Cytotoxicity, cellular localization and photophysical properties of Re(I) tricarbonyl complexes bound to cysteine and its derivatives

The potential chemotherapeutic properties coupled to photochemical transitions make the family of fac -[Re(CO) 3 ( N,N )X] 0/+ ( N,N = a bidentate diimine such as 2,2′-bipyridine (bpy); X = halide, H 2 O, pyridine derivatives, PR 3 , etc.) complexes of special interest. We have investigated reactions of the aqua complex fac -[Re(CO) 3 (bpy)(H 2 O)](CF 3 SO 3 ) ( 1 ) with potential anticancer activity with the amino acid l- cysteine (H 2 Cys), and its derivative N -acetyl- l -cysteine (H 2 NAC), as well as the tripeptide glutathione (H 3 A), under physiological conditions (pH 7.4, 37 °C), to model the interaction of 1 with thiol-containing proteins and enzymes, and the impact of such coordination on its photophysical properties and cytotoxicity. We report the syntheses and characterization of fac -[Re(CO) 3 (bpy)(HCys)]·0.5H 2 O ( 2 ), Na( fac -[Re(CO) 3 (bpy)(NAC)]) ( 3 ), and Na( fac -[Re(CO) 3 (bpy)(HA)])·H 2 O ( 4 ) using extended X-ray absorption spectroscopy, IR and NMR spectroscopy, electrospray ionization spectrometry, as well as the crystal structure of { fac -[Re(CO) 3 (bpy)(HCys)]} 4 ·9H 2 O ( 2 + 1.75 H 2 O). The emission spectrum of 1 displays a variance in Stokes shift upon coordination of l -cysteine and N -acetyl- l -cysteine. Laser excitation at λ = 355 nm of methanol solutions of 1 – 3 was followed by measuring their ability to produce singlet oxygen ( 1 O 2 ) using direct detection methods. The cytotoxicity of 1 and its cysteine-bound complex 2 was assessed using the MDA-MB-231 breast cancer cell line, showing that the replacement of the aqua ligand on 1 with l -cysteine significantly reduced the cytotoxicity of the Re(I) tricarbonyl complex. Probing the cellular localization of 1 and 2 using X-ray fluorescence microscopy revealed an accumulation of 1 in the nuclear and/or perinuclear region, whereas the accumulation of 2 was considerably reduced, potentially explaining its reduced cytotoxicity. Graphic abstract Replacing the aqua ligand with cysteine in the antitumor active fac -[Re(CO) 3 (bpy)(H 2 O)](CF 3 SO 3 ) complex significantly reduced its cellular accumulation and cytotoxicity against the MDA-MB-213 breast cancer cell line, shifted its maximum emission to considerably higher energies, and decreased its fluorescence quantum yield.