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

摘要

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 Po/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, >1,100). 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.