Inclusion Complexes of Gold(I)‐Dithiocarbamates with β‐Cyclodextrin: A Journey from Drug Repurposing towards Drug Discovery

Abstract The gold(I)‐dithiocarbamate (dtc) complex [Au(N,N‐diethyl)dtc]2 was identified as the active cytotoxic agent in the combination treatment of sodium aurothiomalate and disulfiram on a panel of cancer cell lines. In addition to demonstrating pronounced differential cytotoxicity to these cell lines, the gold complex showed no cross‐resistance in therapy‐surviving cancer cells. In the course of a medicinal chemistry campaign on this class of poorly soluble gold(I)‐dtc complexes, >35 derivatives were synthesized and X‐ray crystallography was used to examine structural aspects of the dtc moiety. A group of hydroxy‐substituted complexes has an improved solubility profile, and it was found that these complexes form 2 : 1 host–guest inclusion complexes with β‐cyclodextrin (CD), exhibiting a rarely observed “tail‐to‐tail” arrangement of the CD cones. Formulation of a hydroxy‐substituted gold(I)‐dtc complex with excess sulfobutylether‐β‐CD prevents the induction of mitochondrial reactive oxygen species, which is a major burden in the development of metallodrugs.


IR spectra of [Au(N, N-diethyl)dtc]2 (5)
: Solid state IR-spectra (KBr pellet) of the isolated reaction product from ATM and DSF (1:1); see Scheme 1. The spectrum of the obtained precipitate (orange) is identical to the spectrum of the material obtained by recrystallization from hot DMF (blue) that was identified as gold(I)-dtc complex 5 by X-ray crystallography. 4000 3900 3800  3700  3600  3500  3400  3300  3200  3100  3000  2900  2800  2700  2600  2500  2400  2300  2200  2100  2000  1900  1800  1700  1600  1500  1400  1300  1200  1100  1000  900  800  700  600  500 wave number [cm -1 ]  To each well was added 2 L of the complex stock solution. A manual 16-channel Finnpipette (Thermo Scientific) was used for mixing by pipetting up and down (eight times). Finally, 40 L of each well were transferred into the 384well Nephelo-plate and measured. Measurements were performed on a Nephelostar Galaxy (BMG Labtech). Raw data (light scatter intensities) were recorded with the corresponding software version 4.30-0; subsequent data processing was done with GraphPad Prism (Version 7.05) using the segmental linear regression model. NMR spectra show a distinct 2:1 host-guest ratio. However, a difference of the chemical shifts of -CD or the gold(I)-dtc complexes compared to the individual compounds was not observed. This is indicative for a dissociation of the inclusion complexes in DMSO that might successfully displace the organic ligands from the cavity of the CD cones. [1] Determination of Inclusion Complex Structural Parameters Figure S5: Determination of the structural parameters for the description of the arrangement of the CD cones within the inclusion complexes on the example of [43/(-CD)2] using Mercury. [2] For clarity the gold(I)-dtc complex was deleted. For each CD cone a mean plane (purple and yellow, respectively) through all seven glycosidic oxygens (highlighted as red balls) as well as the corresponding centroid (green balls) were defined. The angle between the CD cones is defined as the angle between both formerly defined planes. The sidewards shift of the CD cones is calculated using the Pythagorean theorem as depicted above -the mean of both possible values is reported (the difference in both values is a result of the angle between both planes).   Langaro et al. [13] S9 13 hexakis(μ2-N-(3,6,9,12-Tetraoxatetradecane-1,14diyl)dithiocarbamato)-hexa-gold (i)   No eightmembered ring  chelate   ---VOCRUB  645163 Arias et al. [14] [

Syntheses of the Gold(I)-dtc Complexes [15]
[Au I (N,N-diethyl)dtc]2 5: A solution of ATM (2.0 g, 5.13 mmol, 1.0 equiv.), dissolved in 80.0 mL of water, and a solution of sodium diethyldithiocarbamate trihydrate (1.39 g, 6.15 mmol, 1.2 equiv.), dissolved in 20.0 mL of water, were combined and vigorously stirred at room temperature over night. The obtained orange powder was filtered and thoroughly washed with water and dried under high vacuum over night (1.55 g, 2.24 mmol, 87%). This material was recrystallized from hot DMF (approximately 500 mL) to afford orange needles as the pure product in a yield of 82% (1.

