Bioorthogonal Activation of Dual Catalytic and Anti-Cancer Activities of Organogold(I) Complexes in Living Systems.

Controllably activating the bio-reactivity of metal complexes in living systems is challenging but highly desirable because it can minimize off-target bindings and improve spatiotemporal specificity. Herein, we report a new bioorthogonal activation approach by employing Pd(II)-triggered transmetallation reactions to conditionally activate the bio-reactivity of NHC-Au(I)-phenylacetylide complexes (1 a) in vitro and in vivo. A combination of 1 H NMR, LC-MS, DFT calculation and fluorescence screening assays reveals that 1 a displays a reasonable stability against biological thiols, but its phenylacetylide ligand can be efficiently transferred to Pd(II), leading to in situ formation of labile NHC-Au(I) species that is catalytically active inside living cells and zebrafish, and can meanwhile effectively suppress the activity of thioredoxin reductase, potently inhibit the proliferation of cancer cells and efficiently suppress angiogenesis in zebrafish models.

Palladium-Catalyzed Monoarylation of Arylhydrazines with Aryl Tosylates.

A palladium-catalyzed C-N bond coupling reaction between arylhydrazines and aryl tosylates for facile synthesis of unsymmetrical N,N-diarylhydrazines has been developed. Employing the catalyst system of Pd(TFA)2 associated with newly developed phosphine ligand L1, the monoarylation of arylhydrazine proceeds smoothly to afford desired products in good-to-excellent yields (up to 95%) with good functional group compatibility. This method provides an alternative synthetic pathway for accessing structurally diversified N,N-diarylhydrazines from simple and easily accessible coupling components.

Cyclometalated Gold(III)-Hydride Complexes Exhibit Visible Light-Induced Thiol Reactivity and Act as Potent Photo-Activated Anti-Cancer Agents.

The specific gold-sulfur binding interaction renders gold complexes as promising anti-cancer agents that can potentially overcome cisplatin resistance; while their unbiased binding towards non-tumoral off-target thiol-proteins has posed a big hurdle to clinical application. Herein we report that cyclometalated gold(III) complexes bearing hydride ligands are highly stable towards thiols in the dark but can efficiently dissociate the auxiliary hydride moiety and generate a gold-thiol adduct when excited with visible light. In consequence, the photo-activated gold(III) complexes potently inhibited thioredoxin reductase in association with up to >400-fold increment of photocytotoxicity (vs. dark condition) without deactivation by serum albumin and along with strong anti-angiogenesis activity in zebrafish embryos. Importantly, the gold(III)-hydride complexes could be activated by two-photon laser irradiation at the phototherapeutic window as effectively as blue-light irradiation.

Tandem Cross-Coupling/Spirocyclization/Mannich-Type Reactions of 3-(2-Isocyanoethyl)indoles with Diazo Compounds toward Polycyclic Spiroindolines.

Tandem reactions of Pd-catalyzed cross-coupling of 3-(2-isocyanoethyl)indoles with diazoacetates and subsequent spirocyclization/Mannich-type reaction have been developed to assemble polycyclic spiroindoline skeletons. Formation of spiroindolenines has been proven as the crucial step for the following Mannich-type cyclization reaction. Accordingly, a novel approach on chiral phosphoric acid catalyzed Mannich-type cyclization toward the formation of diastereomerically and enantiomerically enriched pentacyclic spiroindolines has been established. Moreover, the products of the reaction are versatile building blocks in synthetic chemistry, as demonstrated by the synthesis of the key framework of aspidosperma and kopsia alkaloids.

Synthesis of multisubstituted arylsulfones via a one-pot, three-component [3 + 3] benzannulation reaction.

A one-pot, three-component [3 + 3] benzannulation reaction of α,ß-unsaturated carbonyl compounds, bromoallylic sulfones, and sodium sulfinates had been developed. A series of multisubstituted arylsulfones were prepared with moderate to good yields. This method has the advantages of good step-economy, broad substrate scope and operational simplicity.

Palladium-Catalyzed Direct Arylation of Polyfluoroarenes for Accessing Tetra- ortho-Substituted Biaryls: Buchwald-type Ligand Having Complementary -PPh2 Moiety Exhibits Better Efficiency.

