Cyclometalated Ruthenium(II) Complexes Derived from α‑Oligothiophenes as Highly Selective Cytotoxic or Photocytotoxic Agents

The photophysical and photobiological properties of a new class of cyclometalated ruthenium­(II) compounds incorporating π-extended benzo­[h]­imidazo­[4,5-f]­quinoline (IBQ) cyclometalating ligands (C^N) bearing thienyl rings (n = 1–4, compounds 1–4) were investigated. Their octanol–water partition coefficients (log P o/w) were positive and increased with n. Their absorption and emission energies were red-shifted substantially compared to the analogous Ru­(II) diimine (N^N) complexes. They displayed C^N-based intraligand (IL) fluorescence and triplet excited-state absorption that shifted to longer wavelengths with increasing n and N^N-based metal-to-ligand charge transfer (MLCT) phosphorescence that was independent of n. Their photoluminescence lifetimes (τem) ranged from 4–10 ns for 1IL states and 12–18 ns for 3MLCT states. Transient absorption lifetimes (τTA) were 5–8 μs with 355 nm excitation, ascribed to 3IL states that became inaccessible for 1–3 with 532 nm excitation (1–3, τTA = 16–17 ns); the 3IL of 4 only was accessible by lower energy excitation, τTA = 3.8 μs. Complex 4 was nontoxic (EC50 > 300 μM) to SK-MEL-28 melanoma cells and CCD1064-Sk normal skin fibroblasts in the dark, while 3 was selectively cytotoxic to melanoma (EC50= 5.1 μM) only. Compounds 1 and 2 were selective for melanoma cells in the dark, with submicromolar potencies (EC50 = 350–500 nM) and selectivity factors (SFs) around 50. The photocytotoxicities of compounds 1–4 toward melanoma cells were similar, but only compounds 3 and 4 displayed significant phototherapeutic indices (PIs; 3, 43; 4, >1100). The larger cytotoxicities for compounds 1 and 2 were attributed to increased cellular uptake and nuclear accumulation, and possibly related to the DNA-aggregating properties of all four compounds as demonstrated by cell-free gel mobility-shift assays. Together, these results demonstrate a new class of thiophene-containing Ru­(II) cyclometalated compounds that contain both highly selective chemotherapeutic agents and extremely potent photocytotoxic agents.