Non-Covalent Interaction-Directed Coordination-Driven Self-Assembly of Non-Trivial Supramolecular Topologies.

The design of molecules with non-trivial topologies is an essential step in the development of methods to mimic biological transformation in artificial systems. However, the generation of supramolecular topologies of increasing complexity, such as [n]catenanes, rotaxanes, knots and links, is relatively rare and challenging. Primarily, selective and quantitative synthesis of supramolecular topologies is a formidable challenge. Template-free, non-covalent interaction-directed coordination-driven self-assembly provides an alternative approach for constructing non-trivial topologies in selective and quantitative manner. This review briefly summarizes and provides a comprehensive insight into non-trivial topologies obtained via template-free, coordination and non-covalent interaction-driven self-assembly.

The First Quantitative Synthesis of a Closed Three-Link Chain (613) Using Coordination and Noncovalent Interactions-Driven Self-Assembly.

Engineering of supramolecular topologies offers potential opportunities for tailoring their properties to various function and applications. However, the synthesis of interlocked or intertwined compounds, catenanes, links or knots, is a challenge. Previously, we used coordination-driven self-assembly and noncovalent interactions (NCIs) between metal-based acceptors and multipyridyl donors to create supramolecular topologies with increasing complexity. Self-assembling components of fixed length and geometry have been utilized for the production of topologies such as Borromean rings, Solomon links, Hopf's link, "rectangle in rectangle", and an 818 molecular knot. However, recent synthesis of a linear [3]catenane by us witnessed the importance of flexible ligands along with coordination-driven self-assembly and NCIs in self-assembling units. This flexibility provides distinctive angularity for the recognition of various NCIs and thus offers tremendous possibilities for realizing complex supramolecular topologies. This study proposed a selective and quantitative synthesis, and also the first X-ray characterization of a closed three-link chain (a prime link of [3]catenane with 6 crossings) via two component coordination-driven self-assembly. The experiments based upon concentration, guest template, and solvent effects were systematically presented. Furthermore, the experimental finding was supported by density functional theory calculations, which highlighted the necessity of the multiple NCIs along with appropriate geometry of the [2 + 2] rings.

Coordination-Driven Self-Assembly of Triazole-Based Apoptosis-Inducible Metallomacrocycles.

Ru(II)-metallomacrocycles containing 4-pyridyl-1,2,3-triazole moiety were realized by coordination-driven self-assembly. All new compounds were characterized by electrospray ionisation mass spectrometry, elemental analysis, and 1H and 13C NMR spectroscopic techniques. The molecular structure of metallomacrocycle 8 was determined by single-crystal X-ray crystallography. The anticancer activities of metallomacrocycles 5-8 were evaluated by cytotoxicity, cell cycle analysis, and related protein expression. Metallomacrocycle 7 showed the highest cytotoxicity in HepG2 human hepatocellular carcinoma cells. In addition, apoptotic HepG2 cells were analyzed when metallomacrocycle 7 was treated. Our results suggest that metallomacrocycle 7 induces liver cancer cell death by increasing apoptosis and cell cycle arrest and that it has potential use as an agent for the treatment of human hepatocellular carcinoma.

Selective and quantitative synthesis of a linear [3]catenane by two component coordination-driven self-assembly.

Here we report the synthesis of a linear [3]catenane comprised of three interlocking rings, by coordination-driven self-assembly. Naphthalene-based acceptor A1 and triazole-based donor L1 were utilized for the self-assembly reaction, which facilitated the formation of linear [3]catenane topology through synergistic non-covalent intercycler interactions (π-π, CH-π and CH-N).

New Self-assembled Supramolecular Bowls as Potent Anticancer Agents for Human Hepatocellular Carcinoma.

