Visible Light-Induced Polymerization to Access Polyamides.

Visible light-induced polymerization, as a promising and green strategy, is showing great potential in preparing value-added polymers. Herein, a visible light photoredox catalysis method is reported to afford a library of polyamide with high yields (up to 99%) and high molecular weights (Mws) (up to 71 000 g mol-1). Dithioacids and diamines as the monomers, and 9-mesityl-10-methylacridinium tetrafluoroborate (Mes-Acr-MeBF4) as the organic photoredox catalyst give the polyamides with structural diversity in air under mild conditions without extra metal, base, or additives.

Chemical fixation of CO2/CS2 to access iodoallenyl oxazolidinones and allenyl thiazolidine-thiones.

Constructing heterocyclic compounds by chemical fixation of CO2/CS2 as a C1 building block is a promising approach. An efficient and environmentally friendly synthetic approach has been developed using CO2/CS2 to prepare complicated allenyl heterocycles with high yields and diastereoselectivities in a metal-free manner under mild conditions. NIS promoted CO2 fixation and the cyclization reaction by exclusive 1,4-syn-addition of 1,3-enynes rather than 1,2-addition or 3,4-addition, while CS2 participated in unique 1,4-syn-hydrothiolation of 1,3-enynes to afford allenyl heterocycles with different reaction patterns.

Synthesis of thioesters using an electrochemical three-component reaction involving elemental sulfur.

An electrochemical three-component reaction involving elemental sulfur is disclosed for achieving a metal-free, oxidant-free synthesis of thioesters in a high atom-economical, step-economical and chemoselective manner. A mechanistic investigation indicates that the use of elemental sulfur to trap acyl radical derived from radical umpolung of α-keto acid with an electrochemical design can efficiently generate a carbonyl thiyl radical, which can further be captured by diazoalkane to afford various thioesters.

Au-allenylidene promoted decarboxylative annulation to access unsaturated γ-lactams/lactones.

A novel Au-allenylidene promoted decarboxylative annulation by intramolecular α-nucleophilic addition has been disclosed. The unsaturated cyclic ethynylethylene carbamates/carbonates can be converted to unique nucleophiles attached with alkylidene ketenes by sequential decarboxylation and oxidation processes. Such alkylidene ketenes can be rapidly trapped by intramolecular α-attacking annulation to generate potential biological active unsaturated γ-lactams/lactones with broad scope, facile post-modification, high regioselectivity and efficiency.

Multifunctional Calcium-Manganese Nanomodulator Provides Antitumor Treatment and Improved Immunotherapy via Reprogramming of the Tumor Microenvironment.

Ions play a vital role in regulating various biological processes, including metabolic and immune homeostasis, which involves tumorigenesis and therapy. Thus, the perturbation of ion homeostasis can induce tumor cell death and evoke immune responses, providing specific antitumor effects. However, antitumor strategies that exploit the effects of multiion perturbation are rare. We herein prepared a pH-responsive nanomodulator by coloading curcumin (CU, a Ca2+ enhancer) with CaCO3 and MnO2 into nanoparticles coated with a cancer cell membrane. This nanoplatform was aimed at reprogramming the tumor microenvironment (TME) and providing an antitumor treatment through ion fluctuation. The obtained nanoplatform, called CM NPs, could neutralize protons by decomposing CaCO3 and attenuating cellular acidity, they could generate Ca2+ and release CU, elevating Ca2+ levels and promoting ROS generation in the mitochondria and endoplasmic reticulum, thus, inducing immunogenic cell death. Mn2+ could decompose the endogenous H2O2 into O2 to relieve hypoxia and enhance the sensitivity of cGAS, activating the cGAS-STING signaling pathway. In addition, this strategy allowed the reprogramming of the immune TME, inducing macrophage polarization and dendritic cell maturation via antigen cross-presentation, thereby increasing the immune system's ability to combat the tumor effectively. Moreover, the as-prepared nanoparticles enhanced the antitumor responses of the αPD1 treatment. This study proposes an effective strategy to combat tumors via the reprogramming of the tumor TME and the alteration of essential ions concentrations. Thus, it shows great potential for future clinical applications as a complementary approach along with other multimodal treatment strategies.

Gold-Catalyzed Anti-Markovnikov Oxidation of Au-Allenylidene to Generate Alkylidene Ketene.

