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1.
Chem Commun (Camb) ; 60(48): 6154-6157, 2024 Jun 11.
Article in English | MEDLINE | ID: mdl-38804515

ABSTRACT

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.

2.
Chem Commun (Camb) ; 60(29): 3926-3929, 2024 Apr 04.
Article in English | MEDLINE | ID: mdl-38497367

ABSTRACT

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.

3.
ACS Nano ; 17(16): 15449-15465, 2023 08 22.
Article in English | MEDLINE | ID: mdl-37530575

ABSTRACT

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.


Subject(s)
Nanoparticles , Neoplasms , Humans , Calcium , Manganese , Hydrogen Peroxide , Manganese Compounds/pharmacology , Tumor Microenvironment , Oxides/pharmacology , Immunotherapy , Neoplasms/drug therapy , Cell Line, Tumor
4.
Org Lett ; 25(16): 2798-2805, 2023 Apr 28.
Article in English | MEDLINE | ID: mdl-37052465

ABSTRACT

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.

5.
Chem Commun (Camb) ; 58(95): 13234-13237, 2022 Nov 29.
Article in English | MEDLINE | ID: mdl-36354168

ABSTRACT

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.


Subject(s)
Nanoparticles , Water , Metals , Light , Polymers
6.
Chem Commun (Camb) ; 58(88): 12353-12356, 2022 Nov 03.
Article in English | MEDLINE | ID: mdl-36263456

ABSTRACT

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.


Subject(s)
Sulfhydryl Compounds , Thiocarbamates
7.
Org Lett ; 24(32): 6006-6012, 2022 Aug 19.
Article in English | MEDLINE | ID: mdl-35930056

ABSTRACT

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.

8.
Nat Commun ; 13(1): 4362, 2022 Jul 27.
Article in English | MEDLINE | ID: mdl-35896596

ABSTRACT

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.

9.
Org Lett ; 24(14): 2733-2737, 2022 Apr 15.
Article in English | MEDLINE | ID: mdl-35377664

ABSTRACT

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.

10.
Int J Biol Sci ; 18(3): 1238-1253, 2022.
Article in English | MEDLINE | ID: mdl-35173550

ABSTRACT

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.


Subject(s)
Bone Neoplasms , Lung Neoplasms , Osteosarcoma , Adenosine Diphosphate/metabolism , Animals , Cytoskeletal Proteins , Lung Neoplasms/drug therapy , Mice , Osteosarcoma/drug therapy , Phosphorylation , Poly (ADP-Ribose) Polymerase-1/metabolism , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Ribose
11.
Biomacromolecules ; 22(11): 4783-4793, 2021 11 08.
Article in English | MEDLINE | ID: mdl-34623134

ABSTRACT

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.


Subject(s)
Hypoxia-Inducible Factor 1, alpha Subunit , Photochemotherapy , Porphyrins , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Photosensitizing Agents/pharmacology , Photosensitizing Agents/therapeutic use , Reactive Oxygen Species , Singlet Oxygen
12.
ACS Appl Mater Interfaces ; 13(23): 27513-27521, 2021 Jun 16.
Article in English | MEDLINE | ID: mdl-34086446

ABSTRACT

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.


Subject(s)
Carcinoma, Hepatocellular/therapy , Drug Delivery Systems , Genetic Therapy , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Photochemotherapy , Porphyrins/administration & dosage , RNA, Small Interfering/administration & dosage , Animals , Apoptosis , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Cations/chemistry , Cell Proliferation , Combined Modality Therapy , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Liver Neoplasms/therapy , Mice , Porphyrins/chemistry , Reactive Oxygen Species , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
13.
Biomater Sci ; 9(13): 4630-4638, 2021 Jun 29.
Article in English | MEDLINE | ID: mdl-34190235

ABSTRACT

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.


Subject(s)
Nanoparticles , Photochemotherapy , Porphyrins , Photosensitizing Agents , Singlet Oxygen
14.
Carbohydr Res ; 501: 108257, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33588231

ABSTRACT

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.


