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The exploration of a ring expansion reaction from indole cyclopentanone to generate a range of diversely functionalized 4-hydroxyl carbazole frameworks, representing the core structure of numerous carbazole alkaloids, has been conducted under mild reaction conditions. This approach exhibits broad functional group tolerance and moderate to good yields. The practical applicability of this strategy has been demonstrated through the concise syntheses of carbazomycins A, D, and G.
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Dual-target agents have more advantages than drug combinations for cancer treatment. Here, we designed and synthesized a series of novel VEGFR-2/tubulin dual-target inhibitors through a molecular hybridization strategy, and the activities of all the synthesized compounds were tested against tubulin and VEGFR-2. Among which, compound 19 exhibited strong potency against tubulin and VEGFR-2, with IC50 values of 0.76 ± 0.11 µM and 15.33 ± 2.12 nM, respectively. Additionally, compound 19 not only had significant antiproliferative effects on a series of human cancer cell lines, especially MGC-803 cells (IC50 = 0.005 ± 0.001 µM) but also overcame drug resistance in Taxol-resistant MGC-803 cells, with an RI of 1.8. Further studies showed that compound 19 could induce tumor cell apoptosis by reducing the mitochondrial membrane potential, increasing the level of ROS, facilitating the induction of G2/M phase arrest, and inhibiting the migration and invasion of tumor cells in a dose-dependent manner. In addition, compound 19 also exhibits potent antiangiogenic effects by blocking the VEGFR-2/PI3K/AKT pathway and inhibiting the tubule formation, invasion, and migration of HUVECs. More importantly, compound 19 demonstrated favorable pharmacokinetic profiles, robust in vivo antitumor efficacy, and satisfactory safety profiles. Overall, compound 19 can be used as a lead compound for the development of tubulin/VEGFR-2 dual-target inhibitors.
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BACKGROUND: Limited benefit population of immunotherapy makes it urgent to select effective biomarkers for screening appropriate treatment population. Herein, we have investigated the predictive values of circulating CD8+ T cells and CD8+T/CD4+T cell ratio in advanced gastric cancer patients receiving immunotherapy. METHODS: A retrospective cohort analysis of 187 advanced gastric cancer patients receiving sintilimab combined with oxaliplatin and capecitabine therapy in The Affiliated Xinghua People's Hospital, Medical School of Yangzhou University between December 2019 and February 2023 was conducted. The corresponding clinical outcomes of the variables were analyzed by receiver operating characteristic (ROC) curve, chi-square test, Kaplan-Meier methods and Cox proportional hazards regression models. RESULTS: The optimal cutoff values for percentages of CD8+ T cells, naive CD8+ T cells (CD8+ Tn) and memory CD8+ T cells (CD8+ Tm) expressing programmed cell death -1(PD-1) as well as PD-1+CD8+T/PD-1+CD4+T cell ratio were 21.0, 21.5, 64.3 and 0.669, respectively. It was found that the mean percentages of CD8+ T and CD8+ Tm expressing PD-1 as well as PD-1+CD8+T/PD-1+CD4+T cell ratio were significantly higher in responder (R) than non-responder (NonR) advanced gastric cancer patients associated with a longer progression free survival (PFS) and overall survival (OS). We also observed this correlation in programmed cell death-ligand 1(PD-L1) combined positive score (CPS) ≥ 5 subgroups. Univariate and multivariate Cox regression analyses demonstrated that lower CD8+ T and CD8+ Tm expressing PD-1 as well as PD-1+CD8+T/PD-1+CD4+T cell ratio were independent risk factors in advanced gastric cancer patients receiving immunotherapy plus chemotherapy. CONCLUSION: The circulating memory PD-1+CD8+ T cells and PD-1+CD8+T/PD-1+CD4+T cell ratio revealed high predictive values for response and prolonged survival outcomes in advanced gastric cancer patients receiving immunotherapy. Memory PD-1+CD8+ T cells and PD-1+CD8+T/PD-1+CD4+T cell ratio might be effective for screening benefit population of immunotherapy in advanced gastric cancer patients based on this preliminary evidence.