We report herein on the design, synthesis and biological activity of Ru-based self-assembled supramolecular bowls as a potent anticancer therapeutic in human hepatocellular cancer. The potent complex induces production of reactive oxygen species (ROS) by higher fatty acid ß-oxidation and down-regulation of glucose transporter-mediated pyruvate dehydrogenase kinase 1 via reduced hypoxia-inducible factor 1α. Also, overexpressed acetyl-CoA activates the tricarboxylic acid cycle and the electron transport system and induces hypergeneration of ROS. Finally, ROS overexpressed through this pathway leads to apoptosis. Furthermore, we demonstrate that the naphthalene derived molecular bowl activates classical apoptosis via crosstalk between the extrinsic and intrinsic signal pathway. Our work into the mechanism of Ru-based self-assembled supramolecular bowls can provide valuable insight into the potential for use as a promising anticancer agent.

Preparation of a chiral Pt12 tetrahedral cage and its use in catalytic Michael addition reaction.

The reaction of chiral cis-[(1S,2S)-dch]Pt(NO3)2 (M) [where (1S,2S)-dch = (1S,2S)-1,2-diaminocyclohexane] with a hexadentate ligand (L) in 3 : 1 stoichiometric ratio yielded a [12+4] self-assembled chiral M12L4 molecular tetrahedron (T). The cage T features an internal 3D nanocavity with large open 'windows', enabling it to catalyze Michael addition reactions of a series of nitrostyrene derivatives with indole in a 9 : 1 water : methanol mixture.

Coordination-Driven Self-Assembly of a Molecular Knot Comprising Sixteen Crossings.

Molecular knots have become highly attractive to chemists because of their prospective properties in mimicking biomolecules and machines. Only a few examples of molecular knots from the billions tabulated by mathematicians have been realized and molecular knots with more than eight crossings have not been reported to date. We report here the coordination-driven [8+8] self-assembly of a higher-generation molecular knot comprising as many as sixteen crossings. Its solid-state X-ray crystal structure and multinuclear 2D NMR findings confirmed its architecture and topology. The formation of this molecular knot appears to depend on the functionalities and geometries of donor and acceptor in terms of generating appropriate angles and strong π-π interactions supported by hydrophobic effects. This study shows coordination-driven self-assembly offers a powerful potential means of synthesizing more and more complicated molecular knots and of understanding differences between the properties of knotted and unknotted structures.

Coordination-Driven Self-Assembly of Heterotrimetallic Barrel and Bimetallic Cages Using a Cobalt Sandwich-Based Tetratopic Donor.

Three-dimensional molecular architectures self-assembled with tripodal and tetratopic donors are valuable because of their encapsulation properties. Here, we present Co(I)-Fe(II)-Pd(II) heterotrimetallic trifacial barrel 1, which was self-assembled using a newly synthesized tetratopic donor [CpCo(CbR4)] [L; Cp = cyclopentadienyl, Cb = cyclobudiene, and R = 4-(4-pyridylphenyl)] and a 90° acceptor [ cis-(dppf)Pd(OTf)2] (A1; dppf = (diphenylphosphino)ferrocene and OTf = CF3SO3-). The heterotrimetallic barrel 1 exhibited selective 1:1 interaction with a N, N'-dimethyl-1,4,5,8-naphthalenetetracarboxylic diimide guest, as revealed by 1H NMR analysis. The self-assembly of donor L with two other Ru(II)-based 180° acceptors [( p-cymene)2Ru2(OO∩OO)(OTf)2] [OO∩OO = 6,11-dioxido-5,12-naphthacenedione (A2) and oxalate (A3)] resulted in tetragonal-prismatic cages. Self-assembly using the longer acceptor A2 provided rare isomers of a tetragonal-prismatic cage by varying the orientation of the cyclopentadienyl moiety out-out (2a) or out-in (2b) of the cavity, whereas self-assembly using the shorter acceptor A3 selectively resulted in the tetragonal-prismatic cage 3. The three-dimensional molecular architectures 1-3 were characterized by combined spectroscopic and elemental analyses. The structures of molecular barrel 1 and prismatic cage 3 were elucidated by single-crystal X-ray analysis.

Flexible ligated ruthenium(II) self-assemblies sensitizes glioma tumor initiating cells in vitro.

