In vivo anticancer activity of rhomboidal Pt(II) metallacycles

The development of novel antitumor agents that have high efficacy in suppressing tumor growth, have low toxicity to nontumor tissues, and exhibit rapid localization in the targeted tumor sites is an ongoing avenue of research at the interface of chemistry, cancer biology, and pharmacology. Supramolecular metal-based coordination complexes (SCCs) have well-defined shapes and geometries, and upon their internalization, SCCs could affect multiple oncogenic signaling pathways in cells and tissues. We investigated the uptake, intracellular localization, and antitumor activity of two rhomboidal Pt(II)-based SCCs. Laser-scanning confocal microscopy in A549 and HeLa cells was used to determine the uptake and localization of the assemblies within cells and their effect on tumor growth was investigated in mouse s.c. tumor xenograft models. The SCCs are soluble in cell culture media within the entire range of studied concentrations (1 nM–5 µM), are nontoxic, and showed efficacy in reducing the rate of tumor growth in s.c. mouse tumor xenografts. These properties reveal the potential of Pt(II)-based SCCs for future biomedical applications as therapeutic agents.Molecular assemblies of nanoscale-size and well-defined geometries have recently emerged as an interesting new paradigm in drug design and drug delivery. To date, liposomes, the self-assembled lipid nanoparticles held together by weak interactions, are among the most widely studied and clinically successful nanoparticle-based drug carriers. Their use allows the drug to achieve sustained plasma levels while encapsulated, with the size preventing the fast clearance by the kidneys that often occurs with the free drug. However, liposomes themselves do not produce a therapeutic effect and their application as drug carriers for medical purposes has often been hindered by poor loading capacity (<5 wt %) and the inability to pass through biological barriers (1, 2). Inorganic and hybrid porous materials, such as molecular organic frameworks (MOFs), have also shown promise due to their higher loading capacities (>25 wt %) (3–5), but MOFs have poor hydrolytic stability (6, 7). Recent studies on materials from Institut Lavoisier (MIL)-100(Cr) and MIL-100(Fe), however, suggest that MOFs can persist in biologically relevant environments and can act as vehicles for some anticancer and antiviral agents (8–10). These early findings have prompted further investigations into the biomedical applications of supramolecular coordination complexes (SCCs) (11–24). SCCs preserve the attractive properties of MOFs, such as building block modularity (22, 23, 25), yet afford an increased solubility in the biological milieu and lend themselves to small-molecule characterization techniques due to their well-defined structure.Although development of SCCs for biomedical applications is in its infancy, some SCCs, such as trigonal prisms self-assembled from p-cymene and ruthenium-based metal fragments with pyridyl donors, have shown the ability to act as effective carriers of some chemotherapeutic agents (26–28). Moreover, a library of cytotoxic to cancer cells p-cymene ruthenium-based polygons and cages has also been developed (11). For biomedical applications, the information about the cellular uptake, delivery of a guest, and metabolism of the drug delivery vehicle is critical, although currently the fate of SCCs in biological environments is not well understood. In a rare report, a systematic investigation of the structural stability of a water-soluble, hexacationic ruthenium-based trigonal prism was performed; however, it was determined that the ruthenium-based trigonal prisms decompose in the presence of amino acids histidine, lysine, and arginine (29).An intriguing approach is the design of tumor-targeted modalities that combine detection and treatment through the self-assembly of emissive, metal-based coordination complexes. Such modalities can be especially valuable as they often do not require photoexcitation to elicit cytotoxicity. Recently Gray, Gross, and Medina-Kauwe and coworkers reported HerGa, a self-assembled tumor-targeted particle that bears the Ga(III)-metalated derivative of the sulfonated corrole (30, 31). The particle, which contained Ga(III)-corrole noncovalently bound to the tumor-targeting cell penetration protein HerPBK10, provided both tumor detection and elimination. Systemic injection of this protein–corrole complex resulted in tumor accumulation, which can be visualized in vivo due to the red corrole fluorescence. Cytotoxic and cytostatic properties of these targeted Ga(III) corroles were found to be cell-line dependent, with the ability to induce late M-phase arrest in several cancer cell lines (32).Despite the well-known cytotoxic properties of mono- and multinuclear platinum complexes (33–35), studies of the antitumor properties of platinum-based SCCs are rare (17, 36). Moreover, recent reports have demonstrated that platinum-based SCCs can act as effective hosts for guests and have interesting photophysical properties (37–42). In particular, highly emissive rhomboids based on aniline-containing donors and Pt-based metal acceptors have been developed that display different photophysical properties from those of their constituent subunits (40). These assemblies are interesting targets to investigate the cytotoxicity of organoplatinum SCCs, whereas their emission spectra could be used for interrogating the structural integrity in vitro. Here, for the first time to our knowledge, we report the uptake of SCCs in vitro in cell-based assays, determined by using laser-scanning confocal microscopy, and an in vivo assessment of the anticancer activity of SCCs in mouse s.c. tumor xenograft models.     

