Gold complexes have recently gained increasing attention in the design of new metal-based anticancer therapeutics. Gold(
iii
) complexes are generally reactive/unstable under physiological conditions
...via
intracellular redox reactions, and the intracellular Au
III
to Au
I
reduction reaction has recently been "traced" by the introduction of appropriate fluorescent ligands. Similar to most Au(
i
) complexes, Au(
iii
) complexes can inhibit the activities of thiol-containing enzymes, including thioredoxin reductase,
via
ligand exchange reactions to form Au-S(Se) bonds. Nonetheless, there are examples of physiologically stable Au(
iii
) and Au(
i
) complexes, such as Au(TPP)Cl (H
2
TPP = 5,10,15,20-tetraphenylporphyrin) and Au(dppe)
2
Cl (dppe = 1,2-bis(diphenylphosphanyl)ethane), which are known to display highly potent
in vitro
and
in vivo
anticancer activities. In this review, we summarize our current understanding of anticancer gold complexes, including their mechanisms of action and the approaches adopted to improve their anticancer efficiency. Some recent examples of gold anticancer chemotherapeutics are highlighted.
Anticancer gold complexes, including their mechanisms of action and the approaches adopted to improve the anticancer efficiency are described.
New anticancer platinum(II) compounds with distinctive modes of action are appealing alternatives to combat the drug resistance and improve the efficacy of clinically used platinum chemotherapy. ...Herein, we describe a rare example of an antitumor PtII complex targeting a tumor‐associated protein, rather than DNA, under cellular conditions. Complex (bis‐NHC)Pt(bt)PF6 (1 a; Hbt=1‐(3‐hydroxybenzobthiophen‐2‐yl)ethanone) overcomes cisplatin resistance in cancer cells and displays significant tumor growth inhibition in mice with higher tolerable doses compared to cisplatin. The cellular Pt species shows little association with DNA, and localizes in the cytoplasm as revealed by nanoscale secondary ion mass spectrometry. An unbiased thermal proteome profiling experiment identified asparagine synthetase (ASNS) as a molecular target of 1 a. Accordingly, 1 a treatment reduced the cellular asparagine levels and inhibited cancer cell proliferation, which could be reversed by asparagine supplementation. A bis‐NHC‐ligated Pt species generated from the hydrolysis of 1 a forms adducts with thiols and appears to target an active‐site cysteine of ASNS.
The platinum complex (bis‐NHC)Pt(bt)PF6 (1 a) exhibits anticancer activity towards a wide range of cancer cells and displays significant in vivo tumor growth inhibition in mice. Asparagine synthetase (ASNS) was identified as a molecular target of 1 a. Binding studies suggest that (bis‐NHC)Pt2+ forms adducts with thiols and targets the active‐site N‐terminal cysteine of ASNS.
Palladium(II) complexes are generally reactive toward substitution/reduction, and their biological applications are seldom explored. A new series of palladium(II) N‐heterocyclic carbene (NHC) ...complexes that are stable in the presence of biological thiols are reported. A representative complex, Pd(C^N^N)(N,N′‐nBu2NHC)(CF3SO3) (Pd1 d, HC^N^N=6‐phenyl‐2,2′‐bipyridine, N,N′‐nBu2NHC=N,N′‐di‐n‐butylimidazolylidene), displays potent killing activity toward cancer cell lines (IC50=0.09–0.5 μm) but is less cytotoxic toward a normal human fibroblast cell line (CCD‐19Lu, IC50=11.8 μm). In vivo anticancer studies revealed that Pd1 d significantly inhibited tumor growth in a nude mice model. Proteomics data and in vitro biochemical assays reveal that Pd1 d exerts anticancer effects, including inhibition of an epidermal growth factor receptor pathway, induction of mitochondrial dysfunction, and antiangiogenic activity to endothelial cells.
Stable antitumor agent: Pd(C^N^N)(NHC)+ complexes demonstrate excellent stability in vitro and in aqueous solutions containing physiological thiols. This may allow the complexes to show potent in vitro cytotoxicity against cancer cells and in vitro angiogenesis at sub‐cytotoxic concentrations, as well as effective in vivo anticancer activities toward tumor xenografts in nude mice with no observable toxicity.