The tumorigenic potentials of residual cancer stem-like cells within tumors represent limitations of current cancer therapies. Here, the authors describe the effects of synthesized flexible, ligated, supramolecular self-assembled chair type tetranuclear ruthenium (II) metallacycles (2-5) on glioblastoma and glioma stem like cells. These self-assemblies were observed to be selectively toxic to glioma cells and CD133-positive glioma stem like cells population. Of the self-assembled compounds tested, metallacycle 4 more efficiently induced glioma stem like cells death within a brain cancer cell population and simultaneously inhibited the formation of free-floating gliospheres by reducing the sphere size. Detailed cell death studies revealed that treatment with metallacycle 4 reduced mitochondrial membrane potentials (an indicator of apoptosis) of glioma stem like cells. These results shows the elimination of cancer stem-like cells using an appropriate ligand binding adaptor offers a potential means of developing metal-based compounds for the treatment of chemo-resistant tumors.

Catalytic Intramolecular Cycloaddition Reactions by Using a Discrete Molecular Architecture.

A discrete tetragonal tube-shaped complex (MT-1) has been synthesised by coordination-driven self-assembly of a carbazole-based tetraimidazole donor L and a Pd(II) 90° acceptor, that is, [cis-(dppf)Pd(OTf)2 ] (dppf=diphenylphosphinoferrocene, OTf=CF3 SO3- ). Complex MT-1 was characterised by multinuclear NMR, ESI-MS and single-crystal X-ray diffraction analysis (SCXRD), which showed its symmetrical tetrafacial tube-shaped architecture possessing a large cavity described by four aromatic walls. This coordination cage was successfully utilised as a molecular vessel to perform intramolecular cycloaddition reactions of O-allylated benzylidinebarbituric acid derivatives inside its confined nanospace. The presence of a catalytic amount of MT-1 promoted [4+2] cycloaddition reactions in a regio- and stereoselective manner, yielding the corresponding penta/tetracyclouracil derivatives in good yields under mild reaction conditions. This protocol is interesting compared with the literature reports for the synthesis of similar chromenopyran pyrimidinedione derivatives under high-temperature reflux conditions or solid-state melt reactions (SSMRs).

Coordination-Driven Self-Assembly Using Ditopic Pyridyl-Pyrazolyl Donor and p-Cymene Ru(II) Acceptors: [2]Catenane Synthesis and Anticancer Activities.

Coordination-driven self-assembly of m-bis[3-(4-pyridyl)pyrazolyl]xylene (L) and [(p-cymene)2Ru2(OO∩OO)2(OTf)2] (A1) (OO∩OO = 6,11-dioxido-5,12-naphthacenedione) in methanol resulted in a mixture of [2]catenane 1 and macrocycle 2, and self-assembly in nitromethane resulted in pure macrocycle 2, whereas the coordination-driven self-assembly of L and similar acceptors [(p-cymene)2Ru2(OO∩OO)2(OTf)2] [OO∩OO = 5,8-dioxido-1,4-naphthoquinonnato (A2); 2,5-dioxido-1,4-benzoquinonato (A3); oxalato (A4)] resulted in the formations of monomeric macrocycles 3-5, respectively. All self-assembled macrocycles were obtained in excellent yields (>90%) as triflate salts and were fully characterized by multinuclear NMR, elemental analysis, and electrospray ionization mass spectrometry (ESI-MS). The structures of [2]catenane 1 and macrocycles 5 were confirmed by single-crystal X-ray diffraction analysis. The X-ray structure of 1 confirmed an edge-to-face interaction between the tetracene moiety in parallel-displaced π-π stacks (3.5 Å), and CH···π (2.5 Å) stabilizes the [2]catenane topology. Macrocycles 2-5 were assessed for anticancer activities using human cancer cell lines of different origins, and the macrocycle 3 was found to exhibit the best inhibitory effect and to do so in a dose-dependent manner. Further examination with the Tali apoptosis assay suggested the growth inhibitory effect of 3 involved the induction of the programmed cell death, and this suggestion was supported by observations of PARP and caspase 3 cleavage after treating cells with 3. In addition, exposure to 3 increased the expression of Bax and repressed the expression of Bcl-2, thus indicating the involvement of macrocycle 3 upstream of Bax and Bcl-2 in the apoptotic signaling pathway. Macrocycle 3 also tended to repress metastasis as evidenced by changes in the transcriptional expressions E- and N-cadherin (markers of metastasis). Furthermore, a stability assay demonstrated macrocycle 3 remained stable at high concentration.

