Enhancing the Electromagnetic Performance of Co through the Phase-Controlled Synthesis of Hexagonal and Cubic Co Nanocrystals Grown on Graphene

Cobalt is a promising soft metallic magnetic material used for important applications in the field of absorbing stealth technology, especially for absorbing centimeter waves. However, it frequently presents a weak dielectric property because of its instability, aggregation, and crystallographic form. A method for enhancing the electromagnetic property of metal Co via phase-controlled synthesis of Co nanostructures grown on graphene (GN) networks has been developed. Hexagonal close-packed cobalt (α-Co) nanocrystals and face-centered cubic cobalt (β-Co) nanospheres with uniform size and high dispersion have been successfully assembled on GN nanosheets via a facile one-step solution-phase strategy under different reaction conditions in which the exfoliated graphite oxide (graphene oxide, GO) nanosheets were reduced along with the formation of Co nanocrystals. The as-synthesized Co/GN nanocomposites showed excellent microwave absorbability in comparison with the corresponding Co nanocrystals or GN, especially for the nanocomposites of GN and α-Co nanocrystals (the reflection loss is −47.5 dB at 11.9 GHz), which was probably because of the special electrical properties of the cross-linked GN nanosheets and the perfect electromagnetic match in their microstructure as well as the small particle size of Co nanocrystals. The approach is convenient and effective. Some magnetic metal or alloy materials can also be prepared via this route because of its versatility

Nanocage Structure Derived from Sulfonated β‑Cyclodextrin Intercalated Layered Double Hydroxides and Selective Adsorption for Phenol Compounds

Nanocage structures derived from decasulfonated β-cyclodextrin (SCD) intercalated ZnAl- and MgAl- layered double hydroxides (LDHs) were prepared through calcination-rehydration reactions. The ZnAl- and MgAl-LDH layers revealed different basal spacings (1.51 nm for SCD-ZnAl-LDH and 1.61 nm for SCD-MgAl-LDH) when contacting SCD, while producing similar monolayer and vertical SCD orientations with cavity axis perpendicular to the LDH layer. The structures of the SCD-LDH and carboxymethyl-β-cyclodextrin (CMCD)-LDH intercalates were fully analyzed and compared, and a structural model for the SCD-LDH was proposed. The thermal stability of SCD after intercalation was remarkably enhanced, with decomposition temperature increased by 230 °C. The adsorption property of the SCD-LDH composites for phenol compounds (the effects of adsorption time and phenol concentration on adsorption) was investigated completely. The monolayer arrangement of the interlayer SCD did not affect the adsorption efficiency toward organic compounds, which verified the highly swelling ability of the layered compounds in solvents. Both composites illustrated preferential adsorptive efficiency for 2,3-dimethylphenol (DMP) in comparison with other two phenols of hydroquinone (HQ) and tert-butyl-phenol (TBP), resulting from appropriate hydrophobicity and steric hindrance of DMP. For the two phenols of HQ and TBP, SCD-MgAl-LDH gave better adsorption capacity compared with SCD-ZnAl-LDH. The double-confinement effect due to the combination of the parent LDH host and intercalated secondary host may impose high selectivity for guests. This kind of nanocage structure may have potential applications as adsorbents, synergistic agents, and storage vessels for particular guests

Synthetic Antibodies with a Human Framework That Protect Mice from Lethal Sudan Ebolavirus Challenge

The ebolaviruses cause severe and rapidly progressing hemorrhagic fever. There are five ebolavirus species; although much is known about Zaire ebolavirus (EBOV) and its neutralization by antibodies, little is known about Sudan ebolavirus (SUDV), which is emerging with increasing frequency. Here we describe monoclonal antibodies containing a human framework that potently inhibit infection by SUDV and protect mice from lethal challenge. The murine antibody 16F6, which binds the SUDV envelope glycoprotein (GP), served as the starting point for design. Sequence and structural alignment revealed similarities between 16F6 and YADS1, a synthetic antibody with a humanized scaffold. A focused phage library was constructed and screened to impart 16F6-like recognition properties onto the YADS1 scaffold. A panel of 17 antibodies were characterized and found to have a range of neutralization potentials against a pseudotype virus infection model. Neutralization correlated with GP binding as determined by ELISA. Two of these clones, E10 and F4, potently inhibited authentic SUDV and conferred protection and memory immunity in mice from lethal SUDV challenge. E10 and F4 were further shown to bind to the same epitope on GP as 16F6 with comparable affinities. These antibodies represent strong immunotherapeutic candidates for treatment of SUDV infection

