In-vitro and in-vivo investigations into the carbene-gold anticancer drug candidates NHC*-Au-SCSNMe2 and NHC*-Au-S-GLUC against advanced prostate cancer PC3

Abstract

The anticancer drug candidates 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative exhibited nanomolar in-vitro activity against prostate cancer cells advanced prostate cancer (PC3) and micromolar inhibition of mammalian thioredoxin reductase. Encouraging maximum tolerable dose experiments led to human prostate cancer subcutaneous xenograft experiments; 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative were applied twelve times at two doses in groups of n = 5 PC3 to tumor-bearing NMRI:nu/nu mice. 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative at the dose of 10 and 20 mg/kg showed good tolerability, while no significant body weight loss was seen in both groups. In particular, for the drug 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate the tumor growth inhibition suggested to be dose dependent, reflected by the respective optimal T/C values of 0.45 at the dose of 10 mg/kg and of 0.31 at the dose of 20 mg/kg. By contrast, the 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative treated groups showed no indication for dose-dependent antitumoral activity, as reflected by the optimal T/C values of 0.44 for the 10 mg/kg and for the 20 mg/kg treated mice. Immunohistochemical experiments involving Ki67 staining of tumor tissue showed that both compounds reduced PC3 cell proliferation against the difficult to treat advanced human prostate tumors derived from PC3.

Breast Cancer Treatment: The Case of Gold(I)-Based Compounds as a Promising Class of Bioactive Molecules

“…Even though many in vitro studies have been led to test the cytotoxic activities of gold(I) carbenes against numerous panels of cancer cells, only a few recent studies report in vivo tests and none of them is about breast cancer models. After an extensive in vitro study highlighting a mechanism of action mainly involving mammalian TrxR inhibition in the lower micromolar range, a preclinical report on a 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative and 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate describes prostate cancer growth inhibition on an advanced prostate cancer (PC3) xenograft model [ 58 , 64 ]. The anticancer effect of these compounds was associated with a good tolerability by mice in terms of weight loss and general wellness.…”

Novel Anticancer NHC*-Gold(I) Complexes Inspired by Lepidiline A

“…A slight shift in the CH 2 peak from δ = 5.44 ppm to 5.45 and 5.49 ppm, for 5a and 5b-5e respectively, confirmed conjugation. 19 F-NMR spectroscopy proved useful as it detected the presence of the alkynyl ligand for 5d and 5e. More significantly, in the 13 C-NMR spectra two signals for the alkyne appeared: δ = 121.8-125.9 ppm and 103.9-105.3 ppm.…”

“…Solvents were dried according to the standard procedures, when necessary. 1 H, 13 C, 19 F and 31 P spectra were recorded on either a 300, 400 or 500 MHz Varian spectrometer at room temperature (rt). Both chloroform (CDCl 3 ) and dimethyl sulfoxide (DMSO) were used as deuterated solvents.…”

“…1 H-NMR (400 MHz, CDCl 3 , δ ppm): 7.45 (dd, J = 8.7, 5.5 Hz, 130.9 (CH), 129.3 (CH), 128.7 (CH), 128.6 (CH), 128.1 (CH), 127.7 (CH), 127.6 (CH), 121.8 (C≡C), 115.1 (C), 114.9 (CH), 104.1 (C≡C), 52.9 (CH2). 19 In a procedure identical to above reaction: phenyl](trimethylsilyl)acetylene (20.4 μL, 0.087 mmol, 1.1 equiv. ), 2a (50 mg, 0.079 mmol, 1.0 equiv.)…”

“…The refinement of NHCs has resulted in many cytotoxic NHC-gold(I) complexes, thus confirming their eligibility as potential chemotherapeutic agents [7]. Recently, we have reported the in vivo anticancer activity of two gold(I)-based complexes, NHC*-Au(I)-SC(S)N(CH 3 ) 2 and NHC*-Au(I)-(2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl-1-thiolate), against the human prostate cancer PC3 tumour model [19]. These two complexes were selected to compare the effect of the non-targeting and targeting moieties adjacent to the NHC*-gold(I) species.…”