Platinum(II) N-heterocyclic carbene complexes arrest metastatic tumor growth.

Vimentin is a cytoskeletal intermediate filament protein that plays pivotal roles in tumor initiation, progression, and metastasis, and its overexpression in aggressive cancers predicted poor prognosis. Herein described is a highly effective antitumor and antimetastatic metal complex [PtII(C^N^N)(NHC2Bu)]PF6 (Pt1a; HC^N^N = 6-phenyl-2,2'-bipyridine; NHC= N-heterocyclic carbene) that engages vimentin via noncovalent binding interactions with a distinct orthogonal structural scaffold. Pt1a displays vimentin-binding affinity with a dissociation constant of 1.06 µM from surface plasmon resonance measurements and fits into a pocket between the coiled coils of the rod domain of vimentin with multiple hydrophobic interactions. It engages vimentin in cellulo, disrupts vimentin cytoskeleton, reduces vimentin expression in tumors, suppresses xenograft growth and metastasis in different mouse models, and is well tolerated, attributable to biotransformation to less toxic and renal-clearable platinum(II) species. Our studies uncovered the practical therapeutic potential of platinum(II)‒NHC complexes as effective targeted chemotherapy for combating metastatic and cisplatin-resistant cancers.

Dynamic supramolecular self-assembly of platinum(ii) complexes perturbs an autophagy-lysosomal system and triggers cancer cell death.

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[triple bond, length as m-dash]CArOGlu)](CF3SO3) (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.

Anticancer Gold(III) Compounds With Porphyrin or N-heterocyclic Carbene Ligands.

The use of gold in medicine has a long history. Recent clinical applications include anti-inflammatory agents for the treatment of rheumatoid arthritis (chrysotherapy), and is currently being developed as potential anticancer chemotherapeutics. Gold(III), being isoelectronic to platinum(II) as in cisplatin, is of great interest but it is inherently unstable and redox-reactive under physiological conditions. Coordination ligands containing C and/or N donor atom(s) such as porphyrin, pincer-type cyclometalated and/or N-heterocyclic carbene (NHC) can be employed to stabilize gold(III) ion for the preparation of anticancer active compounds. In this review, we described our recent work on the anticancer properties of gold(III) compounds and the identification of molecular targets involved in the mechanisms of action. We also summarized the chemical formulation strategies that have been adopted for the delivery of cytotoxic gold compounds, and for ameliorating the in vivo toxicity.

An anticancer gold(III)-activated porphyrin scaffold that covalently modifies protein cysteine thiols.

Cysteine thiols of many cancer-associated proteins are attractive targets of anticancer agents. Herein, we unequivocally demonstrate a distinct thiol-targeting property of gold(III) mesoporphyrin IX dimethyl ester (AuMesoIX) and its anticancer activities. While the binding of cysteine thiols with metal complexes usually occurs via M-S bond formation, AuMesoIX is unique in that the meso-carbon atom of the porphyrin ring is activated by the gold(III) ion to undergo nucleophilic aromatic substitution with thiols. AuMesoIX was shown to modify reactive cysteine residues and inhibit the activities of anticancer protein targets including thioredoxin, peroxiredoxin, and deubiquitinases. Treatment of cancer cells with AuMesoIX resulted in the formation of gold-bound sulfur-rich protein aggregates, oxidative stress-mediated cytotoxicity, and accumulation of ubiquitinated proteins. Importantly, AuMesoIX exhibited effective antitumor activity in mice. Our study has uncovered a gold(III)-induced ligand scaffold reactivity for thiol targeting that can be exploited for anticancer applications.

Selective catecholamine detection in living cells by a copper-mediated oxidative bond cleavage.

The development of a new triggered-release system for selective detection of catecholamines in biological samples including living cells is reported. Catecholamines are a class of tightly regulated hormones and neurotransmitters in the human body and their dysregulation is implicated in various neurodegenerative diseases. It is highly challenging to selectively sense and detect catecholamines in a complex biological environment due to their small size, non-specific molecular shape and trivial chemical properties. In this study, a copper-based, catecholamine-triggered oxidation that releases a fluorescent reporter is described. The probe is highly sensitive and selective for detecting changes in catecholamine levels in aqueous buffer, human plasma, and cellular models of neuronal differentiation and Parkinson's disease. This new catecholamine sensing strategy features chemical reactivity as part of small molecule recognition as opposed to the conventional use of a well-designed host for reversible binding.

