A strategy for combinatorial parallel coordination chemistry is introduced that provides access to libraries of tris-heteroleptic ruthenium complexes in an economical fashion. Using this method, a library of 560 constitutionally unique, monocationic ruthenium complexes was synthesized, followed by a screening for anticancer activity and resulting in the identification of three hits with promising cytotoxic properties in HeLa cancer cells. A subsequent structure–activity relationship led to the discovery of the surprisingly simple anticancer complex [Ru(tBu2bpy)2(phox)]PF6 (complex 1), with tBu2bpy = 4,4′-di-tert-buty-2,2′-bipyridine and Hphox = 2-(2′-hydroxyphenyl)oxazoline, displaying an LC50 value in HeLa cells of 1.3 μM and 0.3 μM after incubation for 24 and 72 h, respectively. Complex 1 also shows remarkable antiproliferative and apoptotic properties at submicromolar concentrations in more clinically relevant Burkitt-like lymphoma cells. A reduction of the mitochondrial membrane potential by 1 indicates the involvement of the intrinsic pathway of programmed cell death. Further investigations reveal that 1 requires caspase-3 for the induction of apoptosis but is insensitive to the proapoptotic and antiapoptotic proteins Smac and Bcl-2, respectively.
Available at: http://works.bepress.com/seann_mulcahy/1/