An Interface-Directed Coassembly Approach To Synthesize Uniform Large-Pore Mesoporous Silica Spheres

A facile and controllable interface-directed coassembly (IDCA) approach is developed for the first time to synthesize uniform discrete mesoporous silica particles with a large pore size (ca. 8 nm) by using 3-dimensional macroporous carbon (3DOMC) as the nanoreactor for the confined coassembly of template molecules and silica source. By controlling the amount of the precursor solution and using Pluronic templates with different compositions, we can synthesize mesoporous silica particles with diverse morphologies (spheres, hollow spheres, and hemispheres) and different mesostructure (e.g., 2-D hexagonal and 3D face centered cubic symmetry), high surface area of about 790 m²/g, and large pore volume (0.98 cm³/g). The particle size can be tunable from submicrometer to micrometer regimes by changing the macropore diameter of 3DOMC. Importantly, this synthesis concept can be extended to fabricate multifunctional mesoporous composite spheres with a magnetic core and a mesoporous silica shell, large saturated magnetization (23.5 emu/g), and high surface area (280 m²/g). With the use of the magnetic mesoporous silica spheres as a magnetically recyclable absorbent, a fast and efficient removal of microcystin from water is achieved, and they can be recycled for 10 times without a significant decrease of removal efficiency for microcystin

Polymerization-Induced Colloid Assembly Route to Iron Oxide-Based Mesoporous Microspheres for Gas Sensing and Fenton Catalysis

Iron oxide materials have wide applications due to their special physicochemical properties; however, it is a great challenge to synthesize mesoporous iron oxide-based microspheres conveniently and controllably with high surface area, large pore volume, and interconnected porous structures. Herein, mesoporous α-Fe₂O₃-based microspheres with high porosity are synthesized via a facile polymerization induced colloid assembly method through polymerization of urea–formaldehyde resin (UF resin) and its simultaneously cooperative assembly with Fe­(OH)₃ colloids in an aqueous solution, followed by subsequent thermal treatment. Remarkably, by controlling the cross-linking degree of UF, pure mesoporous α-Fe₂O₃ and α-Fe₂O₃/carbon hybrid microspheres can be synthesized controllably, respectively. They exhibit a uniform spherical morphology with a particle size of around 1.0 μm, well-interconnected mesopores (24.5 and 8.9 nm, respectively), and surface area of 54.4 m²/g (pure mFe₂O₃ microspheres) and 144.7 m²/g (hybrids), respectively. As a result, mesoporous pure α-Fe₂O₃ microspheres exhibited excellent H₂S sensing performance with a good selectivity, high response to low concentration H₂S at 100 °C, and quick response (4 s)/recovery (5 s) dynamics owing to the high surface area, open mesopores, and crystalline structure of the n-type α-Fe₂O₃ semiconductor. Moreover, mesoporous α-Fe₂O₃/carbon hybrid microspheres were used as a novel Fenton-like catalyst for the decomposition of methylene blue in a mild condition and exhibit quick degradation rate, high removal efficiency (∼93% within 35 min), and stable recycling performance owing to the synergetic effect of a high surface area and the carbon-protected α-Fe₂O₃

A General Chelate-Assisted Co-Assembly to Metallic Nanoparticles-Incorporated Ordered Mesoporous Carbon Catalysts for Fischer–Tropsch Synthesis

The organization of different nano objects with tunable sizes, morphologies, and functions into integrated nanostructures is critical to the development of novel nanosystems that display high performances in sensing, catalysis, and so on. Herein, using acetylacetone as a chelating agent, phenolic resol as a carbon source, metal nitrates as metal sources, and amphiphilic copolymers as a template, we demonstrate a chelate-assisted multicomponent coassembly method to synthesize ordered mesoporous carbon with uniform metal-containing nanoparticles. The obtained nanocomposites have a 2-D hexagonally arranged pore structure, uniform pore size (∼4.0 nm), high surface area (∼500 m²/g), moderate pore volume (∼0.30 cm³/g), uniform and highly dispersed Fe₂O₃ nanoparticles, and constant Fe₂O₃ contents around 10 wt %. By adjusting acetylacetone amount, the size of Fe₂O₃ nanoparticles is readily tunable from 8.3 to 22.1 nm. More importantly, it is found that the metal-containing nanoparticles are partially embedded in the carbon framework with the remaining part exposed in the mesopore channels. This unique semiexposure structure not only provides an excellent confinement effect and exposed surface for catalysis but also helps to tightly trap the nanoparticles and prevent aggregating during catalysis. Fischer–Tropsch synthesis results show that as the size of iron nanoparticles decreases, the mesoporous Fe–carbon nanocomposites exhibit significantly improved catalytic performances with C₅₊ selectivity up to 68%, much better than any reported promoter-free Fe-based catalysts due to the unique semiexposure morphology of metal-containing nanoparticles confined in the mesoporous carbon matrix

Templated Fabrication of Core–Shell Magnetic Mesoporous Carbon Microspheres in 3‑Dimensional Ordered Macroporous Silicas