Self-Assembled Novel BODIPY-Based Palladium Supramolecules and Their Cellular Localization.

Four new palladium metal supramolecules with triangular/square architectures derived from boron dipyrromethane (BODIPY) ligands were synthesized by self-assembly and fully characterized by 1H and 31P NMR, electrospray ionization mass spectrometry, and single-crystal X-ray diffraction. These supramolecules were more cytotoxic to brain cancer (glioblastoma) cells than to normal lung fibroblasts. Their cytotoxicity to the glioblastoma cells was higher than that of a benchmark metal-based chemotherapy drug, cisplatin. The characteristic green fluorescence of the BODIPY ligands in these supramolecules permitted their intracellular visualization using confocal microscopy, and the compounds were localized in the cytoplasm and on the plasma membrane.

Selective synthesis of iridium(iii)-derived molecular Borromean rings, [2]catenane and ring-in-ring macrocycles via coordination-driven self-assembly.

This paper reports the formation of unprecedented iridium(iii)-derived topological macrocycles. Discrete molecular Borromean rings 1 and 3 in pure form are synthesized via coordination-driven self-assembly of an acceptor [(Cp*Ir)2(OO∩OO)](OTf)2 (Cp* = pentamethylcyclopentadienyl, OO∩OO = 6,11-dioxido-5,12-naphthacenedione) (A) with dipyridyl donors 1,4-bis(4-pyridinylethynyl)benzene (L1) and 2,5-bis(4-pyridinylethynyl)thiophene (L2) respectively in methanol. Self-assembly using the same acceptor under similar conditions with two other donors 9,10-bis(4-pyridinylethynyl)anthracene (L3) and 1,4-di(4-pyridinylethynyl)buta-1,3-diyne (L4) resulted in [2]catenane 5 and non-catenane ring-in-ring topological macrocycle 7 respectively. Rectangular macrocycles 2, 4, 6, and 8 were respectively obtained when the self-assembly of acceptor A with one of the donors L1-L4 was carried out under dilute conditions in nitromethane or methanol. All these new macrocycles were characterized by 1H and 13C NMR, 2D NMR, ESI-MS and elemental analyses. Single crystal X-ray structures of Borromean rings 1 and 3, and ring-in-ring macrocycle 7 revealed that the length and functionality of donors enabling CHπ and ππ interactions govern the topology.

Coordination-Driven Self-Assembly and Anticancer Potency Studies of Ruthenium-Cobalt-Based Heterometallic Rectangles.

Three new cobalt-ruthenium heterometallic molecular rectangles, 1-3, were synthesized through the coordination-driven self-assembly of a new cobalt sandwich donor, (η5 -Cp)Co[C4 -trans-Ph2 (4-Py)2 ] (L; Cp: cyclopentyl; Py: pyridine), and one of three dinuclear precursors, [(p-cymene)2 Ru2 (OO∩OO)2 Cl2 ] [OO∩OO: oxalato (A1 ), 5,8-dioxido-1,4-naphthoquinone (A2 ), or 6,11-dioxido-5,12-naphthacenedione (A3 )]. All of the self-assembled architectures were isolated in very good yield (92-94 %) and were fully characterized by spectroscopic analysis; the molecular structures of 2 and 3 were determined by single-crystal X-ray diffraction analysis. The anticancer activities of bimetallic rectangles 1-3 were evaluated with a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, an autophagy assay, and Western blotting. Rectangles 1-3 showed higher cytotoxicity than doxorubicin in AGS human gastric carcinoma cells. In addition, the autophagic activities and apoptotic cell death ratios were increased in AGS cells by treatment with 1-3; the rectangles induced autophagosome formation by promoting LC3-I to LC3-II conversion and apoptotic cell death by increasing caspase-3/7 activity. Our results suggest that rectangles 1-3 induce gastric cancer cell death by modulating autophagy and apoptosis and that they have potential use as agents for the treatment of human gastric cancer.

