A water mediated multicomponent reaction for the synthesis of novel spirooxindole derivatives and their antifungal activity.

A water mediated three-component reaction of isatin, 4-aminocoumarin, and 1,3-cyclodicarbonyl compounds is reported for the synthesis of spiro[chromeno[4,3-b]cyclopenta[e]pyridine-7,3'-indoline]trione and the spiro[chromeno[4,3-b]quinoline 7,3'-indoline]trione. Up to 27 different spirooxindole derivatives were synthesized by this method. The bioactivity of these spirooxindole derivatives was evaluated and they were found to show antifungal activity against Cercospora arachidicola, Physalospora piricola, Rhizoctonia cerealis, and Fusarium moniliforme.

Stimuli-triggered multilayer films in response to temperature and ionic strength changes for controlled favipiravir drug release.

The block copolymer micelles and natural biopolymers were utilized to form layer-by-layer (LbL) films via electrostatic interaction, which were able to effectively load and controllably release favipiravir, a potential drug for the treatment of coronavirus epidemic. The LbL films demonstrated reversible swelling/shrinking behavior along with the manipulation of temperature, which could also maintain the integrity in the structure and the morphology. Due to dehydration of environmentally responsive building blocks, the drug release rate from the films was decelerated by elevating environmental temperature and ionic strength. In addition, the pulsed release of favipiravir was observed from the multilayer films under the trigger of temperature, which ensured the precise control in the content of the therapeutic reagents at a desired time point. The nanoparticle-based LbL films could be used for on-demandin vitrorelease of chemotherapeutic reagents.

Polydentate hydrazones as multitasking catalysts in visible-light-induced coupling reactions of amines.

A Cu/hydrazone catalyst has been applied in the coupling reactions of anilines for the synthesis of diarylamines and azobenzenes. The copper complex that is formed in situ plays a double duty by harnessing photon energy as a photocatalyst and then by catalysing organometallic elementary steps as a transition metal catalyst. By the selection of hydrazones and bases, the reaction selectivity of aniline can be tuned between homo-coupling and its cross-coupling with arylboronic acid, exhibiting the great potential of such hydrazones in organic synthesis.

Ligand-enabled Ni-catalyzed hydroarylation and hydroalkenylation of internal alkenes with organoborons.

The transition metal-catalyzed hydrofunctionalization of alkenes offers an efficient solution for the rapid construction of complex functional molecules, and significant progress has been made during last decades. However, the hydrofunctionalization of internal alkenes remains a significant challenge due to low reactivity and the difficulties of controlling the regioselectivity. Here, we report the hydroarylation and hydroalkenylation of internal alkenes lacking a directing group with aryl and alkenyl boronic acids in the presence of a nickel catalyst, featuring a broad substrate scope and wide functional group tolerance under redox-neutral conditions. The key to achieving this reaction is the identification of a bulky 1-adamantyl ß-diketone ligand, which is capable of overcoming the low reactivity of internal 1,2-disubstituted alkenes. Preliminary mechanistic studies unveiled that this reaction undergoes an Ar-Ni(II)-H initiated hydroarylation process, which is generated by the oxidative addition of alcoholic solvent with Ni(0) species and sequential transmetalation. In addition, the oxidative addition of the alcoholic solvent proves to be the turnover-limiting step.

Steric Effects in the Deposition Mode and Drug-Delivering Efficiency of Nanocapsule-Based Multilayer Films.

Using surface-initiated atom transfer radical polymerization (ATRP), block polymers with a series of quaternization degrees were coated on the surface of silica nanocapsules (SNCs) by the "grafting-from" technique. Molnupiravir, an antiviral medicine urgently approved for the treatment of SARS-CoV-2, was encapsulated in polymer-coated SNCs and further incorporated into well-defined films with polystyrene sulfonate (PSS) homopolymers by layer-by-layer (LBL) self-assembly via electrostatic interactions. We investigated the impact of the quaternization degree of the polymers and steric hindrance of functional groups on the growth mode, swelling/deswelling transition, and drug-delivering efficiency of the obtained LBL films. The SNCs were derived from coronas of parent block polymers of matched molecular weights-poly(N-isopropylacrylamide)-block-poly(N,N-dimethylaminoethyl methacrylate) (PNIPAM-b-PDMAEMA)-by quaternization with methyl sulfate. As revealed by the data results, SNCs with coronas with higher quaternization degrees resulted in a larger layering distance of the film structure because of weaker ionic pairing (due to the presence of a bulky methyl spacer) between SNCs and PSS. Interestingly, when comparing the drug release profile of the encapsulated drugs from SNC-based films, the release rate was slower in the case of capsule coronas with higher quaternization degrees because of the larger diffusion distance of the encapsulated drugs and stronger hydrophobic-hydrophobic interactions between SNCs and drug molecules.

Heterogeneous copper-catalyzed synthesis of diaryl sulfones.

