RESUMO
Selectively producing a variety of valuable compounds using controlled chemical reactions starting from a common material is an appealing yet complex concept. Herein, a photocatalytic approach for the selective synthesis of (E)-ß-aminovinyl sulfones and (E)-ß-amidovinyl sulfones from allenamides and sodium sulfinates was established. This reaction exhibits the traits of an eco-friendly solvent and adjustable amide cleavage, and can accommodate a diverse range of substrates with exceptional functional group tolerance. Based on control experiments and deuterium labeling experiments, a plausible radical reaction pathway is proposed.
RESUMO
Liver cancer is a common malignant tumor, and its incidence is increasing yearly. Millions of people suffer from liver cancer annually, which has a serious impact on global public health security. Licochalcone A (Lico A), an important component of the traditional Chinese herb licorice, is a natural small molecule drug with multiple pharmacological activities. In this study, we evaluated the inhibitory effects of Lico A on hepatocellular carcinoma cell lines (HepG2 and Huh-7), and explored the inhibitory mechanism of Lico A on hepatocellular carcinoma. First, we evaluated the inhibitory effects of Lico A on hepatocellular carcinoma, and showed that Lico A significantly inhibited and killed HepG2 and Huh-7 cells in vivo and in vitro. Transcriptomic analysis showed that Lico A inhibited the expression of solute carrier family 7 member 11 (SLC7A11), which induced ferroptosis. We confirmed through in vivo and in vitro experiments that Lico A promoted ferroptosis in hepatocellular carcinoma cells by downregulating SLC7A11 expression, thereby inhibiting the glutathione (GSH)-glutathione peroxidase 4 (GPX4) pathway and inducing activation of reactive oxygen species (ROS). In this study, we suggest that Lico A is a potential SLC7A11 inhibitor that induces ferroptotic death in hepatocellular carcinoma cells, thereby providing a theoretical basis for the development of natural small molecule drugs against hepatocellular carcinoma.
Assuntos
Carcinoma Hepatocelular , Ferroptose , Neoplasias Hepáticas , Humanos , Espécies Reativas de Oxigênio/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Sistema y+ de Transporte de AminoácidosRESUMO
This study presents a convenient approach to the synthesis of indole- and benzofuran-based benzylic sulfones using unactivated alkynes containing aryl iodides and sodium sulfinates under visible light irradiation. The procedure involves a sequential series of dehalogenation, carbo-cyclization, and radical sulfonylation. Plausible insights into the reaction mechanism are derived from control experiments, leading to the proposal of a radical cascade reaction pathway.
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The re-emerging mpox (formerly monkeypox) virus (MPXV), a member of Orthopoxvirus genus together with variola virus (VARV) and vaccinia virus (VACV), has led to public health emergency of international concern since July 2022. Inspired by the unprecedent success of coronavirus disease 2019 (COVID-19) mRNA vaccines, the development of a safe and effective mRNA vaccine against MPXV is of high priority. Based on our established lipid nanoparticle (LNP)-encapsulated mRNA vaccine platform, we rationally constructed and prepared a panel of multicomponent MPXV vaccine candidates encoding different combinations of viral antigens including M1R, E8L, A29L, A35R, and B6R. In vitro and in vivo characterization demonstrated that two immunizations of all mRNA vaccine candidates elicit a robust antibody response as well as antigen-specific Th1-biased cellular response in mice. Importantly, the penta- and tetra-component vaccine candidates AR-MPXV5 and AR-MPXV4a showed superior capability of inducing neutralizing antibodies as well as of protecting from VACV challenge in mice. Our study provides critical insights to understand the protection mechanism of MPXV infection and direct evidence supporting further clinical development of these multicomponent mRNA vaccine candidates.
Assuntos
COVID-19 , Mpox , Animais , Camundongos , COVID-19/prevenção & controle , Vacinas Sintéticas/genética , Vaccinia virus/genética , Monkeypox virus , Vacinas contra COVID-19 , Anticorpos Antivirais , Vacinas de mRNARESUMO
An atom-economic method of preparing allylic sulfones via hydrosulfonylation of allenes with sulfinic acids under Pd(0)-catalysis was reported. This process has a high degree of regio- and stereoselectivity, and provides the target product with a moderate to excellent yield. A wide range of nitrogen- or oxygen-containing linear E-allylic sulfones have been synthesized. With the support of experimental research, a possible mechanism was proposed.
