Cancer cell-selective modulation of mitochondrial respiration and metabolism by potent organogold(iii) dithiocarbamates.

Chemical Science
R Tyler MertensSamuel G Awuah

Abstract

Metabolic reprogramming is a key cancer hallmark that has led to the therapeutic targeting of glycolysis. However, agents that target dysfunctional mitochondrial respiration for targeted therapy remains underexplored. We report the synthesis and characterization of ten (10) novel, highly potent organometallic gold(iii) complexes supported by dithiocarbamate ligands as selective inhibitors of mitochondrial respiration. The structure of dithiocarbamates employed dictates the biological stability and cellular cytotoxicity. Most of the compounds exhibit 50% inhibitory concentration (IC50) in the low-micromolar (0.50-2.9 μM) range when tested in a panel of aggressive cancer types with significant selectivity for cancer cells over normal cells. Consequently, there is great interest in the mechanism of action of gold chemotherapeutics, particularly, considering that DNA is not the major target of most gold complexes. We investigate the mechanism of action of representative complexes, 1a and 2a in the recalcitrant triple negative breast cancer (TNBC) cell line, MDA-MB-231. Whole-cell transcriptomics sequencing revealed genes related to three major pathways, namely: cell cycle, organelle fission, and oxidative phosphorylation. 2a irreve...Continue Reading

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Citations

May 18, 2021·Journal of Medicinal Chemistry·Juzheng ZhangHong Liang
Dec 10, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Adedamola S ArojojoyeSamuel G Awuah
Jun 11, 2021·Dalton Transactions : an International Journal of Inorganic Chemistry·Andrea PettenuzzoLuca Ronconi
Oct 28, 2021·Chemical Communications : Chem Comm·Sumit Kumar Pramanik, Amitva Das
Sep 24, 2021·Molecular Cancer Therapeutics·Tianyuan WangLi Zhang

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Datasets Mentioned

BETA
GM130456

Methods Mentioned

BETA
X-ray
RNA-seq
Hi-seq
fluorescence activated cell sorting
flow cytometry
FACS
NMR

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