Cyclopentadienyl Half-Sandwich Rhodium(III) Azopyridine Anticancer Complexes with Activity Tuned by Ligand Substituents

We report the synthesis and characterization of ten novel half-sandwich Rh(III) azopyridine complexes as potential anticancer agents, with the general formula [(η⁵-Cp^x)Rh(4-R₂-phenylazopy-5-R₁)Cl]PF₆, where Cp^x = Cp*, Cp^xPh or Cp^xPhPh, R₁ = H, Br, or CF₃, and R₂ = H, OH or NMe₂. X-ray crystallographic data for complex 2 (R₁ = Br, R₂ = OH, Cp^x = Cp^xPh) and complex 3 (R₁ = CF₃, R₂ = OH, Cp^x= Cp^xPh) confirm their typical half-sandwich “piano-stool” geometry. The substituents have a major influence on the cytotoxicity of these complexes toward human ovarian (A2780 and cisplatin-resistant A2780cis), lung (A549) and prostate (PC-3) cancer cells, and non-cancerous human lung fibroblasts (MRC-5). Potencies range from sub-micromolar to inactive (>50 µM). They were non-cross-resistant with cisplatin, and complex 9 (R₁ = H, R₂ = NMe₂, Cp^x= Cp^*) showed some selectivity (>3x) for A549 cancer cells versus normal cells. The highly active, lipophilic complex 2 was strongly accumulated by cells and catalyzed the oxidation of NADH (reduced nicotinamide adenine dinucleotide) to NAD⁺, and GSH (glutathione) to GSSG. Notably, complex 2 is almost an order of magnitude less toxic toward zebrafish in vivo than cisplatin, despite being 10-fold more active in A549 cells. These studies demonstrate how the chemical and biological activities of this series of half-sandwich organorhodium(III) complexes can be finely tuned by the choice of substituents on the cyclopentadienyl and azopyridine ligands. The complexes appear to have an unusual mechanism of anticancer activity, associated not only with Rh(III) but also with the phenylazopyridine, cyclopentadienyl, and the chlorido ligands.