Inclusion Complexes of Gold(I)-Dithiocarbamates with β-Cyclodextrin: A Journey from Drug Repurposing towards Drug Discovery.
Michael MorgenPiotr FabrowskiEberhard AmtmannNikolas GunkelAubry K MillerPublished in: Chemistry (Weinheim an der Bergstrasse, Germany) (2021)
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.
Keyphrases
- drug discovery
- reactive oxygen species
- silver nanoparticles
- molecular docking
- oxidative stress
- drug delivery
- high resolution
- magnetic resonance imaging
- squamous cell carcinoma
- stem cells
- gold nanoparticles
- mouse model
- magnetic resonance
- mesenchymal stem cells
- papillary thyroid
- young adults
- sensitive detection
- cell therapy