A carbon-supported copper nanoparticle (Cu-NP) with high catalytic activity for the synthesis of diaryl sulfones is reported. For the first time, this Cu-NP is proved to be able to effectively promote the reaction of arylboronic acids and arylsulfonyl hydrazides to generate diaryl sulfones at room temperature. The reaction shows excellent substrate universality, and substrates with different substituents can undergo the reaction smoothly, leading to the desired products in good yields. The Cu-NP is found to be made of low valence Cu based on XRD. Hence, the reaction catalyzed by the Cu-NP is believed to involve a Cu-mediated organometallic cycle.

Construction of α-Amino Azines via Thianthrenation-Enabled Photocatalyzed Hydroarylation of Azine-Substituted Enamides with Arenes.

α-Amino azines are widely found in pharmaceuticals and ligands. Herein, we report a practical method for accessing this class of compounds via photocatalyzed hydroarylation of azine-substituted enamides with the in situ-generated aryl thianthrenium salts as the radical precursor. This reaction features a broad substrate scope, good functional group tolerance, and mild conditions and is suitable for the late-stage installation of α-amino azines in complex structures.

Vinyl Sulfonium Salts as the Radical Acceptor for Metal-Free Decarboxylative Alkenylation.

Vinyl sulfonium salts typically act as an electrophilic Michael acceptor, thus initiating many tandem cyclization reactions. Herein, we disclosed the novel reactivity of vinyl sulfonium salts as a radical acceptor. Using redox-active ester as an alkyl radical precursor, metal-free decarboxylative alkenylation with vinyl sulfonium salts was realized using eosin Y as a photocatalyst. This process features a broad substrate scope and tolerates with a broad range of primary, secondary, tertiary carboxylic acids.

Ynamide Smiles Rearrangement Triggered by Visible-Light-Mediated Regioselective Ketyl-Ynamide Coupling: Rapid Access to Functionalized Indoles and Isoquinolines.

In the past decades, significant advances have been made on radical Smiles rearrangement. However, the eventually formed radical intermediates in these reactions are limited to the amidyl radical, except for the few examples initiated by a N-centered radical. Here, a novel and practical radical Smiles rearrangement triggered by photoredox-catalyzed regioselective ketyl-ynamide coupling is reported, which represents the first radical Smiles rearrangement of ynamides. This method enables facile access to a variety of valuable 2-benzhydrylindoles with broad substrate scope in generally good yields under mild reaction conditions. In addition, this chemistry can also be extended to the divergent synthesis of versatile 3-benzhydrylisoquinolines through a similar ketyl-ynamide coupling and radical Smiles rearrangement, followed by dehydrogenative oxidation. Moreover, such an ynamide Smiles rearrangement initiated by intermolecular photoredox catalysis via addition of external radical sources is also achieved. By control experiments, the reaction was shown to proceed via key ketyl radical and α-imino carbon radical intermediates.

Synthesis of α-functionalized ketones by visible-light promoted oxygenation of alkenes.

This article gives a short review on the visible-light promoted synthesis of α-functionalized ketones from alkenes. Various α-functionalized ketones, including α-halo, sulfinyl/sulfonyl, aryl, azido and thiocyanato ketones can be synthesized from the reaction of alkenes with different radical species generated by visible-light catalysis. These transformations typically use dioxygen as the terminal oxidant and do not require a transition metal to activate the double bond, which is quite different from the transition-metal catalysed reactions (Wacker oxidation or hydroformylation).

Visible-light promoted aerobic difunctionalization of alkenes with sulfonyl hydrazides for the synthesis of ß-keto/hydroxyl sulfones.

A practical method has been developed for the conversion of alkenes to ß-keto/hydroxyl sulfones by their reaction with sulfonyl hydrazides under metal-free conditions. This reaction proceeds through the oxidative addition of alkenes by sulfonyl radicals that are generated by visible-light induced oxidation of sulfonyl hydrazides. Notaly the reaction uses O2 as the terminal oxidant, instead of metal catalysts or oxidants like TBHP, leading to H2O and N2 as the clean by-products. The key features of this reaction include readily available reagents, mild reaction conditions and broad substrate scope.

Electrostatically Assembled Multilayered Films of Biopolymer Enhanced Nanocapsules for on-Demand Drug Release.

We describe layer-by-layer (LbL) buildup and pH-responsive behavior of multilayer films of alginate/chitosan/alginate -modified silica nanocapsules (SNCs) and chitosan (CS) biopolymers via electrostatic interaction. The SNC/CS films exhibit pH-triggered swelling/deswelling transitions under physiological conditions. Fulvestrant, an FDA-approved selective estrogen receptor down-regulator agent for the treatment of breast cancer, was encapsulated in SNCs and further incorporated into the LbL films. The drug release profile from the films was dependent on pH value of the surrounding environment. At pH 7.4, the films were able to efficiently entrap fulvestrant, with only ∼38% released in 120 days, whereas exposure to a lower pH value (pH 5.0) triggered faster fulvestrant release in phosphate buffer solution at 37 °C. Atomic force microscopy and ellipsometry showed that the films retained their structural integrity in PBS after several swelling/deswelling cycles. SNC/CS LbL films demonstrated repeated on/off drug release under external triggers, allowing consistent fulvestrant release (∼14-18% of encapsulated fulvestrant released for each cycle) over a 10-day period without significant change in drug release rate. This work demonstrates the first proof-of-concept platform of SNC-incorporated films with well-defined internal structure, good stability, high loading capacity, and controlled/sustained release profile for on-demand drug delivery. With great versatility to use various active compounds and building blocks, the films may have high potential for broad applications such as implantable biosensors and antifouling coatings.