Synthesis and photophysical studies of self-assembled multicomponent supramolecular coordination prisms bearing porphyrin faces

Multicomponent self-assembly, wherein two unique donor precursors are combined with a single metal acceptor instead of the more common two-component assembly, can be achieved by selecting Lewis-basic sites and metal nodes that select for heteroligated coordination spheres. Platinum(II) ions show a thermodynamic preference for mixed pyridyl/carboxylate coordination environments and are thus suitable for such designs. The use of three or more unique building blocks increases the structural complexity of supramolecules. Herein, we describe the synthesis and characterization of rectangular prismatic supramolecular coordination complexes (SCCs) with two faces occupied by porphyrin molecules, motivated by the search for new multichromophore complexes with promising light-harvesting properties. These prisms are obtained from the self-assembly of a 90° Pt(II) acceptor with a meso-substituted tetrapyridylporphyrin (TPyP) and dicarboxylate ligands. The generality of this self-assembly reaction is demonstrated using five dicarboxylate ligands, two based on a rigid central phenyl ring and three alkyl-spaced variants, to form a total of five free-base and five Zn-metallated porphyrin prisms. All 10 SCCs are characterized by ³¹P and ¹H multinuclear NMR spectroscopy and electrospray ionization mass spectrometry, confirming the structure of each self-assembly and the stoichiometry of formation. The photophysical properties of the resulting SCCs were investigated revealing that the absorption and emission properties of the free-base and metallated porphyrin prisms preserve the spectral features associated with free TPyP.The use of sunlight is ubiquitous as the input for carbon-neutral, renewable energy schemes (1). Every strategy that relies on solar energy conversion, ranging from direct conversion to electricity in photovoltaics (2) to the generation of fuels via electrocatalysis (3), photoanode (4, 5), or photocathode devices (6), or photocatalysis (7) requires that photons be absorbed by a molecule or material as the first step in providing the driving force for subsequent transformation. Natural systems have evolved light-harvesting complexes, comprising multiprotein ensembles embedded with pigment molecules to enhance photon absorption for photosynthesis (8). These pigment-rich sites are arranged such that excitation of a distal chromophore will ultimately result in energy transfer to a reaction center via a series of migration and transfer processes (9). Strategies to replicate natural light-harvesting complexes necessarily demand the organization of multiple chromophores (10), a requirement that makes self-assembly and supramolecular chemistry particularly well suited for such efforts (11–13). As such, a variety of approaches have been applied toward the development of new materials that exhibit broadband absorption and efficient energy transfer (14–16). The subsequent studies of such materials span investigations of the fundamental science behind energy migration and transfer, to practical applications in devices.Many of these designs incorporate porphyrin-based molecules (17–22), a pigment that is related to the ubiquitous chlorophyll found in natural light-harvesting systems (23). Porphyrins possess characteristic structural and photophysical properties that make them well suited for adaptation into artificial designs, not only for solar energy conversion but also for applications in photodynamic therapy (24–29), enzyme mimics (30–32), catalysis (33–37), and molecular electronic devices (38, 39). In the context of solar energy, many multiporphyrin light-harvesting designs have been developed ranging from organic polymers, metal-organic frameworks, and supramolecular ensembles. Porphyrins are remarkable precursors for incorporation into supramolecular designs due to their established syntheses that facilitate well-defined functionalization, the commercial availability of simple variants, and their ability to accommodate a wide range of metal ions, thus unlocking suites of complexes for a given design (40, 41). The absorption spectra of porphyrin molecules are dominated by so-called Soret bands in the 380- to 500-nm range, accompanied by a set of weaker, but still considerably intense Q bands in the 500- to 700-nm range. Because these bands result in the absorption of visible photons, the attractiveness of porphyrins in solar conversion schemes becomes apparent. Furthermore, the emission wavelengths of a given porphyrin may align with its Q-band absorption, providing the spectral overlap that is required for efficient energy migration.Although extended structures such as polymers and metal-organic frameworks can organize similar numbers of pigments as are found in natural systems (42–47), their study can be complemented by relatively smaller supramolecules that facilitate characterization and study, preserving attractive properties such as solubility and facile tenability (48, 49). As such, coordination-driven self-assembly has been used to explore porphyrin-based supramolecular coordination complexes in traditional one- or two-component schemes (50-53).The recent development of new strategies for multicomponent self-assembly has provided a method to increase the structural complexity of chromophoric supramolecular coordination complexes (SCCs) wherein three or more building blocks can assemble into a single thermodynamically favored product (54, 55). One method to achieve multicomponent assembly is to identify metal nodes and ligands that prefer heteroligated coordination spheres, thus avoiding statistical mixtures of products. For example, when Pt(II) ions are combined with pyridyl and carboxylate-based ligands, mixed Pt-N,O coordination environments are formed exclusively (56). This method has been used recently to construct a variety of 2D and 3D SCCs and also provides the basis for supramolecule-to-supramolecule transformation, wherein a Pt-pyridyl SCC may be mixed in the proper stoichiometry with a Pt-carboxylate SCC to quantitatively furnish a third multicomponent SCC (56). Furthermore, traditional two-component assembly typically requires the use of rigid building blocks so as to maintain the angularity and directionality that determines the structural outcome of a reaction. In contrast, multicomponent approaches also permit the use of structurally ambiguous ligands, provided the remaining building blocks enforce a proper degree of directionality. As such, alkyl-based building blocks may be used in such self-assembly schemes, despite the fact that rotation about the carbon–carbon bonds means that a single orientation of the coordination vectors is not maintained (57).We report here a unification of many recent themes of coordination-driven self-assembly: the formation of multichromophore complexes as motivated by the need for new light-harvesting materials, multicomponent self assembly using Pt(II) heteroligation, and alkyl-based dicarboxylates in the formation of 3D prisms that demonstrate a hitherto-underexplored class of building blocks for coordination-driven self-assembly. The synthesis and characterization of a suite of 10 prisms is described, thus demonstrating the structural modularity and tunability that is possible through self-assembly approaches. Five prisms are formed containing free-based tetrapyridyl porphyrin, with the remaining five being their Zn-containing analogs. The absorption and emission properties of the SCCs are evaluated and compared with free tetrapyridylporphyrin (TPyP) revealing that, upon incorporation into prisms, the photophysical properties remain largely unchanged. In addition, the solubility of the prisms far exceeds that of the parent TPyP, indicating that coordination-driven self-assembly may be a powerful method to optimize the physiochemical characteristics of new light-harvesting materials.     