Selective Synthesis of Molecular Borromean Rings: Engineering of Supramolecular Topology via Coordination-Driven Self-Assembly.

Molecular Borromean rings (BRs) is one of the rare topology among interlocked molecules. Template-free synthesis of BRs via coordination-driven self-assembly of tetracene-based Ru(II) acceptor and ditopic pyridyl donors is reported. NMR and single-crystal XRD analysis observed sequential transformation of a fully characterized monomeric rectangle to molecular BRs and vice versa. Crystal structure of BRs revealed that the particular topology was enforced by the appropriate geometry of the metallacycle and multiple parallel-displaced π-π interactions between the donor and tetracene moiety of the acceptor. Computational studies based on density functional theory also supported the formation of BRs through dispersive intermolecular interactions in solution.

Antitumor and biological investigation of doubly cyclometalated ruthenium(II) organometallics derived from benzimidazolyl derivatives.

In this study, we report the synthesis, anticancer and biological properties of three doubly cyclometalated phenylbenzimidazole derived ruthenium(ii) organometallics () and their corresponding three organic ligands. The structures of were fully characterized by various analytical techniques, and the meso stereoisomer of the doubly cyclometalated ruthenacycle was unambiguously confirmed by single crystal X-ray diffraction. The anticancer effects of the newly synthesized compounds were tested against selected human cancer cell lines AGS (gastric carcinoma), SK-hep-1 (hepatocellular carcinoma), and HCT-15 (colorectal carcinoma). The growth inhibitory effects of ruthenacycles on cancer cells were found to be considerably more effective against the abovementioned cancer cells than the reference drug oxaliplatin. Compound exhibited a more specific effect on the AGS cells. Gene-fishing and ELISA array were performed to analyze the target genes and cytokine secretion by . As a result, a significant reduction was observed in RPS21 by . Moreover, increased the secretion of cytokines such as IFNγ in macrophages and reduced the release of cytokines such as rantes and IGF-1. These results show that could be a very good anticancer drug through the regulation of the RPS21 gene and cytokines.

Template-Free Synthesis of a Molecular Solomon Link by Two-Component Self-Assembly.

A molecular Solomon link was synthesized in high yield through the template-free, coordination-driven self-assembly of a carbazole-functionalized donor and a tetracene-based dinuclear ruthenium(II) acceptor. The doubly interlocked topology was realized by a strategically chosen ligand which was capable of participating in multiple CH⋅⋅⋅π and π-π interactions, as evidenced from single-crystal X-ray analysis and computational studies. This method is the first example of a two-component self-assembly of a molecular Solomon link using a directional bonding approach. The donor alone was not responsible for the construction of the Solomon link, and was confirmed by its noncatenane self-assemblies obtained with other similar ruthenium(II) acceptors.

Anticancer activities of self-assembled molecular bowls containing a phenanthrene-based donor and Ru(II) acceptors.

