Cytotoxicity, cellular localization and photophysical properties of Re(I) tricarbonyl complexes bound to cysteine and its derivatives
JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY(2020)
摘要
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.
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关键词
Re(I) tricarbonyl complexes,Cysteine and thiol-containing biomolecules,Photochemistry,Cytotoxicity,X-ray fluorescence miscorscopy
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