It remains a long-standing challenge to directly convert alkynes to carboxylic derivatives. Herein, a unexpectedly anti-Markovnikov oxidation of a unique Au-allenylidene pathway instead of a traditional α-oxo gold carbene routine is disclosed for in situ formation and transformation of highly unsaturated alkylidene ketenes, which are subsequently trapped by broad nucleophiles such as alcohols, phenols, water, amines, and sulfoximines to easily access α,ß-unsaturated drugs and natural product derivatives by a multicomponent reaction. Based on this scenario, polyacrylate and polyacrylamide are efficiently afforded by corresponding multicomponent polymerization.

Metal-free polyporphyrin based photocatalysts for the functionalization of C(sp3)-H bonds in water.

The development of metal-free and water-compatible photocatalysts for visible light-induced environmentally friendly transformation in water is highly desirable. Herein, two types of polyporphyrin based heterogeneous photocatalysts with different water-solubility in water, namely, an insoluble polymer and a water-dispersible nanoparticle, were disclosed. Both of them exhibited excellent photocatalytic activity in visible-light induced functionalization of C(sp3)-H bonds on a wide range of substrates in water. The reusable and recyclable photocatalysts provided a green and sustainable approach for photocatalysis in water.

Synthesis and application of thiocarbamates via thiol-dioxazolone modified Lossen rearrangement.

Thiocarbamates could be synthesized in green solvents via thiol-dioxazolone modified Lossen rearrangement under transition-metal free, additive free, and mild conditions. Polythiocarbamates were further prepared with excellent self-healing and shape-memory properties, showing great potential in the development of functional materials.

Copper-Catalyzed One-Step Formation of Four C-N Bonds toward Polyfunctionalized Triazoles via Multicomponent Reaction.

A novel four-component reaction of alkynes, amines, azides, and 2H-azirines has been developed for the first time by the efficient formation of four C-N bonds in one step under mild conditions, rapidly preparing polyfunctionalized triazoles with molecular diversity involving three different intermediates of copper-acetylide, copper-allenylidene, and copper-vinyl nitrene. Propargylic ester is disclosed as a "three-in-one" building block possessing triplicate cycloaddition and nucleophilic and electrophilic properties, which could enable such a four-component transformation by high yields, broad substrate scope, and functionalization.

Copper-catalyzed Z-selective synthesis of acrylamides and polyacrylamides via alkylidene ketenimines.

It remains very important to discover and study new fundamental intermediates consisting of carbon and nitrogen as the abundant elements of organic molecules. The unique alkylidene ketenimine could be formed in situ under mild conditions by an unexpected copper-catalyzed three-component reaction of alkyne, azide and water involving a successive cycloaddition, N2 extrusion and carbene-assisted rearrangement. Only Z-α,ß-unsaturated amides instead of E-α,ß-unsaturated amides or triazoles were acquired from alkylidene ketenimines with excellent selectivities and stereospecificities. In addition, a series of "approximate" alternating copolymers (poly (triazole-alt-Z-acrylamides)) with high Mns and yields were efficiently afforded by multicomponent polymerization through a very simple operation basing on this multicomponent reaction.

Visible-Light-Induced N-Acylation of Sulfoximines.

A metal-, base-, and additive-free N-acylation of sulfoximines was developed under mild conditions using organic photoredox catalyst. This green strategy featured broad substrate scope, good compatibility with air, and high yields (up to 96%). It could be further applied to amino acid modifications and α-keto N-acyl sulfoximine synthesis without any complicated transformations or operations.

Poly (ADP-ribose) polymerase 1 (PARP1) inhibition promotes pulmonary metastasis of osteosarcoma by boosting ezrin phosphorylation.

Due to the large proportion of BRCA deficiency and chromosomal instability in OS patients, poly (ADP-ribose) polymerase inhibitors (PARPi) could be an effective strategy for anti-OS therapy. In two orthotopic OS mouse models, we discovered that although PARPi had inhibitory effect on the growth of the orthotopic OS tumors regardless of BRCA deficiency, the treatment of PARPi essentially aggravated the pulmonary metastasis of OS in both models. A protein playing a crucial role in OS metastasis, ezrin, was identified as an interactive protein for PARP1. The phosphorylation of ezrin was significantly promoted during PARP inhibition. Besides the traditional function of phosphorylated ezrin at plasma membrane, we newly identified its nuclear speckle localization and its function with mRNA export. Ezrin knockdown or phosphorylation inhibition could partially rescue PARPi induced metastasis. Collectively, we unveiled a new mechanism for PARP-involved OS metastasis, which proposed a novel combinational therapy strategy using PARP and ezrin inhibitors for future OS treatment.

