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.
The
gold drugs, gold sodium thiomalate (Myocrisin), aurothioglucose
(Solganal), and the orally administered auranofin (Ridaura), are utilized
in modern medicine for the treatment of inflammatory arthritis including
rheumatoid and juvenile arthritis; however, new gold agents have been
slow to enter the clinic. Repurposing of auranofin in different disease
indications such as cancer, parasitic, and microbial infections in
the clinic has provided impetus for the development of new gold complexes
for biomedical applications based on unique mechanistic insights differentiated
from auranofin. Various chemical methods for the preparation of physiologically
stable gold complexes and associated mechanisms have been explored
in biomedicine such as therapeutics or chemical probes. In this Review,
we discuss the chemistry of next generation gold drugs, which encompasses
oxidation states, geometry, ligands, coordination, and organometallic
compounds for infectious diseases, cancer, inflammation, and as tools
for chemical biology via gold–protein interactions. We will
focus on the development of gold agents in biomedicine within the
past decade. The Review provides readers with an accessible overview
of the utility, development, and mechanism of action of gold-based
small molecules to establish context and basis for the thriving resurgence
of gold in medicine.
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.
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.
Cancer remains one of the leading causes of death worldwide and despite several attempts using chemotherapy to combat the deadly disease, toxic side effects and drug resistance temper efficacy [1]. Thus, drugs with potentially new mechanisms and lower toxicity to normal cells are needed. Metalloids such as arsenic compounds have been clinically beneficial in fighting cancer, but germanium is yet to gain such prominence [2,3]. We report the synthesis of four octahedral germanium(IV) complexes bearing acetylacetonato ligand, [Ge IV (acac) 3 )] + , with different anions (3 -6) using a streamlined synthetic approach. The compounds were structurally and electrochemically characterized using NMR, MS, X-ray crystallography, and cyclic voltammetry. The cyclic voltammogram of 3-5 revealed distinct irreversible peaks in the range of −0.9 to −1.9 V, corresponding to Ge(IV)/ Ge(II) or Ge(II)/Ge(0) couple in DMSO. We explored the anticancer activity of the complexes against a panel of cancer cell lines with IC 50 values in the sub-micromolar range (9-15 μM). The compounds display ~3-fold selectivity in cancer cells over normal epithelial cells. In addition to the promising anticancer activity, the compounds display high complex stability in biological media, induces G1 arrest, reactive oxygen stress (ROS) accumulation, and mitochondria membrane depolarization in cancer cells. Furthermore, the compounds induce significant apoptosis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.