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A novel copper-catalyzed cyclization reaction for the synthesis of pyrazolo[1,5-a]quinoline, triazolo[1,5-a]quinoline, and pyrrolo[1,2-a]quinoline derivatives is described. The process is initiated by di-tert-butyl peroxide-mediated C(sp3)-H activation to generate the α-functionalized radical, which supervenes a cascade radical addition/cyclization sequence to access the N-fused quinolines in good yields with broad functional group tolerance.
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A facile strategy for the synthesis of isoxazoles has been efficaciously developed, which involves oxidation of propargylamines to the corresponding oximes followed by CuCl-mediated intramolecular cyclization of the latter. This protocol shows a straightforward way to construct a series of isoxazole cores with a wide range of functional group compatibility. Meanwhile, a gram-scale experiment and synthetic applications can be successfully operated.
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A novel solvent-free, TfOH-promoted decyanative cyclization approach for the synthesis of 2,1-benzisoxazoles has been developed. The reactions are complete instantly at room temperature and result in the formation of the desired 2,1-benzisoxazoles in a 34-97% isolated yield.
Assuntos
Ciclização , Estrutura Molecular , SolventesRESUMO
Seven novel 4-amino acid derivative substituted pyrimidine nucleoside analogues were designed, synthesized, and tested for their anti-CVB3 activity. Initial biological studies indicated that among these 4-amino acid derivative substituted pyrimidine nucleoside analogues, 4-N-(2'-amino-glutaric acid-1'-methylester)-1-(2'- deoxy-2'-ß-fluoro-4'-azido)-furanosyl-cytosine 2 exhibited the most potent anti-CVB activity (IC50â¯=â¯9.3⯵M). The cytotoxicity of these compounds has also been assessed. The toxicity of compound 2 was similar to that of ribavirin.
Assuntos
Nucleosídeos de Pirimidina/síntese química , Humanos , Relação Estrutura-AtividadeRESUMO
(±)-Sodium5-bromo-2-(α-hydroxypentyl) benzoate (brand name: brozopine, BZP, 1a), derived from L-3-n-butylphthalide (L-NBP), has been reported to protect the brain from stoke and has been approved by CFDA in Phase I-II clinical trials. However, it remains to be investigated whether 1a may exhibit any cardioprotective effect on ischemia-reperfusion (I/R) injury. In the current study, C57BL/6 and ICR mice were pretreated with 1a, and myocardium I/R were then performed. We found that 1a not only significantly reduced the infarct size and improved cardiac contractile function after acute MI/R in both species, but also protected hearts from chronic MI-related cardiac injury. Mechanically, we found that 1a physically binds to 12/15-LOX-2 using molecular docking. The shRNA-mediated 12/15-LOX-2 knockdown almost completely blocked the protective effect of 1a. Our findings, for the first time, strongly indicate that 1a may serve as a potent and promising cardioprotective agent in treatment of I/R related injury, at least partially through targeting 12/15-LOX-2.
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Araquidonato 15-Lipoxigenase/genética , Cardiotônicos/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Araquidonato 15-Lipoxigenase/efeitos dos fármacos , Benzoatos/farmacologia , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Coração/efeitos dos fármacos , Coração/fisiopatologia , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Ligação Proteica/efeitos dos fármacos , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologiaRESUMO
The alkaloids containing a carbazole nucleus are an established class of natural products with wide range of biological activities. A combination of thermodynamic and enzymatic activity studies provides an insight into the recognition of Clausine E by the fat mass and obesity-associated protein (FTO). The binding of Clausine E to FTO was driven by positive entropy and negative enthalpy changes. Results also indicated that the hydroxyl group was crucial for the binding of small molecules with FTO. The structural and thermodynamic information provides the basis for the design of more effective inhibitors for FTO demethylase activity.
