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

JBIC Journal of Biological Inorganic Chemistry volume 25, pages 759–776 (2020)Cite this article

Abstract

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, H2O, pyridine derivatives, PR3, etc.) complexes of special interest. We have investigated reactions of the aqua complex fac-[Re(CO)3(bpy)(H2O)](CF3SO3) (1) with potential anticancer activity with the amino acid l-cysteine (H2Cys), and its derivative N-acetyl-l-cysteine (H2NAC), as well as the tripeptide glutathione (H3A), 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)]·0.5H2O (2), Na(fac-[Re(CO)3(bpy)(NAC)]) (3), and Na(fac-[Re(CO)3(bpy)(HA)])·H2O (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)]}4·9H2O (2 + 1.75 H2O). 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 (1O2) 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)(H2O)](CF3SO3) 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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Abbreviations

ESI–MS:

Electrospray ionization mass spectrometry

EXAFS:

Extended X-ray absorption fine structure spectroscopy

XFM:

X-ray fluorescence microscopy

PDT:

Photodynamic therapy

PACT:

Photo-activated chemotherapy

MT:

Metallothionein

GC-TCD:

Gas chromatography with thermal conductivity detection

HOMO:

Highest occupied molecular orbital

LUMO:

Lowest unoccupied molecular orbital

TD-DFT:

Time-dependent density functional theory

MLLCT:

Metal–ligand to ligand charge transfer

ILCT:

Intra-ligand charge transfer

bpy:

2,2′-Bipyridine

phen:

1,10-Phenanthroline

dmphen:

2,9-Dimethyl-1,10-phenantroline

DMEM:

Dulbecco’s Modified Eagles Medium

PBS:

Phosphate-buffered saline

IC50 :

Half-maximal inhibitory concentration

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Acknowledgements

We express our sincere appreciation to Mr. Wade White at the instrumentation facility at the Department of Chemistry for his assistance with the ESI–MS measurements, and to Ms. Valerie Brunskill for measuring the 13C and 1H NMR spectra of cysteine and glutathione solutions. A.E.G acknowledges University of Calgary Eyes High, and Faculty of Science Dean’s Open Competitions Doctoral Scholarships. N.M. acknowledges NSERC for an Alexander Graham Bell Canada Graduate Scholarship-Doctoral and Alberta Innovates for a Nanotechnology Doctoral Scholarship. This work was financially supported by the Natural Science and Engineering Research Council of Canada (NSERC), the Canadian Cancer Society, the Canadian Foundation for Innovation (CFI), Department of Innovation and Science of Province of Alberta. X-ray absorption spectra were measured at the Photon Factory (PF; proposal no. 2018G563) and X-ray fluorescence microscopy data were collected at the Advanced Photon Source (APS; proposal no. 53103). Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract No. DE-AC02-06CH11357.

Funding

The following funding is acknowledge: Natural Science and Engineering Research Council of Canada (Grant no. RGPIN 2016-04546 to FJ and RGPIN 2018-04773 to CS), Canadian Cancer Society (Grant no. 300072 to CS); Canadian Foundation for Innovation (Grant no. 9479 to FJ); Department of Innovation and Science of Province of Alberta (Grant to FJ).

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Authors and Affiliations

  1. Department of Chemistry, University of Calgary, Calgary, AB, T2N 1N4, Canada

    Miles S. Capper, Alejandra Enriquez Garcia, Nicolas Macia, Jian-Bin Lin, Belinda Heyne & Farideh Jalilehvand

  2. Advanced Photon Source, X-Ray Science Division, Argonne National Laboratory, Argonne, IL, 60439, USA

    Barry Lai

  3. Institute for Materials Structure Science, High Energy Accelerator Research Organization, Oho 1-1, Tsukuba, 305-0801, Japan

    Masaharu Nomura

  4. Department of Chemical and Petroleum Engineering, University of Calgary, Calgary, AB, T2N 1N4, Canada

    Amir Alihosseinzadeh & Sathish Ponnurangam

  5. Department of Biological Sciences, University of Calgary, Calgary, AB, T2N 1N4, Canada

    Carrie S. Shemanko

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  1. Miles S. Capper
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Capper, M.S., Enriquez Garcia, A., Macia, N. et al. Cytotoxicity, cellular localization and photophysical properties of Re(I) tricarbonyl complexes bound to cysteine and its derivatives. J Biol Inorg Chem 25, 759–776 (2020). https://doi.org/10.1007/s00775-020-01798-9

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Keywords

  • Re(I) tricarbonyl complexes
  • Cysteine and thiol-containing biomolecules
  • Photochemistry
  • Cytotoxicity
  • X-ray fluorescence miscorscopy