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Inclusion Complexes of Gold(I)‐Dithiocarbamates with β‐Cyclodextrin: A Journey from Drug Repurposing towards Drug Discovery
Author(s) -
Morgen Michael,
Fabrowski Piotr,
Amtmann Eberhard,
Gunkel Nikolas,
Miller Aubry K.
Publication year - 2021
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202101366
Subject(s) - chemistry , dithiocarbamate , cyclodextrin , moiety , cytotoxicity , reactive oxygen species , combinatorial chemistry , gold compounds , drug , chelation , stereochemistry , pharmacology , in vitro , organic chemistry , biochemistry , biology
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.