Tunable electrochemical diverse sulfurization of sulfoxonium ylides with disulfides.

An electrochemical protocol for the synthesis of sulfursulfoxonium ylides and 1,3-dithioketals by reacting sulfoxonium ylides with disulfides has been developed under simple and mild conditions. By changing the solubility of the raw materials and the dielectric parameters of the electrolyte, sulfurization enabled a selective dehydrogenation of C-S and the construction of 1,3-dithioketals. The transformation is an ideal approach to prepare organosulfur reagents with a broad functional group tolerance as well as high selectivity, which leads to vicinal difunctionalized organosulfur compounds.

Electrochemical synthesis of peptide aldehydes via C‒N bond cleavage of cyclic amines.

Peptide aldehydes are crucial biomolecules essential to various biological systems, driving a continuous demand for efficient synthesis methods. Herein, we develop a metal-free, facile, and biocompatible strategy for direct electrochemical synthesis of unnatural peptide aldehydes. This electro-oxidative approach enabled a step- and atom-economical ring-opening via C‒N bond cleavage, allowing for homoproline-specific peptide diversification and expansion of substrate scope to include amides, esters, and cyclic amines of various sizes. The remarkable efficacy of the electro-synthetic protocol set the stage for the efficient modification and assembly of linear and macrocyclic peptides using a concise synthetic sequence with racemization-free conditions. Moreover, the combination of experiments and density functional theory (DFT) calculations indicates that different N-acyl groups play a decisive role in the reaction activity.

Regio- and Stereoselective Synthesis of 3-Selenylazaflavanones and 3-Selenylflavanones via Electrochemically Facilitated Selenylation Cascade.

Herein, an oxidant- and metal-free electrochemical selenylation reaction of chalcones with diselenides for the synthesis of 3-selenylazaflavanones and 3-selenylflavanones at room temperature was reported. The method proceeded under mild conditions, exhibited a broad substrate scope, and provided the selenylated products in moderate to excellent yields with high regio- and stereoselectivity. The reaction could also be readily scaled up with high efficiency. Detailed mechanistic studies through control experiments disclosed that a selenium-based radical might participate in this electrochemical transformation.

The electrochemically enabled α-C(sp3)-H azolation of ketones.

C-H/N-H cross-coupling has become a key technology for the selective conjugation of azole drug molecules. However, the development of new synthetic models and green chemical methods is imperative to enhance the construction of multi-functional compounds and compounds with unique functional groups. We herein reported an electrochemical synthesis of α-tetrazolyl ketones with excellent yields and broad substrate scope, encompassing electron-donating and electron-withdrawing groups of aryl ketones, heterocycles, and alkyl and various ketone drugs. It was further proved that α-iodoketone was involved in this transformation of the reaction as a critical intermediate.

The mirrored cationic peptide as miRNA vehicle for efficient lung cancer therapy.

Gene therapy has emerged as a potential approach for lung cancer therapy. However, the application of gene therapy is still limited by their properties, such as low specificity to the cancer cells, negatively charged groups, short systemic circulation time, and rapid degradation by nucleases. The progression of lung adenocarcinoma (LUAD) can be promoted through the methylation process of miR-148a-3p promoter, as confirmed by our previous research. In the current study, we are the first to design a mirrored Arg-Gly-Asp (RGD)-modified cationic peptide (RD24) as a microRNA (miRNA) vehicle, which enabled to pack the miRNA (miR-148a-3p) efficiently and generate RD24/miR-148a-3p nanoparticles (RPRIN) by self-assembling. RPRIN exhibited a high transfection efficiency in lung cancer cells via the conjugation between RGD and integrins on the surface of lung cancer cells. Furthermore, RD24 showed matrix metallopeptidase 2 (MMP2) responsiveness, which improved lung cancer cell inhibition induced by the miRNA intracellularly. In addition, RPRIN exhibits several advantages, such as prolonged circulation duration, reduced toxicity, and immune escape. Experiments conducted both in vitro and in vivo revealed that RPRIN effectively suppressed the growth and progression of lung cancer. Thus, the mirrored RGD-modified cationic peptide showed great potential in transducing miRNA for lung cancer therapy.

Electrochemical Selenylation of Sulfoxonium Ylides for the Synthesis of gem-Diselenides as Antimicrobials against Fungi.

Organoselenium compounds are important scaffolds in pharmaceutical molecules. Herein, we report metal-free, electrochemical, highly chemo- and regioselective synthesis of gem-diselenides through the coupling of α-keto sulfoxonium ylides with diselenides. The versatility of the electrochemical manifold enabled the selenylation with ample scope and broad functional group tolerance, as well as setting the stage for modification of complex bioactive molecules. Detailed mechanistic studies revealed that the key C-Se bond was constructed using n-Bu4NI as an electrolyte and catalyst through the electrosynthetic protocol. Finally, the desired α-keto gem-diselenides showed excellent antimicrobial activity against Candida albicans, which can be identified as the lead compounds for further exploration.