The first general examples of direct C-H arylation of electron-deficient polyfluoroarenes with challenging di- ortho-substituted aryl(heteroaryl) chlorides for tetra- ortho-substituted biaryl synthesis are reported. Key to success is the use of Buchwald-type biaryl phosphine ligand, notably with inexpensive -PPh2 moiety (instead of -PCy2 group). Pd(OAc)2 associated with ligand L9 exhibits even higher efficiency than the corresponding SPhos toward this reaction. A wide range of sterically hindered di- ortho-substituted chloroarenes bearing electron-donating or -withdrawing groups are found applicable. Excellent product yields are obtained under mild reaction conditions, and the catalyst loading down to 0.25 mol % of Pd can also be achieved.

Dinuclear Gold(I) Pyrrolidinedithiocarbamato Complex: Cytotoxic and Antimigratory Activities on Cancer Cells and the Use of Metal-Organic Framework.

A dinuclear gold(I) pyrrolidinedithiocarbamato complex (1) with a bidentate carbene ligand has been constructed and shows potent in vitro cytotoxic activities towards cisplatin-resistant ovarian cancer cells A2780cis. Its rigid scaffold enables a zinc(II)-based metal-organic framework (Zn-MOF) to be used as a carrier in facilitating the uptake and release of 1 in solutions. Instead of using a conventional dialysis approach for the drug-release testing, in this study, a set of transwell assay-based experiments have been designed and employed to examine the cytotoxic and antimigratory activities of 1@Zn-MOF towards A2780cis.

Metallophilicity-driven dynamic aggregation of a phosphorescent gold(I)-silver(I) cluster prepared by solution-based and mechanochemical approaches.

We observed an unusual reversible aggregation process showing stimuli-responsive structural dynamics and optical changes attributed to the formation of a sandwich-like Au3-Ag-Au3 cluster, which can be synthesized through both solution and mechanochemical methods. Unlike many other heteronuclear gold-silver clusters, the affinity of two cyclic Au3 complexes and a Ag(I) ion is solely bound by ligand unsupported Au-Ag bonding. The assembly/disassembly behavior, further forming nanoaggregates, is controllable by adjusting the concentration of the solution. In the solid state, the insertion of Ag(I) ion can be implemented through a mechanochemical approach, accompanied by visual color changes and reversible luminochromism. Furthermore, an uncommon solid-liquid extraction is demonstrated, showing the uniqueness of this labile Au-Ag metallophilicity and hinting at the possibility of manipulating a bonding process through a heterogeneous route.

Janus and Amphiphilic MoS2 2D Sheets for Surface-Directed Orientational Assemblies toward Ex Vivo Dual Substrate Release.

The two-dimensional (2-D) Janus and amphiphilic molybdenum disulfide (MoS2) nanosheet with opposite optical activities on each side (amphichiral) is synthesized by modifying sandwich-like bulk MoS2 with tannic acid and cholesterol through biphasic emulsion method. This new type of amphichiral Janus MoS2 nanosheet consists of a hydrophilic and positive optical activity tannic acid side as well as a hydrophobic and negative optical activity cholesterol side thereby characterized by circular dichroism. Surface-directed orientational differentiation assemblies are performed for the as-synthesized 2D material and are characterized by contact angle, infrared spectroscopy, X-ray photoelectron, and circular dichroism spectroscopies. The amphiphilic nature of the materials is demonstrated by the pre-organization of the nanosheets on either hydrophobic or hydrophilic surfaces, providing unprecedented properties of circular dichroism signal enhancement and wettability. Selective detachment of the surface organic groups (cholesterol and tannic acid fragments) is realized by matrix-assisted laser desorption/ionisation - time-of-flight (MALDI-TOF) mass spectrometry, and the dual substrate release in tissue is detected by ex vivo mass spectrometry imaging.

A high-symmetry coordination cage from 38- or 62-component self-assembly.

Artificial molecular architecture from a large number of subcomponents (>50) via self-assembly remains a formidable challenge for chemists. Reaction of 38 components [14 Ni(2+) and 24 N-methyl-1-(4-imidazolyl)methanimine] under solvothermal conditions reproducibly leads to the formation of a high-symmetry coordination cage. This polyhedral cage can also be obtained in high yield by self-assembly of 62 commercially available subcomponents (24 methylamine, 24 4-formylimidazole, and 14 Ni(2+)) under mild conditions involving synchronized formation of both dynamic covalent bonds and coordination bonds. Guest molecules (e.g., water, methylamine, and methanol) are randomly imprisoned in the cage.