A confined synthesis strategy is demonstrated for the fabrication of core–shell magnetic mesoporous carbon microspheres by solvent evaporation induced self-assembly of ethanolic solutions of precursors (containing resol as carbon source, Pluronic F127 as a structure directing agent) in the cavity of presynthesized 3-dimensional ordered macroporous silica materials with each macropore filled with a magnetite particle. The obtained magnetic mesoporous carbon (Fe₃O₄@FDU-15) microspheres possess uniform diameter of ∼460 nm, ultralarge mesopores of 13.8 nm, high surface area of ∼403 m²/g, and strong magnetization (20.7 emu/g). Sub-4 nm gold nanoparticles are loaded in the porous shell of the magnetic microspheres, resulting in a novel Fe₃O₄@FDU-15/Au nanocatalyst with an excellent performance in catalyzing the epoxidation of styrene with high conversion (72%) and selectivity (85%) toward styrene oxide in 12 h and a good magnetic field-assisted recyclability

Tricomponent Coassembly Approach To Synthesize Ordered Mesoporous Carbon/Silica Nanocomposites and Their Derivative Mesoporous Silicas with Dual Porosities

Highly ordered mesoporous carbon/silica nanocomposites and dual-mesoporous silicas with a 3D cubic structure were successfully synthesized through a facile tricomponent coassembly approach by using the lab-made diblock copolymer poly­(ethylene oxide)-<i>b</i>-polystyrene as a template. The mesoporous silicas exhibit a high surface area and uniform bimodal mesopores. The bimodal mesopores can be tuned by simply changing the ratio of carbon/silica precursors and the pyrolysis temperature in N₂. Gold nanoparticles were successfully loaded in the primary large mesopores for use as a heterogeneous nanacatalyst, which exhibits excellent performance in the epoxidation of styrene, demonstrating their potential for catalyst support

Structure-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo[1,5‑<i>a</i>]pyrazines as ATR Inhibitors

A saturation strategy focused on improving the selectivity and physicochemical properties of ATR inhibitor HTS hit <b>1</b> led to a novel series of highly potent and selective tetrahydropyrazolo­[1,5-<i>a</i>]­pyrazines. Use of PI3Kα mutants as ATR crystal structure surrogates was instrumental in providing cocrystal structures to guide the medicinal chemistry designs. Detailed DMPK studies involving cyanide and GSH as trapping agents during microsomal incubations, in addition to deuterium-labeled compounds as mechanistic probes uncovered the molecular basis for the observed CYP3A4 TDI in the series

Structure-Based Drug Design of Novel, Potent, and Selective Azabenzimidazoles (ABI) as ATR Inhibitors

Compound <b>13</b> was discovered through morphing of the ATR biochemical HTS hit <b>1</b>. The ABI series was potent and selective for ATR. Incorporation of a 6-azaindole afforded a marked increase in cellular potency but was associated with poor PK and hERG ion channel inhibition. DMPK experiments established that CYP P450 and AO metabolism in conjunction with Pgp and BCRP efflux were major causative mechanisms for the observed PK. The series also harbored the CYP3A4 TDI liability driven by the presence of both a morpholine and an indole moiety. Incorporation of an adjacent fluorine or nitrogen into the 6-azaindole addressed many of the various medicinal chemistry issues encountered

Discovery of Novel Allosteric Mitogen-Activated Protein Kinase Kinase (MEK) 1,2 Inhibitors Possessing Bidentate Ser212 Interactions

Using structure-based design, two novel series of highly potent biaryl amine mitogen-activated protein kinase kinase (MEK) inhibitors have been discovered. These series contain an H-bond acceptor, in a shifted position compared with previously disclosed compounds, and an adjacent H-bond donor, resulting in a bidentate interaction with the Ser212 residue of MEK1. The most potent compound identified, <b>1</b> (G-894), is orally active in in vivo pharmacodynamic and tumor xenograft models

Cell Active Hydroxylactam Inhibitors of Human Lactate Dehydrogenase with Oral Bioavailability in Mice

A series of trisubstituted hydroxylactams was identified as potent enzymatic and cellular inhibitors of human lactate dehydrogenase A. Utilizing structure-based design and physical property optimization, multiple inhibitors were discovered with <10 μM lactate IC₅₀ in a MiaPaca2 cell line. Optimization of the series led to <b>29</b>, a potent cell active molecule (MiaPaca2 IC₅₀ = 0.67 μM) that also possessed good exposure when dosed orally to mice

Discovery of Novel PI3-Kinase δ Specific Inhibitors for the Treatment of Rheumatoid Arthritis: Taming CYP3A4 Time-Dependent Inhibition

PI3Kδ is a lipid kinase and a member of a larger family of enzymes, PI3K class IA­(α, β, δ) and IB (γ), which catalyze the phosphorylation of PIP2 to PIP3. PI3Kδ is mainly expressed in leukocytes, where it plays a critical, nonredundant role in B cell receptor mediated signaling and provides an attractive opportunity to treat diseases where B cell activity is essential, e.g., rheumatoid arthritis. We report the discovery of novel, potent, and selective PI3Kδ inhibitors and describe a structural hypothesis for isoform (α, β, γ) selectivity gained from interactions in the affinity pocket. The critical component of our initial pharmacophore for isoform selectivity was strongly associated with CYP3A4 time-dependent inhibition (TDI). We describe a variety of strategies and methods for monitoring and attenuating TDI. Ultimately, a structure-based design approach was employed to identify a suitable structural replacement for further optimization