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Adiposidade , Dioxigenase FTO Dependente de alfa-Cetoglutarato/antagonistas & inibidores , Carbazóis/farmacologia , Adiposidade/efeitos dos fármacos , Alcaloides/farmacologia , Dioxigenase FTO Dependente de alfa-Cetoglutarato/química , Calorimetria , Carbazóis/química , Desmetilação/efeitos dos fármacos , Concentração Inibidora 50 , Ligantes , Modelos Moleculares , Conformação Proteica , Espectrometria de Fluorescência , TermodinâmicaRESUMO
Hepatitis B virus (HBV) is a global health problem requiring more efficient and better tolerated anti-HBV agent. In this paper, a series of novel 2'-deoxy-2'-fluoro-2'-C-methyl-ß-d-arabinofuranosyl 8-azanebularine analogues (1 and 2a) and N4-substituted 8-azaadenosine derivatives (2b-g) were designed, synthesized and screened for in vitro anti-HBV activity. Two concise and practical synthetic routes were developed toward the structural motif construction of 2'-deoxy-2'-fluoro-2'-C-methyl-ß-d-arabinofuranosyl 8-azainosine from the ribonolactone 3 under mild conditions. The in vitro anti-HBV screening results showed that these 8-azanebularine analogues had a significant inhibitory effect on the expression of HBV antigens and HBV DNA at a concentration of 20⯵M. Among them, halogen-substituted 8-azaadenosine derivative 2g displayed activities comparable to that of 3TC. In particular, 2g retained excellent activity against lamivudine-resistant HBV mutants.
Assuntos
Antivirais/farmacologia , Desenho de Fármacos , Vírus da Hepatite B/efeitos dos fármacos , Nucleosídeos de Purina/farmacologia , Ribonucleosídeos/farmacologia , Antivirais/síntese química , Antivirais/química , DNA Viral/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nucleosídeos de Purina/síntese química , Nucleosídeos de Purina/química , Ribonucleosídeos/síntese química , Ribonucleosídeos/química , Relação Estrutura-AtividadeRESUMO
The fat mass and obesity-associated protein (FTO), as an m6A demethylase, is involved in many human diseases. Virtual screening and similarity search in combination with bioactivity assay lead to the identification of the natural compound radicicol as a potent FTO inhibitor, which exhibits a dose-dependent inhibition of FTO demethylation activity with an IC50 value of 16.04 µM. Further ITC experiments show that the binding between radicicol and FTO was mainly entropy-driven. Crystal structure analysis reveals that radicicol adopts an L-shaped conformation in the FTO binding site and occupies the same position as N-CDPCB, a previously identified small molecular inhibitor of FTO. Unexpectedly, however, the 1,3-diol group conserved in radicicol and N-CDPCB assumes strikingly different orientations for interaction with FTO. The identification of radicicol as an FTO inhibitor and revelation of its recognition mechanism not only opens the possibility of developing new therapeutic strategies for treatment of leukemia but also provide clues for elucidation of the acting mechanisms of radicicol, which is a possible clinical candidate worth in-depth study.
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Dioxigenase FTO Dependente de alfa-Cetoglutarato/antagonistas & inibidores , Dioxigenase FTO Dependente de alfa-Cetoglutarato/química , Macrolídeos/química , Macrolídeos/farmacologia , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Calorimetria , Cristalografia por Raios X , Humanos , Espectroscopia de Ressonância Magnética , Modelos MolecularesRESUMO
A unique strategy toward the synthesis of polysubstituted indolizines has been developed. When 2-pyridinyl-2-(2'-bromoallyl)-1-carboxylates were treated with Cs2CO3, the starting material went through a methylenecyclopropane ring formation/opening cascade, and the corresponding indolizines were obtained in moderate to good yield as a single regioisomer.
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On treatment with Pd(OAc)2 and K2CO3, a variety of 3-aryl-2-(2-bromoallyl)-1,3-dicarbonyl compounds went through a monodearoylative dimerization reaction to provide polysubstituted [3]dendralenes in moderate to good isolated yields.