Organogold(III) supramolecular polymers for anticancer treatment.

Gold cures: the depicted gold(III) complex self-assembles into supramolecular polymers which form nanofibrillar networks that display sustained cytotoxicity and can also act as carriers for other cytotoxic agents.

Molecular wheels of ruthenium and osmium with bridging chalcogenolate ligands: edge-shared-octahedron structures and metal-ion binding.

Inventing new wheels: reaction of [M(3)(CO)(12) ] (M=Ru, Os) with 4-RC(6)H(4)SH afforded [{M(S-4-RC(6)H(4))(2)(CO)(2)}(8)] (R=H; I) or [{M(S-4-RC(6)H(4))(2)(CO)(2)}(6)] (R=Me, iPr; II; see scheme), all of which have been structurally characterized. The octamers I are unique metal molecular wheels featuring skew-edge-shared octahedra with a central planar M(8) octagon. [{Ru(S-4-iPrC(6)H(4))(2)(CO)(2)}(6)] selectively binds a Cu(+) or Ag(+) ion to form [M'{Ru(S(4-iPr-C(6)H(4)))(2)(CO)(2)}(6)](+) (III).

Inhibition of human DNA topoisomerase IB by a cyclometalated gold III compound: analysis on the different steps of the enzyme catalytic cycle.

A gold(III) compound [Au(C^N^C)(IMe)]CF(3)SO(3) (Gold III) has been reported to have anticancer properties as it is able to reduce topoisomerase IB activity in vitro and suppress tumor growth in nude mice model. Here we have investigated the mechanism of inhibition of human topoisomerase IB activity by this compound, analyzing the various steps of the catalytic cycle. DNA supercoiled relaxation and the cleavage reaction are inhibited, but Gold III does not perturb the religation reaction, in contrast to what has been observed for camptothecin. Pre-incubation of enzyme with the inhibitor before adding DNA substrate increases the inhibitory effect. In addition, when Gold III is preincubated with the enzyme it prevents the stabilization of the cleavable complex by camptothecin. The analysis of the DNA-topoisomerase binding reaction indicates that the compound acts as a topoisomerase I inhibitor by preventing the enzyme-DNA interaction.

Gold(III) porphyrin 1a prolongs the survival of melanoma-bearing mice and inhibits angiogenesis.

BACKGROUND: Gold(III) meso-tetraphenylporphyrin (gold-1a) has previously been shown to prolong the survival of hepatocellular carcinoma (HCC)-bearing rats and nasopharyngeal carcinoma (NPC) metastasis-bearing mice. It has also been proved to inhibit the tumor growth of mice bearing NPC, neuroblastoma and colon carcinoma. Mechanistically, gold-1a induces apoptosis, inhibits cell migration and invasion. In this study the efficacies of gold-1a in inhibiting melanoma and angiogenesis were investigated. MATERIAL AND METHODS: A mouse melanoma model was used to investigate the efficacy of gold-1a in inhibiting angiogenesis, tumor growth and prolonging the survival of the tumor-bearing animals. The model was established by inoculation of 2 × 10(5) B16-F1 mouse melanoma cells into the right back flanks of the mice by subcutaneous inoculation. When the tumors grew to 0.2-0.4 cm in diameters, the mice were treated with gold-1a, solvent control or dacarbazine (DTIC) for comparison. Tumor sizes and animal survivals were monitored throughout the experiment. Tumor tissues were collected and immunohistochemically stained with CD31 antibodies for evaluation of intra-tumoral microvessel density (iMVD). RESULTS AND CONCLUSION: Gold-1a significantly prolonged the survivals, reduced angiogenesis and tumor growth rates of melanoma-bearing mice. The compound induced necrosis and apoptosis in the mouse melanoma tissues. Gold-1a also downregulated the expression of genes playing roles in angiogenesis. Gold-1a may potentially be used to treat melanoma in patients.

Stable anticancer gold(III)-porphyrin complexes: effects of porphyrin structure.