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A new and expedient photocatalytic protocol for the construction of quinolin-2(1H)-ones via Markovnikov-type sulfonylation/6-endo-trig cyclization/selective C(O)-CF3 bond cleavage starting from N-alkyl-N-(2-ethynylphenyl)-2,2,2-trifluoroacetamides and sulfinic acids has been developed. It is as an unprecedented protocol for the preparation of 4-sulfonylquinoline-2(1H)-ones with high efficiency, mild reaction conditions, acceptable yields and a wide range of substrates.
Assuntos
Alcinos , Quinolinas , Alcinos/química , Ciclização , Estrutura MolecularRESUMO
As a potential cancer therapy, we developed a recombinant adenovirus named Ad-VT, which was designed to express the apoptosis-inducing gene (apoptin) and selectively replicate in cancer cells via E1a manipulation. However, how it performs in bladder cancer remains unclear. We examined the antitumor efficacy of Ad-VT in bladder cancers using CCK-8 assays and xenograft models. Autophagy levels were evaluated by western blotting, MDC staining, and RFP-GFP-LC3 aggregates' analyses. Here, we report the selective replication and antitumor efficacy (viability inhibition and apoptosis induction) of Ad-VT in bladder cancer cells. Using xenograft tumor models, we demonstrate that its effects are tumor specific resulting in the inhibition of tumor growth and improvement of the survival of mice models. Most Importantly, Ad-VT induced a complete autophagy flux leading to autophagic cancer cell death through a signaling pathway involving AMPK, raptor and mTOR. Finally, we suggest that treatment combination of Ad-VT and rapamycin results in a synergistic improvement of tumor control and survival compared to monotherapy. This study suggests that Ad-VT can induce selective autophagic antitumor activities in bladder cancer through the AMPK-Raptor-mTOR pathway, which can be further improved by rapamycin.
Assuntos
Adenoviridae/genética , Autofagia/genética , Terapia Viral Oncolítica/métodos , Neoplasias da Bexiga Urinária/terapia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Proteínas do Capsídeo/genética , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteína Regulatória Associada a mTOR/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Neoplasias da Bexiga Urinária/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Autophagy and apoptosis both promote cell death; however, the relationship between them is subtle, and they mutually promote and antagonize each other. Apoptin can induce apoptosis of various tumor cells; however, tumor cell death is not only caused by apoptosis. Whether apoptin affects tumor cell autophagy is poorly understood. Therefore, the present study aimed to explore the potential mechanisms underlying the effects of apoptin using recombinant adenoviruses expressing apoptin. Reverse transcriptionquantitative polymerase chain reaction, immunoblotting, flow cytometry, fluorescence microscopy and proteomics analyses revealed that apoptin could induce autophagy in MCF7 breast cancer cells. The results also suggested that apoptin affected autophagy in a time and dosedependent manner. During the early stage of apoptin stimulation (6 and 12 h), the expression levels of autophagy pathwayassociated proteins, including Beclin1, microtubuleassociated protein 1A/1Blight chain 3, autophagyrelated 4B cysteine peptidase and autophagyrelated 5, were significantly increased, suggesting that apoptin promoted the upregulation of autophagy in MCF7 cells. Conversely, after 12 h of apoptin stimulation, the expression levels of apoptosisassociated proteins were decreased, thus suggesting that apoptosis may be inhibited. Therefore, it was hypothesized that apoptin may enhance autophagy and inhibit apoptosis in MCF7 cells at the early stage. In conclusion, apoptininduced cell death may involve both autophagy and apoptosis. The induction of autophagy may inhibit apoptosis, whereas apoptosis may inhibit autophagy; however, occasionally both pathways operate at the same time and involve apoptin. This apoptinassociated selection between tumor cell survival and death may provide a potential therapeutic strategy for breast cancer.
