Cancer cell-selective modulation of mitochondrial respiration and metabolism by potent organogold(<scp>iii</scp>) dithiocarbamates

Mertens, Randall Tyler; Parkin, Sean; Awuah, Samuel G.

doi:10.1039/d0sc03628e

Cited by 39 publications

(37 citation statements)

References 112 publications

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“… 17 Alternative metals used in recent metal-based drug discovery include ruthenium, 18,19 rhenium, 20,21 osmium, 22,23 and gold. 24–27 Additionally, developing metal-based anticancer compounds with a known mechanism of action, well differentiated from cisplatin is essential to overcome cisplatin resistance and improve therapeutic performance.…”

Section: Introductionmentioning

confidence: 99%

Anticancer gold(iii)-bisphosphine complex alters the mitochondrial electron transport chain to induce in vivo tumor inhibition

et al. 2021

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Section: Introductionmentioning

confidence: 99%

Anticancer gold(iii)-bisphosphine complex alters the mitochondrial electron transport chain to induce in vivo tumor inhibition

et al. 2021

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“…The compounds were both precipitated from a concentrated DCM solution with excess Et 2 O to afford the yellow solids in good yields (Scheme 1). The compounds were characterized by 1 H NMR, 13 C NMR, 31 P NMR, high-resolution mass spectrometry (HRMS) and the purity was ascertained by elemental analysis (EA). The structure of 2 was further confirmed by X-ray crystallography, indicating that a monocation complex was formed.…”

Section: Synthesis and Characterizationmentioning

confidence: 99%

“…Deuterated solvents were purchased from Cambridge Isotope Laboratories (Andover, MA, USA). NMR spectra were recorded on a Bruker Avance NEO 400 MHz spectrometer and samples calibrated for: 1 H NMR (CDCl3 δ = 7.26 ppm), 13 C NMR (CDCl3 δ = 77.16) and 31 P NMR externally referenced to H3PO4 δ = 0.00. High-resolution mass spectra (HRMS) were obtained by…”

Section: General Experimental Detailsmentioning

confidence: 99%

“…The number of metal-based complexes currently in use for the treatment of cancer is limited to a few platinum complexes (Platinol ® and Paraplatin ® ) and Arsenic dioxide (Trisenox ® ) approved by the Food and Drug Admistration (FDA) [3,10,11], hence the need to develop new metallodrugs for use as anticancer agents. Our lab has been interested in gold metal complexes and their mechanism of action as novel possible anticancer agents [12,13]. We have synthesized and studied a library of gold(I)/(III) compounds with anticancer and antimicrobial activities with a view of understanding their mechanism of action and selectivity for tumor cells [14].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, Characterization, and Antiproliferative Activity of Novel Chiral [QuinoxP*AuCl2]+ Complexes

et al. 2020

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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 HAuCl4.3H2O 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 IC50 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.

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“…We and others have shown that gold compounds can be tuned for mitochondrial localization. 6 Increasing evidence suggests that mitochondrial biological processes participate in acquired drug resistance. Specifically, loss of the mitochondrial protein CLPB compromises mitochondrial structural and functional integrity leading to AML sensitization to apoptosis.…”

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Synthetic Control of Mitochondrial Dynamics: Developing Three-Coordinate Au(I) Probes for Perturbation of Mitochondria Structure and Function

Mertens

Jennings

Ofori

et al. 2021

JACS Au

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Mitochondrial structure and organization is integral to maintaining mitochondrial homeostasis and an emerging biological target in aging, inflammation, neurodegeneration, and cancer. The study of mitochondrial structure and its functional implications remains challenging in part because of the lack of available tools for direct engagement, particularly in a disease setting. Here, we report a gold-based approach to perturb mitochondrial structure in cancer cells. Specifically, the design and synthesis of a series of tricoordinate Au(I) complexes with systematic modifications to group 15 nonmetallic ligands establish structure–activity relationships (SAR) to identify physiologically relevant tools for mitochondrial perturbation. The optimized compound, AuTri-9 selectively disrupts breast cancer mitochondrial structure rapidly as observed by transmission electron microscopy with attendant effects on fusion and fission proteins. This phenomenon triggers severe depolarization of the mitochondrial membrane in cancer cells. The high in vivo tolerability of AuTri-9 in mice demonstrates its preclinical utility. This work provides a basis for rational design of gold-based agents to control mitochondrial structure and dynamics.

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

Abstract: Modulating mitochondrial metabolism is a fruitful arena to target metabolic diseases and cancer. Here, we demonstrate that organometallic gold compounds inhibit mitochondrial OXPHOS to selectively kill aggressive TNBC cancer cells.

Cited by 39 publications

References 112 publications

Anticancer gold(iii)-bisphosphine complex alters the mitochondrial electron transport chain to induce in vivo tumor inhibition

Anticancer gold(iii)-bisphosphine complex alters the mitochondrial electron transport chain to induce in vivo tumor inhibition

Synthesis, Characterization, and Antiproliferative Activity of Novel Chiral [QuinoxP*AuCl2]+ Complexes

Synthetic Control of Mitochondrial Dynamics: Developing Three-Coordinate Au(I) Probes for Perturbation of Mitochondria Structure and Function

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