Identification of a pyridine derivative inducing senescence in ovarian cancer cell lines via P21 activation.

Cellular senescence is a state of irreversible cell growth arrest. Increasing evidence suggests that cellular senescence contribute to tumour suppression in vivo. However, only a few anti-cancer drugs have been discovered to induce cellular senescence. Searching for new compounds which can inhibit cancer cell growth by inducing senescence is becoming one of the most attractive research fields. To test the effects of candidate compounds on cancer cell growth, cell proliferation assays, senescence-associated ß-galactosidase (SA-ß-gal) staining, and flow cytometry assay were performed. Immunofluorescence, western blot, and qRT-PCR experiments were used to further study the molecular mechanisms of the candidate compounds. We demonstrated that a pyridine derivative, 4-(4-fluorophenyl)-2-phenyl-5, 6, 7, 8-tetrahydroquinoline (FPTHQ), from a pool of 46 compounds can induce senescence of ovarian cancer cells in a dose-dependent manner. FPTHQ caused growth inhibition by inducing G0/G1 cell cycle arrest in A2780 cells. Increased activities of SA-ß-gal were observed in FPTHQ-treated A2780, OVCAR-3 and SKOV-3 cell lines. In addition, FPTHQ treatment increased the protein levels of MMP3 and the mRNA levels of IL-6 and IL-8 in A2780 cells, indicating the appearance of senescence-associated secretary phenotype (SASP) in the cells. Furthermore, we found that p21 was up-regulated and DNA damage was accumulated in FPTHQ-treated ovarian cancer cells. So far, our data suggest that FPTHQ can induce senescence in multiple ovarian cancer cell lines through activation of p21 signalling pathway by causing excessive DNA damage.

Facile synthesis of α-alkoxyl amides via scandium-catalyzed oxidative reaction between ynamides and alcohols.

A novel and efficient scandium-catalyzed oxidative reaction between ynamides and alcohols for the facile synthesis of various α-alkoxyl amides is reported in this paper. The reaction avoids the need for the use of α-diazo carbonyls which are unstable and may cause some safety concerns. Instead, by using alkynes as the starting materials, this protocol features readily available substrates, compatibility with a broad range of functional groups, simple procedure, mild reaction conditions, and high chemoselectivity.

Synthesis of α,ß-Unsaturated Amidines through Gold-Catalyzed Intermolecular Reaction of Azides with Ynamides.

A concise and flexible synthesis of α,ß-unsaturated amidines via gold-catalyzed intermolecular ynamide amination/carbene 1,2-shift between ynamides and benzylic azides has been developed. Under mild reaction conditions, various α,ß-unsaturated amidines were obtained in mostly good yields, thus providing an efficient and atom-economic way for the construction of valuable α,ß-unsaturated amidines.

Dual gold/photoredox-catalyzed bis-arylative cyclization of chiral homopropargyl sulfonamides with diazonium salts: rapid access to enantioenriched 2,3-dihydropyrroles.

A novel dual gold/photoredox-catalyzed bis-arylative cyclization of chiral homopropargyl sulfonamides with diazonium salts has been developed, allowing the facile synthesis of various enantioenriched 2,3-dihydropyrroles in generally moderate to good yields with excellent enantioselectivities under very mild conditions without using any strong oxidants. The reaction is proposed to undergo an AuI/AuIII redox cycle promoted by visible-light photoredox catalysis.

Visible-Light Photocatalytic Aerobic Annulation for the Green Synthesis of Pyrazoles.

A selective and high yielding synthesis of polysubstituted pyrazoles through a VLPC (visible light photoredox catalysis)-promoted reaction of hydrazine with Michael acceptors is reported. The method employs very mild reaction conditions and uses air as the terminal oxidant, which makes the process environmentally benign. Different types of Michael acceptors with various substituents can undergo the reaction to afford corresponding pyrazoles in good to excellent yields. The reaction is proposed to go through VLPC-promoted oxidation of hydrazine to diazene followed by its addition to Michael acceptors, other than the conventional condensation of hydrazine with a carbonyl.

Correction: Ylide formal [4 + 1] annulation.

Correction for 'Ylide formal [4 + 1] annulation' by Chunyin Zhu et al., Org. Biomol. Chem., 2015, 13, 2530-2536.

Correction: A mild and facile synthesis of polyfunctionalized pyridines: merging three-component cyclization and aerobic oxidation by amine/metal catalysts.

Correction for 'A mild and facile synthesis of polyfunctionalized pyridines: merging three-component cyclization and aerobic oxidation by amine/metal catalysts' by Chunyin Zhu et al., Org. Biomol. Chem., 2015, 13, 6278-6285.