Metal N‐heterocyclic carbene (NHC) complexes are a promising class of anti‐cancer agents displaying potent in vitro and in vivo activities. Taking a multi‐faceted approach employing two clickable ...photoaffinity probes, herein we report the identification of multiple molecular targets for anti‐cancer active pincer gold(III) NHC complexes. These complexes display potent and selective cytotoxicity against cultured cancer cells and in vivo anti‐tumor activities in mice bearing xenografts of human cervical and lung cancers. Our experiments revealed the specific engagement of the gold(III) complexes with multiple cellular targets, including HSP60, vimentin, nucleophosmin, and YB‐1, accompanied by expected downstream mechanisms of action. Additionally, PtII and PdII analogues can also bind the cellular proteins targeted by the gold(III) complexes, uncovering a distinct pincer cyclometalated metal–NHC scaffold in the design of anti‐cancer metal medicines with multiple molecular targets.
On target: Anti‐cancer active pincer cyclometalated gold(III) complexes containing N‐heterocyclic carbene ligands have been identified to be a type of multi‐target anti‐cancer agent by using a combined photoaffinity labelling and click chemistry approach. The PdII and PtII analogues can competitively bind to the same cellular targets.
In the design of anticancer gold(I) complexes with high in vivo efficacy, tuning the thiol reactivity to achieve stability towards blood thiols yet maintaining the thiol reactivity to target cellular ...thioredoxin reductase (TrxR) is of pivotal importance. Herein we describe a dinuclear gold(I) complex (1‐PF6) utilizing a bridging bis(N‐heterocyclic carbene) ligand to attain thiol stability and a diphosphine ligand to keep appropriate thiol reactivity. Complex 1‐PF6 displays a favorable stability that allows it to inhibit TrxR activity without being attacked by blood thiols. In vivo studies reveal that 1‐PF6 significantly inhibits tumor growth in mice bearing HeLa xenograft and mice bearing highly aggressive mouse B16‐F10 melanoma. It inhibits angiogenesis in tumor models and inhibits sphere formation of cancer stem cells in vitro. Toxicology studies indicate that 1‐PF6 does not show systemic anaphylaxis on guinea pigs and localized irritation on rabbits.
It′s in the blood: A binuclear gold(I) complex 1‐PF6 is stable towards blood thiols and is a tight‐binding inhibitor of thioredoxin reductase (TrxR). In vivo antitumor studies show 81 % inhibition of tumor growth in mice with HeLa xenografts and 62 % inhibition of highly aggressive mouse B16‐F10 melanoma.
Silver compounds have favorable properties as promising anticancer drug candidates, such as low side effects, anti-inflammatory properties, and high potential to overcome drug resistance. However, ...the exact mechanism by which Ag(
i
) confers anticancer activity remains unclear, which hinders further development of anticancer applications of silver compounds. Here, we combine thermal proteome profiling, cysteine profiling, and ubiquitome profiling to study the molecular mechanisms of silver(
i
) complexes supported by non-toxic thiourea (TU) ligands. Through the formation of AgTU complexes, TU ligands deliver Ag
+
ions to cancer cells and tumour xenografts to elicit inhibitory potency. Our chemical proteomics studies show that AgTU acts on the ubiquitin-proteasome system (UPS) and disrupts protein homeostasis, which has been identified as a main anticancer mechanism. Specifically, Ag
+
ions are released from AgTU in the cellular environment, directly target the 19S proteasome regulatory complex, and may oxidize its cysteine residues, thereby inhibiting proteasomal activity and accumulating ubiquitinated proteins. After AgTU treatment, proteasome subunits are massively ubiquitinated and aberrantly aggregated, leading to impaired protein homeostasis and paraptotic death of cancer cells. This work reveals the unique anticancer mechanism of Ag(
i
) targeting the 19S proteasome regulatory complex and opens up new avenues for optimizing silver-based anticancer efficacy.
A silver(
i
) complex AgTU exerts anticancer activities by releasing Ag
+
ions that target and impair the 19S proteasomal complex, resulting in accumulation of ubiquitinated, misfolded proteins.
The physical and chemical properties of silver nanoparticles that are responsible for their antimicrobial activities have been studied with spherical silver nanoparticles (average diameter ...approximately 9 nm) synthesized by the borohydride reduction of Ag+ ions, in relation to their sensitivity to oxidation, activities towards silver-resistant bacteria, size-dependent activities, and dispersal in electrolytic solutions. Partially (surface) oxidized silver nanoparticles have antibacterial activities, but zero-valent nanoparticles do not. The levels of chemisorbed Ag+ that form on the particle's surface, as revealed by changes in the surface plasmon resonance absorption during oxidation and reduction, correlate well with the observed antibacterial activities. Silver nanoparticles, like Ag+ in the form of AgNO3 solution, are tolerated by the bacteria strains resistant to Ag+. The antibacterial activities of silver nanoparticles are related to their size, with the smaller particles having higher activities on the basis of equivalent silver mass content. The silver nanoparticles aggregate in media with a high electrolyte content, resulting in a loss of antibacterial activities. However, complexation with albumin can stabilize the silver nanoparticles against aggregation, leading to a retention of the antibacterial activities. Taken together, the results show that the antibacterial activities of silver nanoparticles are dependent on chemisorbed Ag+, which is readily formed owing to extreme sensitivity to oxygen. The antibacterial activities of silver nanoparticles are dependent on optimally displayed oxidized surfaces, which are present in well-dispersed suspensions.