Molecular aspects on the interaction of protoberberine, benzophenanthridine, and aristolochia group of alkaloids with nucleic acid structures and biological perspectives

Alkaloids occupy an important position in chemistry and pharmacology. Among the various alkaloids, berberine and coralyne of the protoberberine group, sanguinarine of the benzophenanthridine group, and aristololactam-beta-d-glucoside of the aristolochia group have potential to form molecular complexes with nucleic acid structures and have attracted recent attention for their prospective clinical and pharmacological utility. This review highlights (i) the physicochemical properties of these alkaloids under various environmental conditions, (ii) the structure and functional aspects of various forms of deoxyribonucleic acid (DNA) (B-form, Z-form, H(L)-form, protonated form, and triple helical form) and ribonucleic acid (RNA) (A-form, protonated form, and triple helical form), and (iii) the interaction of these alkaloids with various polymorphic DNA and RNA structures reported by several research groups employing various analytical techniques like absorbance, fluorescence, circular dichroism, and NMR spectroscopy; electrospray ionization mass spectrometry, thermal melting, viscosity, and DNase footprinting as well as molecular modeling and thermodynamic studies to provide detailed binding mechanism at the molecular level for structure-activity relationship. Nucleic acids binding properties of these alkaloids are interpreted in relation to their biological activity.     

Annotated normal CT data of the abdomen for deep learning: Challenges and strategies for implementation

PurposeThe purpose of this study was to report procedures developed to annotate abdominal computed tomography (CT) images from subjects without pancreatic disease that will be used as the input for deep convolutional neural networks (DNN) for development of deep learning algorithms for automatic recognition of a normal pancreas.Materials and methodsDual-phase contrast-enhanced volumetric CT acquired from 2005 to 2009 from potential kidney donors were retrospectively assessed. Four trained human annotators manually and sequentially annotated 22 structures in each datasets, then expert radiologists confirmed the annotation. For efficient annotation and data management, a commercial software package that supports three-dimensional segmentation was used.ResultsA total of 1150 dual-phase CT datasets from 575 subjects were annotated. There were 229 men and 346 women (mean age: 45 ± 12 years; range: 18–79 years). The mean intra-observer intra-subject dual-phase CT volume difference of all annotated structures was 4.27 mL (7.65%). The deep network prediction for multi-organ segmentation showed high fidelity with 89.4% and 1.29 mm in terms of mean Dice similarity coefficients and mean surface distances, respectively.ConclusionsA reliable data collection/annotation process for abdominal structures was developed. This process can be used to generate large datasets appropriate for deep learning.     