Codelivery of High-Molecular-Weight Poly-porphyrins and HIF-1α Inhibitors for In Vivo Synergistic Anticancer Therapy.

Photodynamic therapy (PDT) is showing great potential in the treatment of cancer diseases, and photosensitizers play crucial roles in absorbing the energy of light and generating reactive oxygen species (ROS) during PDT. Most of the photosensitizers bearing macrocyclic structures have strong hydrophobicity and suffer from the π-π interaction and undesired aggregation caused quenching (ACQ), which severely limit the PDT efficacy. Moreover, the continuous oxygen consumption during PDT also leads to the upregulated expression of hypoxia-inducible factor-1α (HIF-1α), which can aggravate the growth of tumors. To overcome the abovementioned problems, polymerized photosensitizers repelled by flexible thioketal linkers were designed and synthesized using a multicomponent polymerization (MCP) method to afford the poly-porphyrins with high molecular weight (Mw > 20 000 g/mol) under room temperature. The ACQ effect could be significantly inhibited by introducing flexible chains and increasing Mw, leading to the improvement in the singlet oxygen quantum yield and phototoxicity simultaneously. An HIF-1α inhibitor, Lificiguat (YC-1) was synthesized as a chemodrug and codelivered with poly-porphyrins to decrease the expression of HIF-1α and inhibit tumor growth under hypoxia. With the synergistic PDT and chemotherapy, poly-porphyrin/YC-1 micelles showed excellent therapeutic antitumor efficacy both in vitro and in vivo.

Cationic Polyporphyrins as siRNA Delivery Vectors for Photodynamic and Gene Synergistic Anticancer Therapy.

Successful gene therapy is highly dependent on the efficiency of gene delivery, which is mostly achieved by the carrier. Current gene carriers are generally nontherapeutic and take over most of the proportion in the delivery systems. Therefore, a library of polymerized and cationic photosensitive drugs (polyphotosensitizers, pPSs) with HIF-1α siRNA delivery capability is constructed to realize using "drug" to deliver "gene". The pPS component acts as both a therapeutic carrier for intracellular HIF-1α siRNA delivery and a photosensitive drug with photodynamic therapy (PDT). A reactive oxygen species (ROS)-cleavable linker is used to polymerize PS, allowing the successful segregation of PS monomers in space, avoiding the undesired aggregation-caused quenching (ACQ) effect and enhancing the in vitro and in vivo PDT effect. The complexes formed by pPSs and HIF-1α siRNA exhibited desired siRNA condensation and serum stability at the optimal conditions (pPSs with guanidines/siRNA weight ratio of 15), efficient intracellular internalization, and gene-silencing efficiency (60%) compared with commercial available transfection reagents (40%), as well as synergistic in vitro and in vivo phototoxicity for the combination PDT-gene therapy toward cancer treatment. This study provides a promising paradigm for the design of both the gene delivery carrier and the photosensitizer, as well as for broad utilities in the combination therapy toward cancer treatment.

Linear and high-molecular-weight poly-porphyrins for efficient photodynamic therapy.

Photodynamic therapy (PDT) holds great potential in cancer treatment due to the advantages of non-invasiveness, negligible side-effect, and high spatiotemporal selectivity. Porphyrin is the most widely used photosensitizer in clinical treatment. However, its PDT efficacy is always limited by the undesired aggregation caused quenching (ACQ) effect originating from the planar and rigid structure. In this work, a linear polymeric porphyrin with "structure defects" was developed to overcome the ACQ effect for most of the photosensitizers with conjugated macrocycles. Compared to porphyrin monomers, poly-porphyrins could improve singlet oxygen generation ability, and the singlet oxygen quantum yield enhanced with increasing molecular weight of poly-porphyrins. To achieve efficient in vivo PDT, PEG and acetazolamide were conjugated to the optimized poly-porphyrins to afford pP-PEG-AZ nanoparticles (pP-PEG-AZ NPs) with excellent stability, efficient in vitro intracellular internalization, negligible dark-toxicity, notable photo-toxicity, and in vivo anti-cancer efficacy based on combined PDT and anti-angiogenesis therapy.