Identification of the molecular target(s) of anticancer metal complexes is a formidable challenge since most of them are unstable toward ligand exchange reaction(s) or biological reduction under ...physiological conditions. Gold(III) meso‐tetraphenylporphyrin (gold‐1 a) is notable for its high stability in biological milieux and potent in vitro and in vivo anticancer activities. Herein, extensive chemical biology approaches employing photo‐affinity labeling, click chemistry, chemical proteomics, cellular thermal shift, saturation‐transfer difference NMR, protein fluorescence quenching, and protein chaperone assays were used to provide compelling evidence that heat‐shock protein 60 (Hsp60), a mitochondrial chaperone and potential anticancer target, is a direct target of gold‐1 a in vitro and in cells. Structure–activity studies with a panel of non‐porphyrin gold(III) complexes and other metalloporphyrins revealed that Hsp60 inhibition is specifically dependent on both the gold(III) ion and the porphyrin ligand.
Golden gun: Hsp60 is a direct molecular target of the anticancer compound gold(III) meso‐tetraphenylporphyrin (gold‐1 a) under both in vitro and cellular conditions, as revealed by chemical biology studies employing photo‐affinity labeling, click chemistry, proteomic identification, cellular thermal shift, saturation‐transfer difference NMR, protein fluorescence quenching, and protein chaperone assays.
Self-assembly of platinum(
ii
) complexes to form supramolecular structures/nanostructures due to intermolecular ligand π-π stacking and metal-ligand dispersive interactions is widely used to develop ...functional molecular materials, but the application of such non-covalent molecular interactions has scarcely been explored in medical science. Herein is described the unprecedented biological properties of platinum(
ii
) complexes relevant to induction of cancer cell death
via
manifesting such intermolecular interactions. With conjugation of a glucose moiety to the planar platinum(
ii
) terpyridyl scaffold, the water-soluble complex Pt(tpy)(C&z.tbd;CArOGlu)(CF
3
SO
3
) (
1a
, tpy = 2,2′:6′,2′′-terpyridine, Glu = glucose) is able to self-assemble into about 100 nm nanoparticles in physiological medium, be taken up by lung cancer cells
via
energy-dependent endocytosis, and eventually transform into other superstructures distributed in endosomal/lysosomal and mitochondrial compartments apparently following cleavage of the glycosidic linkage. Accompanying the formation of platinum-containing superstructures are increased autophagic vacuole formation, lysosomal membrane permeabilization, and mitochondrial membrane depolarization, as well as anti-tumor activity of
1a
in a mouse xenograft model. These findings highlight the dynamic, multi-stage extracellular and intracellular supramolecular self-assembly of planar platinum(
ii
) complexes driven by modular intermolecular interactions with potential anti-cancer application.
Self-assembly of platinum(
ii
) glycosylated arylacetylide gave transformable superstructures upon enzymatic action
in cellulo
, leading to perturbation of an autophagy-lysosomal system and cancer cell death.
•Metal-NHC complexes have their metal centers stabilized under physiological conditions and can exhibit anticancer activity.•Metal-NHC complexes having new functionalities can be designed via facile ...NHC ligand modifications.•Au(I)-NHC complexes display thiol reactivity that is tunable by ligand design.•Pincer-type Au(III)-containing, Pt(II)-containing and Pd(II)-containing NHC ligands show effective anti-tumor activities.•Some luminescent metal-NHCs can be used as molecular probes and for bioimaging.
Transition metal compounds are a rich source for anticancer drug development. Judicious application of coordination ligands is a critical success factor in the design of effective anti-tumor compounds. N-heterocyclic carbenes (NHC) are stable ligands that have strong donor strengths in stabilizing metal ions and versatility in structural modifications to provide diverse scaffolds for biological molecular targeting. Remarkable advances have been achieved in the development of metal NHC complexes as anticancer as well as theranostic agents. NHC complexes of gold, platinum and palladium have been designed to elicit potent cancer cell cytotoxicity, effective anti-tumor activities in animal models as well as selective binding to molecular targets (e.g. protein thiols, DNA G-quadraplexes, mismatched DNA). The mechanisms of action of some of these complexes have been elucidated.
PDF