Direct Electrooxidative Selenylation/Cyclization of Alkynes: Access to Functionalized Benzo[b]furans.

A mild, practical, metal and oxidant-free methodology for the synthesis of various C-3 selenylated benzo[b]furan derivatives was developed through the intramolecular cyclization of alkynes promoted with diselenides via electrooxidation. A wide range of selenium-substituted benzo[b]furan derivatives were obtained in good to excellent yields with high regioselectivity under constant current in an undivided cell equipped with carbon and platinum plates as the anode and cathode, respectively. Moreover, the convergent approach exhibited good functional group tolerance and could be easily scaled up with good efficiency, providing rapid access to a diverse range of selenylated benzo[b]furans derivatives from simple, readily available starting materials.

Cyclocarboamination of Alkynes with N-Aminopyridiniums by Photoredox Catalysis.

A visible-light photoredox-catalyzed reaction to access structurally diverse pyridoimidazoles has been developed. This transformation features intermolecular carboamination of N-sulfonylaminopyridiniums with a broad scope of alkynes.

Selenium-Electrocatalytic Cyclization of 2-Vinylanilides towards Indoles of Peptide Labeling.

A novel selenium-electrocatalytic intramolecular cyclization of 2-vinylanilides for synthesis of functionalized indoles and azaindoles has been developed. In contrast to the previous synthetic methods, this sustainable protocol enabled unparalleled broad substrates scope for viable indoles with highly functional and sensitive groups by employing recyclable selenium catalyst, under mild, metal- and external-oxidant-free conditions. The approach can be used to the late-stage modification of complex bioactive molecular system, thereby setting the stage for versatile syntheses of decorated indoles with peptide labeling. A plausible catalytic pathway was proposed.

Electrochemical regioselective C-H selenylation of 2H-indazole derivatives.

Selenium-substituted heteroarenes are biologically active compounds and useful building blocks. In this study, we have developed a metal- and oxidant-free, environmentally friendly protocol for the regioselective selenylation of 2H-indazole derivatives by an electrochemical strategy. A number of selenylated 2H-indazoles with a wide range of functional groups have been synthesized in moderate to good yields under mild and environment-friendly reaction conditions.

Electro-Oxidative C-N Bond Formation through Azolation of Indole Derivatives: An Access to 3-Substituent-2-(Azol-1-yl)indoles.

A practical protocol to synthesize 3-substituent-2-(azol-1-yl)indole derivatives has been developed via an electrochemical oxidative cross coupling process under mild conditions. This electro-oxidative C-N bond formation strategy tolerates a range of functional groups and is amenable to gram scale synthesis. Moreover, this method was applied to the late-stage functionalization of bioactive molecules.

Highly active catalyst using zeolitic imidazolate framework derived nano-polyhedron for the electro-oxidation of l-cysteine and amperometric sensing.

Herein, N-doped porous carbon nano-polyhedron embedded with Co3O4 (Co3O4-NPCN) was reported for the electro-catalytic oxidation and amperometric detection of l-cysteine. Co3O4-NPCN was synthesized by the two-step redox calcination of zeolitic imidazolate framework (ZIF). Surface morphology characterization revealed that Co3O4-NPCN displayed a uniform size and rhombic dodecahedral shape. Structure and composition analysis found that Co3O4-NPCN was a N-doped carbon polyhedral matrix with hollow and porous structure, and Co3O4 nano-spheres were evenly distributed into the polyhedral matrix. Due to the hollow and porous structure, N-doped carbon matrix and embedded Co3O4 nano-spheres, Co3O4-NPCN performed a remarkable electro-catalysis towards the oxidation of l-cysteine at a very low potential of 0.10 V. A diffusion-controlled l-cysteine oxidation process was observed at Co3O4-NPCN prepared electrode. Accordingly, amperometric method was established for l-cysteine detection with a very fast current response in 2 s, wide linear range of 0.05 µM- 5.2 mM and low detection limit of 6.9 nM. Besides, notable selectivity, repeatability, reproducibility and long-term stability were also achieved. Moreover, Co3O4-NPCN sensor was successfully applied to the l-cysteine detection in human serum samples indicating the practical application of the as-developed sensor.

Direct Electrochemical Selenylation/Cyclization of Alkenes: Access to Functionalized Benzheterocycles.

A catalyst-free, environmentally friendly, and efficient electrochemical selenylation/cyclization of alkenes has been developed with moderate to excellent yields. This selenylated transformation proceeds smoothly and tolerates a wide range of synthetically useful groups to deliver diverse functionalized benzheterocycles, including iminoisobenzofuran, lactones, oxindoles, and quinolinones. Moreover, the present synthetic route could also be readily scaled up to gram quantity with convenient operation in an undivided cell.

Nitrogen-doped carbon dodecahedron embedded with cobalt nanoparticles for the direct electro-oxidation of glucose and efficient nonenzymatic glucose sensing.