Magnesium-mediated Wittig reagent-promoted Stereoselective synthesis of L-Sorbopyranoses from D-Glucopyranoses.

l-Sorbose is an important rare sugar that exists in some natural products and widely used in pharmaceutical and chemical industries. Herein, two simple and practical routes were developed using cheap magnesium (II) for the synthesis of 1,3,4,5-tetra-O-benzyl-l-sorbopyranose from 2,3,4,6-tetra-O-benzyl-d-glucopyranose with high stereoselectivity and yield. The first route involved the intramolecular hydride shift from C5 to the C1 of the glucopyranose precursor. Wittig reagent (PPh3CHCOOBn) was used to combined with Mg(II) to promote this isomerization reaction from d-glucopyranose to l-sorbopyranose in the alternative route.

Multicomponent Polymerization toward Cationic Polymers for Efficient Gene Delivery.

A new class of cationic polymers containing tertiary amine, thioether, and hydroxyl groups are prepared via a catalyst-free, multicomponent polymerization method using dithiol, formaldehyde, and di-sec-amine with a ratio of 1:2:1, to access a library of water-soluble polymers with well-defined structures and suitable molecular weights (Mw ranging from 5000 to 8000 Da) in high yields (up to 90%). Such polycations are demonstrated to be promising nonviral gene delivery vectors with high transfection efficiency (up to 3.5-fold of PEI25k) and low toxicity with multiple functionalities: 1) efficient gene condensation by tertiary amine groups; 2) reactive oxygen species scavenging by thioether groups; and 3) positive charge shielding by hydroxyl groups. Both the thioether and hydroxyl groups are contributed to reduce the cytotoxicity of the polycations by tuning the oxidative stress and preventing the undesired serum binding. The optimized polycations can achieve high transfection efficiency under the serum conditions, indicating the great potential as a nonviral gene delivery vector candidate for clinical application.

Visible Light-Induced Amide Bond Formation.

A metal-, base-, and additive-free amide bond formation reaction was developed under an organic photoredox catalyst. This green approach showed excellent functional selectivity without affecting other functional groups such as alcohols, phenols, ethers, esters, halogens, or heterocycles. This method featured a broad substrate scope, good compatibility with water and air, and high yields (≤95%). The potential utilities were demonstrated by the synthesis of important drug molecules such as paracetamol, melatonin, moclobemide, and acetazolamide.

Copper-catalyzed cascade click/nucleophilic substitution reaction to access fully substituted triazolyl-organosulfurs.

A novel cascade click/nucleophilic substitution reaction is developed to access 4-heterofunctionalized fully substituted triazolyl-organosulfurs using thiocyanates as both leaving groups and organosulfur precursors. This method features high regioselectivities and board substrate scope. 33 examples are shown to demonstrate the structural diversity through the synthesis of fully substituted triazolyl-organosulfurs including triazolyl-thiocyanates, triazolyl-sulfinylcyanides, triazolyl-thioethers, triazolyl-thiols and triazolyl-disulfides from internal thiocyanatoalkynes.

Water-Soluble, Zwitterionic Poly-photosensitizers as Carrier-Free, Photosensitizer-Self-Delivery System for in Vivo Photodynamic Therapy.

Polymeric nanoparticles (NPs) have been widely established to deliver most of the hydrophobic chemo-drugs or photosensitizers (PSs) for cancer therapy. However, this strategy is usually hindered by the relatively low drug loading capacity and the undesired toxicity as well as the immunogenicity caused by the nontherapeutic, polymeric carriers. The carrier-free, drug self-delivery systems, in which the chemo-drugs or their prodrugs themselves formed the NPs without the addition of nontherapeutic carriers, have been extensively developed to achieve a high drug loading capacity and low systemic toxicity. However, most of the driving forces to form the NPs were based on the strong hydrophobic interactions, which were the undesired forces for the porphyrin-based hydrophobic PSs due to the parasitic aggregation-caused quenching effect. Herein, the zwitterionic, water-soluble, and reactive oxygen species (ROS)-cleavable poly-photosensitizers (pPSs) were prepared by the polymerization method, which spontaneously introduced different charges associated with the "desired electrostatic effect" and reduced the "undesired aggregation" by separating the PS monomers using flexible and ROS-cleavable linkers. The obtained pPS could be self-assembled into the nanocomplexes based on the electrostatic effect with a high PS loading capacity, improved singlet oxygen generation ability, and efficient phototoxicity. Upon poly(ethylene glycol) (PEG) or hyaluronic acid (HA) coating on the surface, both pPS/PEG and pPS/HA complexes exhibited enhanced stability under physiological environments and excellent in vivo antitumor efficacy. Moreover, HA-coated complexes also exhibited active tumor targeting. Such a polymerization strategy comprehensively addressed the parasitic issues for the hydrophobic PS self-delivery system in the photodynamic therapy area.