Anticancer metal-N-heterocyclic carbene complexes of gold, platinum and palladium.

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.

A multi-functional PEGylated gold(iii) compound: potent anti-cancer properties and self-assembly into nanostructures for drug co-delivery.

Gold(iii) porphyrin-PEG conjugates [Au(TPP-COO-PEG5000-OCH3)]Cl (1) and [Au(TPP-CONH-PEG5000-OCH3)]Cl (2) have been synthesized and characterized. Based on the amphiphilic character of the conjugates, they were found to undergo self-assembly into nanostructures with size 120-200 nm and this did not require the presence of other surfactants or components for nano-assembly, unlike most conventional drug nano-formulations. With a readily hydrolyzable ester linkage, chemotherapeutic [Au(TPP-COOH)]+ exhibited triggered release from the conjugate 1 in acidic buffer solution as well as in vitro and in vivo without the formation of toxic side products. The nanostructures of 1 showed higher cellular uptake into cancer cells compared to non-tumorigenic cells, owing to their energy-dependent uptake mechanism. This, together with a generally higher metabolic rate and more acidic nature of cancer cells which can lead to faster hydrolysis of the ester bond, afforded 1 with excellent selectivity in killing cancer cells compared with non-tumorigenic cells in vitro. This was corroborated by fluorescence microscopy imaging and flow cytometric analysis of co-culture model of colon cancer (HCT116) and normal colon (NCM460) cells. In vivo experiments showed that treatment of nude mice bearing HCT116 xenografts with 1 resulted in significant inhibition of tumor growth and, more importantly, minimal systemic toxicity as revealed by histopathological analysis of tissue sections and blood biochemisty. The latter is explained by a lower accumulation of 1 in organs of treated mice at its effective dosage, as compared to that of other gold(iii) porphyrin complexes. Co-assembly of 1 and doxorubicin resulted in encapsulation of doxorubicin by the nanostructures of 1. The nanocomposites demonstrated a strong synergism on killing cancer cells and could overcome efflux pump-mediated drug-resistance in a doxorubicin-resistant ovarian cancer cell line (A2780adr) which was found in cells incubated with doxorubicin alone. Also, the nanocomposites accumulated more slowly in non-tumorigenic cells, resulting in a lower toxicity toward non-tumorigenic cells. These results indicate the potential application of 1 not only as an anti-cancer agent but also as a nanoscale drug carrier for chemotherapy.

Cyclometalated Palladium(II) N-Heterocyclic Carbene Complexes: Anticancer Agents for Potent In†Vitro Cytotoxicity and In†Vivo Tumor Growth Suppression.

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'-nBu2 NHC)](CF3 SO3 ) (Pd1 d, HC^N^N=6-phenyl-2,2'-bipyridine, N,N'-nBu2 NHC=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.

Identification of "sarsasapogenin-aglyconed" timosaponins as novel Aß-lowering modulators of amyloid precursor protein processing.

The inhibition of amyloid ß (Aß) peptide production is a key approach in the development of therapeutics for the treatment of Alzheimer's disease (AD). We have identified that timosaponins consisting of sarsasapogenin (SSG) as the aglycone can effectively lower the production of Aß peptides and stimulate neurite outgrowth in neuronal cell cultures. Structure-activity relationship studies revealed that the cis-fused AB ring, 3ß-configuration, spiroketal F-ring and 25S-configuration of SSG are the essential structural features responsible for the Aß-lowering effects and neurite-stimulatory activity. New synthetic derivatives that retain the SSG scaffold also exhibited an Aß lowering effect. Treatment of cells with timosaponins led to modulation of amyloid precursor protein (APP) processing through the suppression of ß-cleavage and preferential lowering of the production of the 42-amino acid Aß species (Aß42) without affecting another γ-secretase substrate. The SSG and "SSG-aglyconed" timosaponins also penetrated brain tissue and lowered brain Aß42 levels in mice. Our studies demonstrate that timosaponins represent a unique class of steroidal saponins that may be useful for the development of AD therapeutics.