Thermal Conductivity of Ordered Porous Structures Coupling Gas and Solid Phases: A Molecular Dynamics Study

Heat transfer in a porous solid−gas mixture system is an important process for many industrial applications. Optimization design of heat insulation material is very important in many fields such as pipe insulation, thermal protection of spacecraft, and building insulation. Understanding the micro-mechanism of the solid−gas coupling effect is necessary for the design of insulation material. The prediction of thermal conductivity is difficult for some kinds of porous materials due to the coupling impact of solid and gas. In this study, the Grand Canonical Monte Carlo method (GCMC) and molecular dynamics simulation (MD) are used to investigate the thermal conductivity for the ordered porous structures of intersecting square rods. The effect of gas concentration (pressure) and solid−gas interaction on thermal conductivity is revealed. The simulation results show that for different framework structures the pressure effect on thermal conductivity presents an inconsistent mode which is different from previous studies. Under the same pressure, the thermal conductivity is barely changed for different interactions between gas and solid phases. This study provides the feasibility for the direct calculation of thermal conductivity for porous structures coupling gas and solid phases using molecular dynamics simulation. The heat transfer in porous structures containing gas could be understood on a fundamental level.     

Supramolecular Inhibition of Neurodegeneration by a Synthetic Receptor

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Synthesis,Polymorphism and Thermal Decomposition Process of (n-C4H9)4NRE(BH4)4 for RE = Ho,Tm and Yb

In total, three novel organic derivatives of lanthanide borohydrides, n-But₄NRE(BH₄)₄ (TBAREB), RE = Ho, Tm, Yb, have been prepared utilizing mechanochemical synthesis and purified via solvent extraction. Studies by single crystal and powder X-ray diffraction (SC-XRD and PXRD) revealed that they crystalize in two polymorphic forms, α- and β-TBAREB, adopting monoclinic (P2₁/c) and orthorhombic (Pnna) unit cells, previously found in TBAYB and TBAScB, respectively. Thermal decomposition of these compounds has been investigated using thermogravimetric analysis and differential scanning calorimetry (TGA/DSC) measurements, along with the analysis of the gaseous products with mass spectrometry (MS) and with analysis of the solid decomposition products with PXRD. TBAHoB and TBAYbB melt around 75 °C, which renders them new ionic liquids with relatively low melting points among borohydrides.     

A sense of place,many times over - pattern formation and evolution of repetitive morphological structures

Fifty years ago, Lewis Wolpert introduced the concept of “positional information” to explain how patterns form in a multicellular embryonic field. Using morphogen gradients, whose continuous distributions of positional values are discretized via thresholds into distinct cellular states, he provided, at the theoretical level, an elegant solution to the “French Flag problem.” In the intervening years, many experimental studies have lent support to Wolpert's ideas. However, the embryonic patterning of highly repetitive morphological structures, as often occurring in nature, can reveal limitations in the strict implementation of his initial theory, given the number of distinct threshold values that would have to be specified. Here, we review how positional information is complemented to circumvent these inadequacies, to accommodate tissue growth and pattern periodicity. In particular, we focus on functional anatomical assemblies composed of such structures, like the vertebrate spine or tetrapod digits, where the resulting segmented architecture is intrinsically linked to periodic pattern formation and unidirectional growth. These systems integrate positional information and growth with additional patterning cues that, we suggest, increase robustness and evolvability. We discuss different experimental and theoretical models to study such patterning systems, and how the underlying processes are modulated over evolutionary timescales to enable morphological diversification.     

Mechanical Behaviour of Aluminium-Timber Composite Connections with Screws and Toothed Plates

This paper presents an investigation of the load-slip behaviour of aluminium-timber composite connections. Toothed plates with bolts are often used for connecting timber structural members with steel structural members. In this paper, toothed plates (C2-50/M10G, C2-50/M12G or C11-50/M12) have been used as reinforcement in aluminium-timber screwed connections for the first time. The push-out test specimens consisted of laminated veneer lumber slabs, aluminium alloy beams, and hexagon head wood screws (10 mm × 80 mm and 12 mm × 80 mm). Of the specimens, 12 additionally had toothed plates as reinforcement, while 8 had no reinforcement. The load carrying-capacity, the mode of failure and the load-slip response of the strengthened and non-strengthened screwed connections were investigated. The use of toothed plate connectors was found to be effective in increasing the strength of aluminium-timber composite connections and ineffective in improving their stiffness. The examined stiffness and strength of the connections can be used in the design and numerical modelling of aluminium-timber composite beams with reinforced screwed connections.