Nano-sized multinuclear ruthenium complexes have rapidly emerged as promising therapeutic candidates with unique anticancer activities. Here, we describe the coordination-driven self-assembly and anticancer activities of a set of three organometallic tetranuclear Ru(II) molecular bowls. [2+2] Coordination-driven self-assembly of 3, 6-bis(pyridin-3- ylethynyl) phenanthrene (bpep) (1) and one of the three dinuclear arene ruthenium clips, [(η6-p-iPrC6H4Me)2Ru2-(OO\OO)][OTf]2 (OO\OO =2, 5-dioxido-1, 4-benzoquinonato, OTf = triflate) (2), 5, 8-dioxido-1, 4-naphthoquinonato (3), or 6, 11-dioxido-5, 12-naphthacenediona (4), resulted in three molecular bowls 5-7 of general formula [{(η6-p-iPrC6H4Me)2Ru2-(OO\OO)}2(bpep)2][OTf]4. All molecular bowls were obtained as triflate salts in very good yields (>90%) and were fully characterized using multinuclear nuclear magnetic resonance (NMR), electrospray ionization-mass spectrometry (ESI-MS), and elemental analysis. The structure of the representative molecular bowl 5 was confirmed by single-crystal X-ray diffraction analysis. The anticancer activities of molecular bowls 5-7 were determined by 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide, autophagy, and Western blot analysis. Bowl 6 showed the strongest cytotoxicity in AGS human gastric carcinoma cells and was more cytotoxic than doxorubicin. In addition, autophagic activity and the ratio of apoptotic cell death increased in AGS cells by treatment with bowl 6. Bowl 6 also induced autophagosome formation via upregulation of p62 and promotion of the conversion of LC3-I to LC3-II. Moreover, bowl 6 promoted apoptotic cell death through downregulation of Akt/mTOR activation, followed by increased caspase-3 activity. These results suggest that bowl 6 induces gastric cancer cell death via modulation of autophagy and apoptosis. Bowl 6 is a potent anticancer agent and a potential treatment for human gastric cancer that merits further study.

Investigation of the biological and anti-cancer properties of ellagic acid-encapsulated nano-sized metalla-cages.

Three new large hexanuclear metalla-prisms 9-11 incorporating 1,3, 5-tris(pyridin-4-ylethynyl)benzene (tpeb) 4 and one of the dinuclear arene ruthenium clips [Ru2(p-iPrC6H4Me)2(OO∩OO)][CF3SO3]2 (OO∩OO =2,5-dioxydo-1,4-benzoquinonato [dobq] 1, 5,8-dihydroxy-1,4-naphthaquinonato (donq) 2, and 6,11-dihydroxy-5,12-naphthacenedionato [dotq] 3), which encapsulate the guest molecule ellagic acid (2,3,7,8-tetrahydroxy-chromeno[5,4,3-cde]chromene-5,10-dione, 5) were prepared. All complexes were isolated as triflate salts in good yields and were fully characterized by (1)H NMR spectroscopy and electrospray ionization mass spectrometry. The photophysical properties of these metalla-prisms were also investigated. Compounds 9 and 10 showed potent antioxidant activity, but 10 had the superior ORACPE value (1.30 ± 0.020). Ellagic acid (5) and compound 11 showed weaker activity than that of Trolox. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that the metalla-prism compounds exhibit anticancer properties in vitro. Compound 10 inhibited the growth of all cancer cell lines at micromolar concentrations, with the highest cytotoxicity observed against A549 human lung cancer cells (IC50 =25.9 µM). However, these compounds had a lower anti-cancer activity than that of doxorubicin. In a tumoricidal assay, ellagic acid (5) and compound 10 induced cytotoxicity in tumor cells, while doxorubicin did not. While free ellagic acid had no effect on the granulocyte-colony stimulating factor and regulated on activation normal T cell expressed and secreted protein, the encapsulated metalla-prism 10 stimulated granulocyte-colony stimulating factor and reduced regulated on activation normal T cell expressed and secreted protein expression in the RAW264.7 macrophage line. Our results show that ellagic acid encapsulated in metalla-prisms inhibited cancer cells via the modulation of mRNA induction and protein expression levels of the granulocyte-colony stimulating factor and regulated on activation normal T cell expressed and secreted protein in macrophages.

Selective synthesis of ruthenium(II) Metalla[2]catenane via solvent and guest-dependent self-assembly.

The coordination-driven self-assembly of an anthracene-functionalized ditopic pyridyl donor and a tetracene-based dinuclear Ru(II) acceptor resulted in an interlocked metalla[2]catenane, [M2L2]2, in methanol and a corresponding monorectangle, [M2L2], in nitromethane. Subsequently, guest template, solvent, and concentration effects allowed the self-assembly to be reversibly fine-tuned among monorectangle and catenane structures.