Assuntos
Autofagia/genética , Neoplasias da Mama/terapia , Proteínas do Capsídeo/genética , Terapia Viral Oncolítica/métodos , Adenoviridae/genética , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Vetores Genéticos/genética , Humanos , Células MCF-7 , Vírus Oncolíticos/genéticaRESUMO
PURPOSE: Apoptin can specifically kill cancer cells but has no toxicity to normal cells. Human telomerase reverse transcriptase (hTERT) acts as a tumor-specific promoter, triggering certain genes to replicate or express only in tumor cells, conferring specific replication and killing abilities. This study aimed to investigate the anticancer potential of the recombinant adenovirus Ad-apoptin-hTERTp-E1a (Ad-VT) in prostate cancer. METHODS: The pGL4.51 plasmid was used to transfect PC-3 cells to construct tumor cells stably expressing luciferase (PC-3-luc). Crystal violet staining and MTS assays determined the ability of Ad-VT to inhibit cell proliferation. Ad-VT-induced apoptosis of PC-3-luc cells was detected using Hoechst, Annexin V, JC-1 staining, and caspases activity analysis. PC-3-luc cells invasion and migration were detected using cell-scratch and Transwell assays. In vivo tumor inhibition was detected using imaging techniques. RESULTS: Crystal violet staining and MTS results showed that the proliferation ability of PC-3-luc cells decreased significantly. Hoechst, JC-1, and Annexin V experiments demonstrated that Ad-VT mainly induced apoptosis to inhibit PC-3-luc cell proliferation. Ad-VT could significantly inhibit the migration and invasion of PC-3-luc cells over a short period of time. In vivo, Ad-VT could effectively inhibit tumor growth and prolong survival of the mice. CONCLUSIONS: The recombinant adenovirus, comprising the apoptin protein and the hTERTp promoter, was able to inhibit the growth of prostate cancer PC-3 cells and promote their apoptosis.
Assuntos
Adenoviridae , Terapia Viral Oncolítica/métodos , Neoplasias da Próstata/terapia , Humanos , Masculino , Células PC-3 , Células Tumorais CultivadasRESUMO
A new strategy has been established for the synthesis of functionalized chromene and chroman derivatives via a Cs2CO3-catalyzed domino addition of 2'-hydroxychalcone derivatives with allenoates, which can serve as a general avenue for the construction of multireplaced chromene derivatives. Chemoselectivity of this synthesis was found to depend on substituents on substrates. Good to excellent yields were achieved under simple and mild conditions at room temperature.
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A new Pd(II)-catalyzed carbonyl-directing activation of alkenes has been established, enabling radical-induced selective fluorosulfonylation and aminosulfonylation of carbonyl-tethered 1,7-enynes with sulfinic acids and N-fluorobenzenesulfonimide (NFSI) under mild and redox neutral conditions to access densely functionalized ( E)-3,4-dihydronaphthalen-1(2 H)-ones with generally good yields and high stereoselectivity. The selectivity of these bifunctionalizations relies on the electronic nature of substituents on both aryl rings of 1,7-enynes.
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A novel metal-free double SO2 insertion/multicomponent bicyclization cascade of benzene-linked 1,7-diynes has been established by treatment with aryldiazonium tetrafluoroborates and DABCO-bis(sulfur dioxide) under redox-neutral conditions, providing a range of dual sulfone-containing naphtho[1,2-c]thiophene 2,2-dioxides with generally high stereoselectivity. The reaction pathway is proposed to proceed through the sequence of arylsulfonyl-radical-induced 6-exo-dig/5-endo-trig bicyclization, H-abstraction, and diazotization.
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A new catalytic difluorohydration of ß-alkynyl ketones using NFSI as the fluorinating reagent has been established, diastereoselectively furnishing a range of structurally diverse difluoride 1,5-dicarbonyl products through C(sp3)-H fluorination. Notably, the sterically encumbered t-butyl functionality located at the α-position of the carbonyl group of substrates 1 showed excellent diastereoselectivity (up to >99 : 1 dr). The reaction enabled multiple bond-forming events including two C(sp3)-F formation through Ag-catalysis to provide a highly efficient and practical method toward difluoride 1,5-dicarbonyls, some of which were successfully converted into difluorinated isoquinolines.
