Monofunctional BODIPY-Appended Imidazoplatin for Cellular Imaging and Mitochondria-Targeted Photocytotoxicity

Abstract

Monofunctional platinum(II) complexes of formulation cis-[Pt(NH₃)₂(L)Cl](NO₃), where L is an imidazole base conjugated to 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) with emissive (L¹ in 1) and nonemissive (L² in 2) moieties were prepared and characterized, and their singlet oxygen-mediated photoinduced cytotoxicity was studied. The 1-methylimidazole (1-MeIm) complex 3 was prepared as a control and for structural characterization by X-ray crystallography. Complexes 1 and 2 showed strong visible absorption bands at 500 nm (ε = 2.7 × 10⁴ M^-1 cm^-1) and 540 nm (1.4 × 10⁴ M^-1 cm^-1). Complex 1 is emissive with a band at 510 nm (Φ_F = 0.09) in 1% dimethyl sulfoxide/Dulbecco's Modified Eagle's Medium (pH 7.2). Singlet oxygen generation upon photoirradiation with visible light (400-700 nm) was evidenced from 1,3-diphenylisobenzofuran titration experiments showing significant photosensitizing ability of the BODIPY complexes. Both 1 and 2 were remarkably photocytotoxic in visible light (400-700 nm, 10 J cm^-2) in skin keratinocyte HaCaT and breast cancer MCF-7 cells giving IC₅₀ values in nanomolar concentration. The complexes were, however, essentially nontoxic to the cells in the dark (IC₅₀ > 80 μM). Complex 2 having a diiodo-BODIPY unit is nonemissive but an efficient photosensitizer with high singlet oxygen generation ability in visible light (400-700 nm). Confocal microscopy using the emissive complex 1 showed significant mitochondrial localization of the complex. Cell death via apoptotic pathway was observed from the Annexin-V-FITC/PI assay. The formation of Pt-DNA adducts was evidenced from the binding experiments of the complexes 1 and 2 with 9-ethylguanine as a model nucleobase from ¹H NMR and mass spectral studies.