Mesoporous Zirconium Phenylphosphonates for Selective Enrichment of Phosphopeptides

Mesoporous zirconium phenylphosphonates were synthesized by one-pot co-condensation of ZrCl₄ and phenylphosphonic acid (PPA) under weak acidic medium using sodium dodecyl sulfate (SDS) as a template. The structure and chemical states of the synthesized materials were characterized by N₂ sorption, powder XRD, TEM and FT-IR, ICP, and solid-state NMR, indicating that the hybrids possess mesoporous structure and the frameworks are constructed by the coordination of zirconium­(IV) with phenylphosphonates. These mesoporous materials present a considerable amount of uniformly distributed zirconium­(IV) throughout the frameworks available for the enrichment of phosphopeptides, which causes them to circumvent the complex preloading of metal ions required for traditional immobilized metal affinity chromatographic (IMAC) adsorbents. Thus, the materials are first applied as IMAC adsorbents to enrich phosphopeptides from the tryptic digests of both standard phosphoproteins and a mixture of proteins. MALDI-TOF MS analysis shows that mesoporous zirconium phenylphosphonates exhibit satisfying efficiency and specificity in the enrichment of phosphopeptides from peptides even under strong interference of nonphophopeptides

Bifunctional Mesoporous Zirconium Phosphonates for Delivery of Nucleic Acids

The bifunctional mesoporous zirconium phosphonates (ZrBFs) were synthesized through surfactant-assisted co-condensation of ZrCl₄ with two different phosphonic acids, both 1-phosphomethylproline (H₃PMP) and 1,4-bis­(phosphomethyl)­piperazine (BPMP), in a one-pot procedure. The l-proline group of H₃PMP and piperazine group of BPMP in the frameworks endow ZrBFs with pH-controllable release function and high cell penetration capability, which was derived from the reversible protonation–deprotonation of l-proline groups and piperazine groups on the mesoporous walls under different pH values (pH sensitivity) as well as further functionalization with biological modifiers via the carboxyls in l-proline groups on the outer surface (functionalizability), respectively. ZrBFs, possessing cationic frameworks once formed, exhibit high payload for salmon sperm DNA as model nucleic acid owing to strong electrostatic attraction between them. On the basis of pH-sensitive ZrBFs carriers and assisted by lag-time films coating, the time- and pH-controlled oral colon-targeted nucleic acid delivery systems have been developed, which can carry most of the loaded salmon sperm DNA to the colon under dual control, time control and pH value control. Furthermore, salmon sperm DNA can remain intact during delivery, as evidenced by the fact that the released salmon sperm DNA in the pH transition release experiment still retain its structural integrity and native conformation. Also, fluorescence spectra demonstrate that ZrBFs can be further functionalized with a cell-penetrating peptide of octaarginine (R8) via the carboxyls in l-proline groups of H₃PMP on the outer surface using a coupling agent, which will enhance the penetration capability of ZrBFs through biomembranes. ZrBFs have a potential application as a new kind of carrier in oral delivery of nucleic acids targeting the colon for gene therapy of colon-related diseases due to their unique bifunctionality

sj-pdf-1-tae-10.1177_20420188231187493 – Supplemental material for Exploring the mechanism of metformin action in Alzheimer’s disease and type 2 diabetes based on network pharmacology, molecular docking, and molecular dynamic simulation

Supplemental material, sj-pdf-1-tae-10.1177_20420188231187493 for Exploring the mechanism of metformin action in Alzheimer’s disease and type 2 diabetes based on network pharmacology, molecular docking, and molecular dynamic simulation by Xin Shi, Lingling Li, Zhiyao Liu, Fangqi Wang and Hailiang Huang in Therapeutic Advances in Endocrinology and Metabolism</p

Photoinduced Radical Desulfurative C(sp³)–C(sp²) Coupling via Electron Donor–Acceptor Complexes

Herein, we disclose a radical desulfurative C–C coupling protocol for the synthesis of 4-alkylpyridines. A variety of substituents on both benzyl thiols and 4-cyanopyridines are tolerated. The reaction is carried out under mild and photocatalyst- and transition-metal-free conditions. Preliminary mechanistic studies show that an electron donor–acceptor complex is formed between benzyl thiols and 4-cyanopyridines under alkaline conditions. Then, a variety of 1°, 2°, and 3° C(sp3)-centered radicals was formed by cleavage of the C–S bond, and the 4-alkylpyridines were achieved through a radical–radical coupling with the pyridyl radical anion

Iodine-Catalyzed Oxidative Functionalization of Azaarenes with Benzylic C(sp³)–H Bonds via N‑Alkylation/Amidation Cascade: Two‑Step Synthesis of Isoindolo[2,1‑<i>b</i>]isoquinolin-7(5<i>H</i>)‑one

An efficient and practical iodine-catalyzed oxidative functionalization of azaarenes with benzylic C–H bonds via an N-alkylation and amidation cascade is developed to provide isoquinolin-1­(2<i>H</i>)-ones. This method utilizes readily available unfunctionalized azaarenes and methylarenes as starting materials and proceeds under metal-free conditions with good to excellent yields, avoiding the use of expensive noble metal catalysts and generation of halide and metal wastes. The synthetic utility of this reaction is exemplified by the concise, two-step synthesis of isoindolo­[2,1-<i>b</i>]­isoquinolin-7­(5<i>H</i>)-one