Developing high-performance sensors for glucose detection is extremely desirable for clinical diagnostics and life sciences. Particularly, it is greatly attractive to exploit composite materials with large surface area, doped heterojunction and non-precious metal as highly active electro-catalysts for nonenzymatic glucose sensing. Herein, we reported a N-doped carbon dodecahedron embedded with Co nanoparticles (Co@NCD) for the direct electro-oxidation of glucose and efficient nonenzymatic glucose detection. Co@NCD was synthesized by the pyrolysis of zeolitic imidazolate framework (ZIF). Field emission scanning electron microscope, high-resolution transmission electron microscope, powder X-ray diffraction, X-ray photoelectron spectroscopy and nitrogen adsorption-desorption experiments were performed to investigate Co@NCD. A well-defined dodecahedron morphology with uniform size and shape was observed. Besides, the original framework was carbonized after pyrolysis leading to a hollow and porous graphite dodecahedron containing N-doped carbon heterojunction. Moreover, Co nanoparticles were evenly distributed into the dodecahedron. With porous structure, N-doped carbon and embedded Co nanoparticles, Co@NCD displayed a notable electro-catalysis towards the direct oxidation of glucose (onset potential: 0.20 V). By using Co@NCD as electro-catalyst, an efficient nonenzymatic glucose sensor was obtained with a rapid amperometric response (within 1 s), low detection limit (0.11 µM) and broad detection range (0.2 µM-12.0 mM). In addition, remarkable selectivity, repeatability, reproducibility and long-term stability were also observed. Finally, Co@NCD prepared sensor was also successfully applied to the detection of glucose in human serum. Our results suggested that ZIF templated method could be an innovative solution for active composite catalysts in biomolecular electro-catalysis and Co@NCD prepared sensor could be a substantial preferable sensing platform for the nonenzymatic glucose detection.

Electrochemical Oxidative Phosphorylation of Aldehyde Hydrazones.

The electrochemical phosphorylation of aldehyde hydrazones has been developed under exogenous oxidant-free conditions. The strategy provides expedient access to highly functionalized α-iminophosphine oxides with ample scope and broad functional group tolerance by means of mild, user-friendly electrolysis, in an undivided cell.

Anti-tumor effects and 3D-quantitative structure-activity relationship analysis of bufadienolides from toad venom.

Toad venom (venenum bufonis, also called Chan'su) has been widely used for centuries in China to treat different diseases, especially for cancer. Bufadienolides are mainly responsible for the anti-cancer effects of toad venom. However, systematic chemical composition and cytotoxicity as well as key pharmacophores of these bufadienolides from toad venom have not yet been defined clearly. To enrich the understanding of the diversity of bufadienolides and to find bufadienolides with better activities from toad venom. This study was carried out to isolate chemical constituents, research their anti-tumor effects and mechanisms by MTT assay, flow cytometry and Western blotting, and develop a CoMFA and CoMSIA quantitative structure-activity relationship (QSAR) model for illustrating the vital relationship between the chemical structures and cytotoxicities. Among 47 natural bufadienolides, most of bufadienolides (21 compounds isolated in this study and 26 compounds isolated previously) could significantly inhibit the proliferation of cancer cells, and compounds 1, 8, 12, 18 and 19 showed the most potent inhibitory activity against four types of human tumor cells. Compound 18 induced G2/M cell cycle arrest and apoptosis. Moreover, 3D contour maps generated from CoMFA and CoMSIA identified several pharmacophores of bufadienolides responsible for the anti-tumor activities. Our study might provide reliable information for future structure modification and rational drug design of bufadienolides with anticancer activities in medical chemistry.

Catalyst-Free, Direct Electrochemical Tri- and Difluoroalkylation/Cyclization: Access to Functionalized Oxindoles and Quinolinones.

The catalyst-free electrochemical di- and trifluoromethylation/cyclization of N-substituted acrylamides was realized under external oxidant-free conditions. The strategy provides expedient access to fluoroalkylated oxindoles and 3,4-dihydroquinolin-2(1 H)-ones with ample scope and broad functional group tolerance by mild, direct electrolysis of sodium sulfinates in an undivided cell. Detailed mechanistic studies provided strong support for a SET-based reaction manifold.

Nickel-catalyzed C-H activation of purine bases with alkyl halides.

C-H alkylations of purine nucleosides were achieved by means of user-friendly nickel catalysis with ample substrate scope and high levels of chemo, site and regio control, which among others enabled the direct fluorescent labeling of purines in terms of late stage diversification.

Manganese-Catalyzed C-H Alkynylation: Expedient Peptide Synthesis and Modification.

Manganese(I)-catalyzed C-H alkynylations with organic halides occurred with unparalleled substrate scope, and thus enabled step-economical C-H functionalizations with silyl, aryl, alkenyl, and alkyl haloalkynes. The versatility of the manganese(I) catalysis manifold enabled C-H couplings with haloalkynes featuring, among others, fluorescent labels, steroids, and amino acids, thereby setting the stage for peptide ligation as well as the efficient molecular assembly of acyclic and cyclic peptides. A plausible catalytic cycle was proposed.