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.
We report a mild method for the selective deprotection of the N-Boc group from a structurally diverse set of compounds, encompassing aliphatic, aromatic, and heterocyclic substrates by using oxalyl chloride in methanol.
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.
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.
Immune
checkpoint blockades have revolutionized the treatment landscape
for several cancer indications, yet they have not gained traction
in a range of other tumors such as triple-negative breast cancer.
Despite durable disease control by many patients, a third of cancer
patients relapse due to acquired resistance. Combined immunotherapy
has shown significant promise to overcome these grand challenges.
In this report, we describe the synthesis and characterization of
dual-action small-molecule PARP1/PD-L1 inhibitor conjugates as potential
targeted anticancer agents. These conjugates display significant apoptosis
and cytotoxic efficacy to approximately 2–20-fold better than
their individual agents in a panel of cancer cell lines. This was
underscored by derived combination indices, which was consistent with
strong synergy when cells were treated with the individual agents,
olaparib and BMS-001 using the Chou–Talalay method. Furthermore,
we sought to unravel the mechanistic behavior of the conjugates and
their implications on the PARP/PD-L1 axis. We used apoptosis, cell
cycle, immunoblotting, and T-cell proliferation assays to establish
the synergy imparted by these conjugates. These multifunctional compounds
enable the discovery of small-molecule immunochemotherapeutic agents
and chemical probes to elucidate the cross-talk between DNA repair
and PD-L1 pathways.
Direct targeting of intrinsically disordered proteins, including MYC, by small molecules for biomedical applications would resolve al ongstanding issue in chemical biology and medicine. Thus, we developed gold-based small-molecule MYC reagents that engageM YC inside cells and modulate MYC transcriptional activity.L ead compounds comprise an affinity ligand and ag old(I)o rgold(III) warhead capable of protein chemical modification.C ell-based MYC target engagement studies via CETSA and co-immunoprecipitation reveal specific interaction of compounds with MYC in cells. The lead gold(I) reagent, 1,d emonstrates superior cell-killing potential(up to 35-fold) in aM YC-dependent manner when compared to 10058-F4i nc ellsi ncludingt he TNBC, MDA-MB-231. Subsequently, 1 suppresses MYC transcription factor activity via functional colorimetric assays,a nd gene-profiling using whole-cellt ranscriptomics reveals significant modulation of MYC target genes by 1.T hese findings point to metal-mediated ligand affinity chemistry (MLAC) based on gold as ap romising strategyt od evelop chemical probes and anticancer therapeutics targeting MYC.
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