Subject(s)
Glycosides/chemistry , Magnesium/chemistry , Oligosaccharides/chemical synthesis , Pyrans/chemistry , Molecular Structure , Oligosaccharides/chemistry , Stereoisomerism
15.
Macromol Rapid Commun ; 42(6): e2000464, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33051922

ABSTRACT

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.


Subject(s)
DNA , Polymers , Gene Transfer Techniques , Polymerization , Transfection
16.
Org Lett ; 22(2): 371-375, 2020 01 17.
Article in English | MEDLINE | ID: mdl-31742411

ABSTRACT

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.

17.
Org Biomol Chem ; 17(46): 9933-9941, 2019 11 27.
Article in English | MEDLINE | ID: mdl-31724687

ABSTRACT

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.

18.
ACS Appl Mater Interfaces ; 11(47): 44007-44017, 2019 Nov 27.
Article in English | MEDLINE | ID: mdl-31696699

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/administration & dosage , Drug Delivery Systems/methods , Neoplasms/drug therapy , Photosensitizing Agents/administration & dosage , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor , Drug Carriers/chemistry , Drug Delivery Systems/instrumentation , Female , Humans , Hyaluronic Acid/chemistry , Hydrophobic and Hydrophilic Interactions , Mice, Inbred BALB C , Mice, Nude , Nanoparticles/chemistry , Photochemotherapy , Photosensitizing Agents/chemistry , Polymers/chemistry , Porphyrins/chemistry , Reactive Oxygen Species/chemistry
19.
ACS Appl Mater Interfaces ; 11(20): 18224-18232, 2019 May 22.
Article in English | MEDLINE | ID: mdl-31046231

ABSTRACT

The natural planar and rigid structures of most of the hydrophobic photosensitizers (PSs) [such as tetraphenyl porphyrin (TPP)] significantly reduce their loading efficiencies in polymeric nanoparticles (NPs) because of the strong π-π interaction-induced aggregation. This aggregation-caused quenching will further reduce the quantum yield of singlet oxygen (1O2) generation and weaken the efficiency of photodynamic therapy (PDT). In addition, the small molecular PSs exhibit short tumor retention time and tend to be easily cleared once released. Herein, poly(TPP) NPs, prepared by cross-linking of reactive oxygen species degradable, thioketal linkers and TPP derivatives, followed by coprecipitation, were first developed with quantitative loading efficiency (>99%), uniform NP sizes (without aggregation), increased singlet oxygen quantum yield (ΦΔ = 0.79 in dimethyl sulfoxide compared with 0.52 for original TPP), increased in vitro phototoxicity, extended tumor retention time, light-triggered on-demand release, and enhanced in vivo antitumor efficacy, which comprehensively address the multiple issues for most of the PSs in the PDT area.


Subject(s)
Nanoparticles , Neoplasms, Experimental/drug therapy , Photochemotherapy , Photosensitizing Agents , Porphyrins , Animals , Female , HeLa Cells , Humans , Mice , Mice, Inbred BALB C , Nanoparticles/chemistry , Nanoparticles/therapeutic use , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Porphyrins/chemistry , Porphyrins/pharmacology , Singlet Oxygen/metabolism
20.
Org Biomol Chem ; 17(10): 2663-2669, 2019 03 06.
Article in English | MEDLINE | ID: mdl-30766987

ABSTRACT

A method to access various multisubstituted indoles from propargylic alcohols and readily available enol nucleophiles by copper-catalyzed tandem annulation/enol nucleophilic addition has been developed. Compared to the expensive metal catalysts such as platinum, gold, silver, and palladium used previously, the most economical copper(i) catalyst could achieve this reaction efficiently. The fused heterocyclic compounds, pyrrolo[1,2-a] indoles, could be afforded by further transformation of the products. The allyl cation intermediate may be involved in the mechanism.

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