[Au I (N,N-dimethyl)dtc]2 7:
Chloro(dimethyl sulfide)gold(I) (325.1 mg, 1.1 mmol, 1.0 equiv.) and dimethyldithiocarbamate (157.5 mg, 1.1 mmol, 1.0 equiv.) were dissolved in 20.0 mL of acetonitrile each. The solutions were combined upon which a yellow solid precipitated. The mixture was stirred at room temperature for 3 h and afterwards filtered through a sintered glass funnel (pore 4). The solid was thoroughly washed with water, a small amount of ethanol and diethyl ether successively and dried under high vacuum over night. The product was obtained as a yellow powder in a yield of 35% (121. 8  N-ethylmethyl amine (0.69 g, 1.0 mL, 11.67 mmol, 1.0 equiv.) was dissolved in 50.0 mL of dry THF and cooled to -78°C. Then n-butyllithium (2.5 M in hexane, 4.67 mL, 11.67 mmol, 1.0 equiv.) was added dropwise and the resulting mixture was stirred for 15 minutes whereupon carbon disulfide (0.89 g, 0.7 mL, 11.67 mmol, 1.0 equiv.) was added dropwise. The resulting mixture was stirred at -78°C for 15 minutes and afterwards allowed to warm up to room temperature. After a total reaction time of 3 h the solution was concentrated and dried under high vacuum over night. The product was obtained as a reddish solid in quantitative yield and was used in the next step without further purification.

Compound S5
Compound S4 (4.84 g, 14.51 mmol, 1.0 equiv.) was dissolved in 50.0 mL of dry THF and cooled to -78°C. Then n-butyllithium (2.5 M solution in hexane, 5.8 mL, 14.51 mmol, 1.0 equiv.) was added dropwise and the resulting mixture was stirred for 15 minutes whereupon carbon disulfide (1.1 g, 0.72 mL, 14.51 mmol, 1.0 equiv.) was added dropwise. The resulting mixture was stirred at -78°C for 15 minutes and afterwards allowed to warm up to room temperature. After a total reaction time of 3 h the solution was concentrated and dried under high vacuum over night. The product was obtained as an off-white solid in quantitative yield and was used in the next without further purification. 1 H NMR (400 MHz, CDCl3) δ 4.2 (t, J = 5.8 Hz, 4H), 4.0 (t, J = 5.9 Hz, 4H), 0.88 (s, 18H), 0.05 (s, 12H) ppm.

[Au I (N,N-bis(2-((tert-butyldimethylsilyl)oxy) ethyl) dtc]2 15:
A solution of ATM (0.5 g, 1.28 mmol, 1.0 equiv) and a solution of compound S5 (798.2 mg, 1.92 mmol, 1.5 equiv.), dissolved in 10.0 mL of water each, were combined and vigorously stirred at room temperature for 2 h. The obtained precipitate was filtered and washed with a small amount of water and dried under high vacuum over night. A grey powder was obtained as the pure product in a yield of 44% (509.7 mg, 0.42 mmol). 1 H NMR (400 MHz, CDCl3) [Au I (pyrrolidinyl)dtc]2 20: [18] A solution of ATM (400.0 mg, 1.03 mmol, 1.0 equiv.) and a solution of ammonium pyrrolidine dithiocarbamate (336.8 mg, 2.05 mmol, 2.0 equiv.), dissolved in 5.0 mL of water each, were combined and vigorously stirred at room temperature over night. The obtained orange powder was centrifuged. The supernatant was taken away and the residue was resuspended in water and again centrifuged (procedure repeated twice). The obtained orange solid was dried under high vacuum over night and afterwards recrystallized form hot DMF to S20 afford orange-colored needles as the pure product in a yield of 38% (133. 8