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

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.
Inclusion complex of a complex: The two drugs disulfiram and aurothiomalate react to produce a gold(I)‐dithiocarbamate complex, which selectively kills cancer cells. Hydroxy‐substituted derivatives of this complex form inclusion complexes with β‐cyclodextrin in a rare “tail‐to‐tail” arrangement. Formulation of one gold complex with a β‐cyclodextrin derivative prevents formation of reactive oxygen species in mitochondria.