In the design of physiologically stable anticancer gold(III) complexes, we have employed strongly chelating porphyrinato ligands to stabilize a gold(III) ion [Chem. Commun. 2003, 1718; Coord. Chem. Rev. 2009, 253, 1682]. In this work, a family of gold(III) tetraarylporphyrins with porphyrinato ligands containing different peripheral substituents on the meso-aryl rings were prepared, and these complexes were used to study the structure-bioactivity relationship. The cytotoxic IC(50) values of [Au(Por)](+) (Por=porphyrinato ligand), which range from 0.033 to >100 microM, correlate with their lipophilicity and cellular uptake. Some of them induce apoptosis and display preferential cytotoxicity toward cancer cells than to normal noncancerous cells. A new gold(III)-porphyrin with saccharide conjugation [Au(4-glucosyl-TPP)]Cl (2a; H(2)(4-glucosyl-TPP)=meso-tetrakis(4-beta-D-glucosylphenyl)porphyrin) exhibits significant cytostatic activity to cancer cells (IC(50)=1.2-9.0 microM) without causing cell death and is much less toxic to lung fibroblast cells (IC(50)>100 microM). The gold(III)-porphyrin complexes induce S-phase cell-cycle arrest of cancer cells as indicated by flow cytometric analysis, suggesting that the anticancer activity may be, in part, due to termination of DNA replication. The gold(III)-porphyrin complexes can bind to DNA in vitro with binding constants in the range of 4.9 x 10(5) to 4.1 x 10(6) dm(3) mol(-1) as determined by absorption titration. Complexes 2a and [Au(TMPyP)]Cl(5) (4a; [H(2)TMPyP](4+)=meso-tetrakis(N-methylpyridinium-4-yl)porphyrin) interact with DNA in a manner similar to the DNA intercalator ethidium bromide as revealed by gel mobility shift assays and viscosity measurements. Both of them also inhibited the topoisomerase I induced relaxation of supercoiled DNA. Complex 4a, a gold(III) derivative of the known G-quadruplex-interactive porphyrin [H(2)TMPyP](4+), can similarly inhibit the amplification of a DNA substrate containing G-quadruplex structures in a polymerase chain reaction stop assay. In contrast to these reported complexes, complex 2a and the parental gold(III)-porphyrin 1a do not display a significant inhibitory effect (<10%) on telomerase. Based on the results of protein expression analysis and computational docking experiments, the anti-apoptotic bcl-2 protein is a potential target for those gold(III)-porphyrin complexes with apoptosis-inducing properties. Complex 2a also displays prominent anti-angiogenic properties in vitro. Taken together, the enhanced stabilization of the gold(III) ion and the ease of structural modification render porphyrins an attractive ligand system in the development of physiologically stable gold(III) complexes with anticancer and anti-angiogenic activities.

Gold(III) porphyrin complex is more potent than cisplatin in inhibiting growth of nasopharyngeal carcinoma in vitro and in vivo.

Nasopharyngeal carcinoma (NPC) is a common neoplasm in Southeastern Asia, and cisplatin-containing regimens for combinational chemotherapy are widely used for treating locally recurrent or metastatic diseases. However, resistance to cisplatin is not infrequently seen and its associated side effects may be life-threatening. In this report, another metallo-pharmaceutical agent gold(III) porphyrin complex [Au(TPP)]Cl was investigated in comparison to cisplatin for its in vitro and in vivo anticancer effects. Through induction of the intrinsic apoptosis pathway, [Au(TPP)]Cl exhibited 100-fold higher potency than cisplatin in killing NPC cells, including cisplatin-sensitive and cisplatin-resistant variants, and also an variant harboring the Epstein-Barr virus. In addition, a safety concentration window was demonstrated, allowing [Au(TPP)]Cl to kill tumors with minimal cytotoxicity to noncancerous cells. More importantly, weekly intraperitoneal injection of 3 mg/kg [Au(TPP)]Cl was more effective than the same dose of cisplatin in inducing tumor apoptosis in vivo and remarkably inhibited tumor growth in animals without any noticeable side effect. [Au(TPP)]Cl therefore is a promising chemotherapeutic agent that deserves further development as a novel drug for the treatment of advanced NPC, in particular, for cases with cisplatin-resistance.

Silver nanoparticles inhibit hepatitis B virus replication.