The Discovery of Polo-Like Kinase 4 Inhibitors: Design and Optimization of Spiro[cyclopropane-1,3′[3<i>H</i>]indol]-2′(1′<i>H</i>)‑ones as Orally Bioavailable Antitumor Agents

Polo-like kinase 4 (PLK4), a unique member of the polo-like kinase family of serine-threonine kinases, is a master regulator of centriole duplication that is important for maintaining genome integrity. Overexpression of PLK4 is found in several human cancers and is linked with a predisposition to tumorigenesis. Previous efforts to identify potent and efficacious PLK4 inhibitors resulted in the discovery of (<i>E</i>)-3-((1<i>H</i>-indazol-6-yl)­methylene)­indolin-2-ones, which are superseded by the bioisosteric 2-(1<i>H</i>-indazol-6-yl)­spiro­[cyclopropane-1,3′-indolin]-2′-ones reported herein. Optimization of this new cyclopropane-linked series was based on a computational model of a PLK4 X-ray structure and SAR attained from the analogous alkene-linked series. The racemic cyclopropane-linked compounds showed PLK4 affinity and antiproliferative activity comparable to their alkene-linked congeners with improved physicochemical, ADME, and pharmacokinetic properties. Positive xenograft results from the MDA-MB-468 human breast cancer xenograft model for compound <b>18</b> support the investigation of PLK4 inhibitors as anticancer therapeutics. A PLK4 X-ray co-structure with racemate <b>18</b> revealed preferential binding of the 1<i>R</i>,2<i>S</i> enantiomer to the PLK4 kinase domain

The Discovery of PLK4 Inhibitors: (<i>E</i>)‑3-((1<i>H</i>‑Indazol-6-yl)methylene)indolin-2-ones as Novel Antiproliferative Agents

The family of Polo-like kinases is important in the regulation of mitotic progression; this work keys on one member, namely Polo-like kinase 4 (PLK4). PLK4 has been identified as a candidate anticancer target which prompted a search for potent and selective inhibitors of PLK4. The body of the paper describes lead generation and optimization work which yielded nanomolar PLK4 inhibitors. Lead generation began with directed virtual screening, using a ligand-based focused library and a PLK4 homology model. Validated hits were used as starting points for the design and discovery of PLK4 inhibitors of novel structure, namely (<i>E</i>)-3-((1<i>H</i>-indazol-6-yl)­methylene)­indolin-2-ones. Computational models, based on a published X-ray structure (PLK4 kinase domain), were used to understand and optimize the in vitro activity of the series; potent antiproliferative activity was obtained. The kinase selectivity profile and cell cycle analysis of selected inhibitors are described. The results of a xenograft study with an optimized compound <b>50</b> (designated CFI-400437) support the potential of these novel PLK4 inhibitors for cancer therapy

The Discovery of Polo-Like Kinase 4 Inhibitors: Identification of (1<i>R</i>,2<i>S</i>)‑2-(3-((<i>E</i>)‑4-(((<i>cis</i>)‑2,6-Dimethylmorpholino)methyl)styryl)‑1<i>H</i>‑indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (CFI-400945) as a Potent, Orally Active Antitumor Agent

Previous publications from our laboratory have introduced novel inhibitors of Polo-like kinase 4 (PLK4), a mitotic kinase identified as a potential target for cancer therapy. The search for potent and selective PLK4 inhibitors yielded (<i>E</i>)-3-((1<i>H</i>-indazol-6-yl)­methylene)­indolin-2-ones, which were superseded by the bioisosteric 2-(1<i>H</i>-indazol-6-yl)­spiro­[cyclopropane-1,3′-indolin]-2′-ones, e.g., <b>3</b>. The later scaffold confers improved drug-like properties and incorporates two stereogenic centers. This work reports the discovery of a novel one-pot double S_N2 displacement reaction for the stereoselective installation of the desired asymmetric centers and confirms the stereochemistry of the most potent stereoisomer, e.g., <b>44</b>. Subsequent work keys on the optimization of the oral exposure of nanomolar PLK4 inhibitors with potent cancer cell growth inhibitory activity. A short list of compounds with superior potency and pharmacokinetic properties in rodents and dogs was studied in mouse models of tumor growth. We conclude with the identification of compound <b>48</b> (designated CFI-400945) as a novel clinical candidate for cancer therapy