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

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, 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 thiolcontaining 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.

ReI Tricarbonyl Complexes as Coordinate Covalent Inhibitors for the SARS‐CoV‐2 Main Cysteine Protease

“…The interaction of the chloride ( 1 ) and aqua ( 22 ) Re I tricarbonyl complex with amino acids containing cationic (N α ‐ p ‐tosyl‐L‐arginine methyl ester, L‐histidine methyl ester, L‐lysine methyl ester), anionic (N α ‐ tert ‐butoxycarbonyl‐L‐aspartic acid tert ‐butyl ester), polar (L‐serine methyl ester, L‐asparagine tert ‐butyl ester), and sulphur (L‐cysteine methyl ester, L‐methionine methyl ester) side chains was investigated (Figure 4) using equimolar amounts of metal complex and amino acid. Previous studies have indicated that Re I tricarbonyl complexes are able to react with Cys derivatives [47, 49, 50] and a crystal structure has revealed that the Cys is covalently bound in axial position [49] …”

The effect of sodium thiosulfate on cytotoxicity of a diimine Re(i) tricarbonyl complex

“…The cytotoxicity of compounds 1, 2 and cisplatin were assessed with the MDA-MB-231 breast cancer cell line using the alamarBlue cell viability assay and IC50 values were determined (Table 1); we previously discussed the data for 1 and cisplatin. 46 The results showed greater cytotoxicity for complex 1 (IC50 = 38 ± 6 μM) at 24 h, compared to both cisplatin and 2 (IC50 >100 μM) over the same time period. After 48 h the IC50 of 1 decreased to 26 ± 3 μM, whereas cisplatin was 11 ± 2 μM.…”

“…47 fac-[Re(CO)3(bpy)(H2O)](CF3SO3) (1) was prepared from fac-[Re(CO)3(bpy)Cl] as previously described. 46,48,49 Cell culture. MDA-MB-231 breast cancer cells (American Type Culture Collection; ATCC) were genetically validated and used within 6 months of testing.…”

“…70 Neutral complexes display relatively lower cellular uptake and toxicity. 46,66,71 Consequently changes in the nature of the diimine (N,N) and the ancillary (X) ligands in fac-[Re(CO)3(L)(X)] -,0,+ complexes affecting their charge and lipophilicity, play an important role in their cellular uptake.…”

“…43,44 Using XFM, we were able to explain the significant changes in cytotoxicity of fac-[Re(CO)3(bpy)(H2O)](CF3SO3) (1) 45 as a result of reduced cellular uptake of the product when the aqua ligand is replaced with cysteine (H2Cys), forming fac-[Re(CO)3(bpy)(HCys)]. 46 Here, we present the synthesis and structural characterization of the thiosulfate complex in the compound Na(fac-[Re(CO)3(bpy)(S2O3)]) . H2O (2), obtained from the reaction of 1 with Na2S2O3 in aqueous solution.…”