for X and b) H 2 O>DMSO for L. Specific apoptotic cell death by DNA fragmentation was detected for leukemia (NALM‐6) and lymphoma (BJAB) cells after incubation with 2 , 3 , and 11 (X=Br, L=H 2 O, pp=phen) for 72 h. Loss of the mitochondrial membrane potential in lymphoma cells indicates that apoptosis is mediated via the intrinsic mitochondrial pathway. LDH release assays after 1 or 3 h demonstrate that necrotic damage is negligible.