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

Abstract

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) 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 (τ) ranged from 4-10 ns for IL states and 12-18 ns forMLCT states. Transient absorption lifetimes (τ) were 5-8 μs with 355 nm excitation, ascribed to IL states that became inaccessible for 1-3 with 532 nm excitation (1-3, τ = 16-17 ns); the IL of 4 only was accessible by lower energy excitation, τ = 3.8 μs. Complex 4 was nontoxic (EC > 300 μM) to SK-MEL-28 melanoma cells and CCD1064-Sk normal skin fibroblasts in the dark, while 3 was selectively cytotoxic to melanoma (EC= 5.1 μM) only. Compounds 1 and 2 were selective for melanoma cells in the dark, with submicromolar potencies (EC = 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.

Synthesis and Characterization of Ru(II) Complexes with π‐Expansive Imidazophen Ligands for the Photokilling of Human Melanoma Cells

“… * Singlet oxygen quantum yields (Φ ∆ ) for 1 ‐ 7 were measured in aerated acetonitrile using Eq. 2 relative to [Ru(bpy) 3 ](PF 6 ) 2 (Φ ∆ = 0.57 in aerated acetonitrile) and contains ± 5% error. See Materials and Methods section for more information on the Φ ∆ measurement.…”

Role of Photoactive Phytocompounds in Photodynamic Therapy of Cancer

“…Generally, the aliphatic compounds conjugated with three or more acetylenic bonds are considered phototoxic in nature. Among these, polyacetylenes compounds can produce 1 O 2 under irradiation and thiophenes can provide high photo yield, leading to type 2 PDT reaction yields [ 105 ]. The polyacetylene and thiophenes compounds were reported to be activated or excited at a wavelength range of 314–350 nm absorbance maximum for the relevant photobiological effects [ 75 ].…”

Mechanisms of action of Ru(ii) polypyridyl complexes in living cells upon light irradiation

“…It is possible that redox reactions and complex activation during laser scanning could be the reason for that unexpected phenomena. The good results obtained with TLD-1433 led to the preparation of a series of cyclometalated Ru(II) complexes similar to TLD 1433 structure (1-4,Figure 3) 25.…”