Inertial Microfluidic Syringe Cell Concentrator

Low-cost, easy-to-use cell concentration tools are in urgent demand for biomedical diagnosis in resource-poor settings. Herein, we propose a novel inertial microfluidic syringe cell (IMSC) concentrator that employs inertial focusing to increase cell concentration through ordering the cell and removing the cell-free fluid. A three-part structure, consisting of a cap-shaped upper housing, a circular gasket, and a lower housing with a spiral channel, is adopted for simple fabricating and assembling, which enables the seamless translation of our IMSC concentrator into commercial outcomes without additional redesigning. The performance characterization indicates that our IMSC concentrator is capable of processing samples with different initial concentrations over a broad flow rate range. The satisfactory concentration performances over a broad driving flow rate range make it possible for our IMSC concentrator to be driven by pushing the syringe with single hand. Finally, pollen particles and MCF-7 cells are successfully concentrated at a high throughput of 3.0 mL/min (up to 4.2 × 10⁷ counts/mL) under the hand-powered drive. We envision wide applications of our IMSC concentrator as “centrifugation on a syringe tip” to various cell concentration pretreatments in resource-poor settings

PIDA/I₂‑Mediated α- and β‑C(sp³)–H Bond Dual Functionalization of Tertiary Amines

The α,β-C­(sp³)–H bond dual functionalization of tertiary amines is still a challenging task for both organic and medicinal chemists. Herein a direct, mild, metal-free, and site-specific method mediated by PIDA/I₂ was developed for α,β-C­(sp³)–H bond dual functionalization of tertiary amines, and this method can provide facile access to α-keto lactams or rarely studied α,α-diiodo lactams. Moreover, this method was used for the effective syntheses of three natural products [obscurumine C (<b>13</b>), obscurumine O (<b>17</b>), and strychnocarpine (<b>18</b>)] and direct preparation of mimics of the in vivo metabolites of two FDA-approved drugs (imatinib and donepezil) in 36–60% overall yield. The method represents a promising protocol for the late-stage α,β-C­(sp³)–H bond oxidative dual functionalization of tertiary amine-containing drugs and complex natural products

Quantitative Investigation of Methylation Heterogeneity by Digital Melting Curve Analysis on a SlipChip for Atrial Fibrillation

Methylation is an essential epigenetic modification involved in regulating gene expression and maintaining genome stability. Methylation patterns can be heterogeneous, exhibiting variations in both level and density. However, current methods of methylation analysis, including sequencing, methylation-specific PCR, and high-resolution melting curve analysis (HRM), face limitations of high cost, time-consuming workflows, and the difficulty of both accurate heterogeneity analysis and precise quantification. Here, a droplet array SlipChip-based (da-SlipChip-based) digital melting curve analysis (MCA) method was developed for the accurate quantification of both methylation level (ratio of methylated molecules to total molecules) and methylation density (ratio of methylated CpG sites to total CpG sites). The SlipChip-based digital MCA system supplements an in situ thermal cycler with a fluorescence imaging module for real-time MCA. The da-SlipChip can generate 10,656 droplets of 1 nL each, which can be separated into four lanes, enabling the simultaneous analysis of four samples. This method’s clinical application was demonstrated by analyzing samples from ten healthy individuals and twenty patients with atrial fibrillation (AF), the most common arrhythmia. This method can distinguish healthy individuals from those with AF of both the paroxysmal and persistent types. It also holds potential for broader application in various research and clinical settings requiring methylation analysis

Synthesis of Calcium Bisphosphonate/Calcium Polyacrylate Spheres for Gene Delivery

Calcium bisphosphonate/calcium polyacrylate spheres were synthesized by a facile method and applied for the first time as gene vectors for transfection. The colloidal spheres of the PAA–Ca²⁺–H₂O complex, formed by sodium polyacrylate and calcium ions in the solution, were used as template to synthesize a spherical PAA–Ca²⁺–BPMP composite (CaBPMP/CaPAA) in the presence of 1,4-bis­(phosphomethyl)­piperazine (BPMP). The CaBPMP/CaPAA composite exhibits uniform and well-dispersed spheres with a particle size of about 200 nm as expected. The cytotoxicity assays confirm that CaBPMP/CaPAA spheres are quite safe for different cells even at a high concentration of 500 μg/mL. In vitro transfection results show that CaBPMP/CaPAA spheres serving as gene vectors are capable of transferring exogenous genes into different cells with about 25% of transfection efficiency and good reproducibility. The transfection capacity of CaBPMP/CaPAA spheres may be attributed to the controllable sphere morphology, low cytotoxicity, moderate DNA loading capacity, and bioresorbable property. The application of calcium phosphonates with adjustable surface properties derived from the different organic groups of phosphonic acid in gene delivery provides a new design idea for gene vectors

Total Synthesis of (±)-Cermizine B

A practical synthesis of (±)-cermizine B was achieved. The nine-step synthesis mainly comprised two uninterrupted Michael additions including a highly diastereoselective 1,4-addition of 2-picoline to methyl 4-methyl-6-oxocyclohex-1-ene-1-carboxylate, Krapcho decarboxylation, a double reductive amination that resulted in ring closure and dearomatization of pyridine in 24% overall yield