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A novel I2-mediated benzannulation of 1,7-diyne-involved 1,4-oxo-migration was established, providing a range of unexpected 1-aroyl-2-naphthaldehydes with a 1,4-dicarbonyl unit. The resulting 1-aroyl-2-naphthaldehydes were successfully applied in the synthesis of benzo[e]isoindol-3-ones and benzo[e]benzo[4,5]imidazo[2,1-a]isoindoles using aromatic amines and benzene-1,2-diamines as nucleophiles, respectively. The mechanisms for the formation of these compounds were proposed.
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A new cascade three-component haloazidation of benzene-tethered 1,7-enynes for the formation of biologically interesting azidylated 3,4-dihydroquinolin-2(1H)-ones has been achieved under mild and metal-free conditions using TMSN3 as a N3 source and NIS (or NBS or NCS) as a halogen source. The reaction pathway involves in situ-generated azidyl radical-triggered α,ß-conjugated addition/6-exo-dig cyclization/radical coupling sequence, resulting in successive multiple bond-forming events, including carbon-nitrogen, carbon-carbon, and carbon-halogen bonds to rapidly construct complex heterocyclic molecules. Furthermore, the resulting products would be useful building blocks in the discovery of lead compounds and other biologically interesting N3-containing heterocycles.
Assuntos
Azidas/química , Benzeno/química , Radicais Livres/química , Metais/química , Quinolonas/química , Quinolonas/síntese química , Fenômenos Biológicos , Carbono/química , Catálise , Ciclização , Estrutura Molecular , Nitrogênio/químicaRESUMO
A new cascade three-component halosulfonylation of 1,7-enynes for efficient synthesis of densely functionalized 3,4-dihydroquinolin-2(1H)-ones has been established from readily accessible arylsulfonyl hydrazides and NIS (or NBS). The reaction pathway involves in situ-generated sulfonyl radical-triggered α,ß-conjugated addition/6-exo-dig cyclization/radical coupling sequence, resulting in continuous multiple bond-forming events including C-S, C-C and C-I (or C-Br) bonds to rapidly build up molecular complexity.
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Halogênios/química , Sulfonas/química , Ciclização , Radicais Livres , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Difração de Raios XRESUMO
A new metal-free bicyclization reaction of 1,7-enynes anchored by α,ß-conjugates with arylsulfonyl radicals generated in situ from sulfonyl hydrazides has been established using tert-butyl hydroperoxide and tetrabutylammonium iodide. The reactions occurred through sulfonylation/6-exo-dig/6-exo-trig bicyclization/in situ desulfonylation/5-exo-trig cyclization/alkyl or alkenyl migration cascade mechanism to give benzo[j]phenanthridines regioselectively.
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Benzofenantridinas/síntese química , Benzofenantridinas/química , Catálise , Ciclização , Estrutura Molecular , Estereoisomerismo , terc-Butil Hidroperóxido/químicaRESUMO
A catalytic domino spirocyclization of 1,7-enynes with simple cycloalkanes and cyclo-1,3-dicarbonyls has been established via multiple C-C bond formations from alkynyl/alkenyl functions and dual α,α-C(sp(3))-H abstraction/insertion. The reaction involves addition, 6-exo-dig cyclization and radical coupling sequences under convenient catalytic conditions and provides a concise access to spiro cyclopenta[c]quinolines in good to excellent yields.
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Ciclopentanos/síntese química , Quinolinas/síntese química , Alcanos/síntese química , Alcanos/química , Catálise , Ciclização , Ciclopentanos/química , Modelos Moleculares , Quinolinas/química , Compostos de Espiro/síntese química , Compostos de Espiro/química , EstereoisomerismoRESUMO
A direct and metal-free access toward fully substituted pyrazoles and its sulphenylation has been established through an iodine-mediated three-component [3 + 2] annulation of ß-ketonitrile (or pentane-2,4-dione), arylhydrazines, and aryl sulfonyl hydrazides. The reaction allows the formation of one C-S and two C-N bonds by the multiple bond cleavage including sulfur-oxygen, sulfur-nitrogen, and carbon-oxygen bonds. The method features low-cost and readily accessible substrates, bond-forming efficiency, and broad substrate scopes as well as simple one-pot operation, which makes this strategy highly attractive.