BACKGROUND: Silver nanoparticles have been shown to exhibit promising cytoprotective activities towards HIV-infected T-cells; however, the effects of these nanoparticles towards other kinds of viruses remain largely unexplored. The aim of the present study was to investigate the effects of silver nanoparticles on hepatitis B virus (HBV). METHODS: Monodisperse silver nanoparticles with mean particle diameters of approximately 10 nm (Ag10Ns) and approximately 50 nm (Ag50Ns) were prepared from AgNO3 in HEPES buffer. The in vitro anti-HBV activities of these particles were determined using the HepAD38 cell line as infection model. RESULTS: Ag10Ns and Ag50Ns were able to reduce the extracellular HBV DNA formation of HepAD38 cells by >50% compared with the vehicle control (that is, HepAD38 cells in the absence of silver nanoparticles). Silver nanoparticles had little effect on the amount of HBV covalently closed circular DNA (cccDNA), but could inhibit the formation of intracellular HBV RNA. Gel mobility shift assays indicated that Ag10Ns bound HBV double-stranded DNA at a DNA:silver molar ratio of 1:50; an absorption titration assay showed that the nanoparticles have good binding affinity for HBV DNA with a binding constant (Kb) of (8.8 +/- 1.0)x10(5) dm(3)mol(-1). As both the viral and Ag10Ns systems are in the nanometer size range, we found that Ag10Ns could directly interact with the HBV viral particles as revealed by transmission electronic microscopy. CONCLUSIONS: Silver nanoparticles could inhibit the in vitro production of HBV RNA and extracellular virions. We hypothesize that the direct interaction between these nanoparticles and HBV double-stranded DNA or viral particles is responsible for their antiviral mechanism.

Medicinal Chemistry of Gold Anticancer Metallodrugs.

Since ancient times gold and its complexes have been used as therapeutics against different diseases. In modern medicine gold drugs have been applied for the treatment of rheumatoid arthritis, however, recently other medical applications have come into the focus of inorganic medicinal chemistry. This chapter provides a non-comprehensive overview of key developments in the field of gold anticancer drugs. Exciting findings on gold(I) and gold(III) complexes as antitumor agents are summarized together with a discussion of relevant aspects of their modes of action.

Drug Delivery Systems For Anti-Cancer Active Complexes of Some Coinage Metals.

BACKGROUND: Although cisplatin and a number of platinum complexes have widely been used for the treatment of neoplasia, patients receiving these treatments have frequently suffered from their severe toxic side effects, the development of resistance with consequent relapse. In the recent decades, numerous complexes of coinage metals including that of gold, copper and silver have been reported to display promising in vitro and/or in vivo anti-cancer activities as well as potent activities towards cisplatin-resistant tumors. Nevertheless, the medical development of these metal complexes has been hampered by their instability in aqueous solutions and the nonspecific binding in biological systems. METHODS: One of the approaches to overcome these problems is to design and develop adequate drug delivery systems (DDSs) for the transport of these complexes. By functionalization, encapsulation or formulation of the metal complexes, several types of DDSs have been reported to improve the desired pharmacological profile of the metal complexes, improving their overall stability, bioavailability, anti-cancer activity and reducing their toxicity towards normal cells. CONCLUSION: In this review, we summarized the recent findings for different DDSs for various anti- cancer active complexes of some coinage metals.

Cationic and Neutral N-Heterocyclic Carbene Gold(I) Complexes: Cytotoxicity, NCI-60 Screening, Cellular Uptake, Inhibition of Mammalian Thioredoxin Reductase, and Reactive Oxygen Species Formation.

A structurally diverse library of 14 gold(I) cationic bis(NHC) and neutral mono(NHC) complexes (NHC: N-heterocyclic carbene) was synthesized and characterized in this work. Four of them were new cationic gold(I) complexes containing functionalized NHCs, and their X-ray crystal structures are presented herein. All of the complexes were investigated for their anticancer activities in four cancer cell lines, including a cisplatin-resistant variant, and a noncancerous cell line. Seven of the cationic gold(I) complexes were found to display high and specific cytotoxic activities toward cancer cells. Two of them were even able to overcome cisplatin resistance. Two highly potent cationic complexes (11 and 15) were also submitted to the NCI-60 cancer panel for further cytotoxicity evaluation. Complex 15 showed a surprisingly high potency toward leukemia among the nine examined cancer subtypes, particularly toward the CCRF-CEM leukemia cell line with a concentration for 50 % inhibition of growth down to 79.4 nm. In addition, cationic complex 13, which demonstrated a remarkable cytotoxicity against hepatocellular carcinoma, was selected to obtain insight into the mechanistic aspects in HepG2 cells. Cellular uptake measurements were indicative of good bioavailability. By various biochemical assays, this complex was found to effectively inhibit thioredoxin reductase and its cytotoxicity toward HepG2 cells was found to be reactive oxygen species dependent.