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Triple-negative breast cancer (TNBC) is associated with metabolic heterogeneity and poor prognosis with limited treatment options. New treatment paradigms for TNBC remains an unmet need. Thus, therapeutics that target metabolism are particularly attractive approaches. We previously designed organometallic Au(III) compounds capable of modulating mitochondrial respiration by ligand tuning with high anticancer potency in vitro and in vivo. Here, we show that an efficacious Au(III) dithiocarbamate (AuDTC) compound induce mitochondrial dysfunction and oxidative damage in cancer cells. Efficacy of AuDTC in TNBC mouse models harboring mitochondrial oxidative phosphorylation (OXPHOS) dependence and metabolic heterogeneity establishes its therapeutic potential following systemic delivery. This provides evidence that AuDTC is an effective modulator of mitochondrial respiration worthy of clinical development in the context of TNBC. ONE SENTENCE SUMMARY: Metabolic-targeting of triple-negative breast cancer by gold anticancer agent may provide efficacious therapy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare the following competing financial interest(s): S.G.A. has patents pending to University of Kentucky Research Foundation. S.G.A. serves on the advisory board and is Chief Science Officer for Phronesis AI., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Chemical control of mitochondrial dynamics and bioenergetics can unravel fundamental biological mechanisms and therapeutics for several diseases including, diabetes and cancer. We synthesized stable, water-soluble gold(III) complexes (Auraformin) supported by biguanide metformin or phenylmetformin for efficacious inhibition of mitochondrial respiration. The new compounds were characterized following the reaction of [C N]-cyclometalated gold(III) compounds with respective biguanides. Auraformin is solution stable in a physiologically relevant environment. We show that auraformin decreases mitochondrial respiration efficiently in comparison to the clinically used metformin by 100-fold. The compound displays significant mitochondrial uptake and induces antiproliferative activity in the micromolar range. Our results shed light on the development of new scaffolds as improved inhibitors of mitochondrial respiration., (© 2021 Wiley-VCH GmbH.)

Herein is reported the synthesis of two Au(III) complexes bearing the ( R , R )-(-)-2,3-Bis( tert -butylmethylphosphino)quinoxaline ( R , R -QuinoxP*) or ( S , S )-(+)-2,3-Bis( tert -butylmethylphosphino)quinoxaline ( S,S -QuinoxP*) ligands. By reacting two stoichiometric equivalents of HAuCl 4 .3H 2 O to one equivalent of the corresponding QuinoxP* ligand, ( R , R )-(-)-2,3-Bis( tert -butylmethylphosphino)quinoxalinedichlorogold(III) tetrachloroaurates(III) ( 1 ) and ( S , S )-(+)-2,3-Bis( tert -butylmethylphosphino)quinoxalinedichlorogold(III) tetrachloroaurates(III) ( 2 ) were formed, respectively, in moderate yields. The structure of ( S , S )-(+)-2,3-Bis( tert -butylmethylphosphino)quinoxalinedichlorogold(III) tetrachloroaurates(III) ( 2 ) was further confirmed by X-ray crystallography. The antiproliferative activities of the two compounds were evaluated in a panel of cell lines and exhibited promising results comparable to auranofin and cisplatin with IC 50 values between 1.08 and 4.83 µM. It is noteworthy that in comparison to other platinum and ruthenium enantiomeric complexes, the two enantiomers ( 1 and 2 ) do not exhibit different cytotoxic effects. The compounds exhibited stability in biologically relevant media over 48 h as well as inert reactivity to excess glutathione at 37 °C. These results demonstrate that the Au(III) atom, stabilized by the QuinoxP* ligand, can provide exciting compounds for novel anticancer drugs. These complexes provide a new scaffold to further develop a robust and diverse library of chiral phosphorus Au(III) complexes.