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8-Azanebularine analogues display interesting antiviral, antitumour and biochemical activities. However, typical glycosylation of 8-azapurines always resulted in the desired products in low yields due to the lack of stereo- and regioselectivity of the glycosylation reaction. Herein, a concise synthetic route toward 8-azanebularine analogues has been developed. Key steps involve a copper-catalyzed 1,3-dipolar cycloaddition of a 1-ß-azido sugar moiety with ethyl 3-bromopropiolate and a palladium-catalyzed cascade amidine arylation-intramolecular ester amidation reaction to build the hypoxanthine structural motif. This protocol affords a facile methodology for the synthesis of a series of novel 8-azanebularine analogues from the readily accessible 1-ß-azido sugar moiety under mild conditions.
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Amidinas/química , Ésteres/química , Hipoxantinas/síntese química , Paládio/química , Nucleosídeos de Purina/síntese química , Ribonucleosídeos/síntese química , Catálise , Hipoxantinas/química , Conformação Molecular , Nucleosídeos de Purina/química , Ribonucleosídeos/químicaRESUMO
Fe(II) and α-ketoglutarate-dependent fat mass and obesity associated protein (FTO)-dependent demethylation of m6A is important for regulation of mRNA splicing and adipogenesis. Developing FTO-specific inhibitors can help probe the biology of FTO and unravel novel therapeutic targets for treatment of obesity or obesity-associated diseases. In the present paper, we have identified that 4-chloro-6-(6'-chloro-7'-hydroxy-2',4',4'-trimethyl-chroman-2'-yl)benzene-1,3-diol (CHTB) is an inhibitor of FTO. The crystal structure of CHTB complexed with human FTO reveals that the novel small molecule binds to FTO in a specific manner. The identification of the novel small molecule offers opportunities for further development of more selective and potent FTO inhibitors.
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Fármacos Antiobesidade/farmacologia , Obesidade , Proteínas/antagonistas & inibidores , Proteínas/química , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Fármacos Antiobesidade/química , Fármacos Antiobesidade/uso terapêutico , Cristalização , Células HEK293 , Humanos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Proteínas/metabolismoRESUMO
We described the first total syntheses of clausenapin, indizoline, claulansine M, and a novel synthetic route to clausenaline D via divergent method. Key steps involved TFAA-mediated intramolecular acylation to construct the carbazole core and subsequent Claisen rearrangement to generate key intermediates for further elaboration to target molecules.
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Alcaloides/síntese química , Carbazóis/síntese química , Acilação , Indicadores e Reagentes , Alcaloides Indólicos , Espectroscopia de Ressonância Magnética , EstereoisomerismoRESUMO
Solvent templates induced Co-based metal-organic materials; conformational isomers {[Co2(pdpa)(CH3CN)(H2O)3]·CH3OH·H2O}n (1) and {[Co2(pdpa)(CH3CN)(H2O)3]}n (2) and {[Co5(pdpa)2(µ3-OH)2(H2O)6]·2H2O}n (3) [H4pdpa = 5,5'-(pentane-1,2-diyl)-bis(oxy)diisophthalic acid] were synthesized under the same solvothermal conditions except with different concentrations of cyclic ethers (1,4-dioxane or tetrahydrofuran) as structure-directing agents. Structural transformations from a three-dimensional (3D) framework of 1 containing channels with dimensions of â¼6 Å × 6 Å to a two-dimensional layer structure of 2 consisting of large open channels with a size of â¼15 Å × 8 Å and then to a 3D nonporous framework of 3, resulting from the different concentrations of cyclic ethers, were observed. The anion-π interactions between electron-efficient oxygen atoms of cyclic ethers and electron-deficient dicarboxylic acid aromatic cores in H4pdpa imported into the synthetic process accounted for the conformational change of the ligand H4pdpa and the following structural variations. A systematic investigation was conducted to explore how different concentrations of structure-directing agents affected the frameworks of resultant metal-organic frameworks. Furthermore, 1-3 were shown to be available heterogeneous catalysts for the synthesis of 2-imidazoline and 1,4,5,6-tetrahydropyrimidine derivatives by the cascade cycloaddition reactions of aromatic nitriles with diamines. The results showed that the catalytic activity of 2 was much higher than that of 1 and 3, because of its unique structural features, including accessible catalytic sites and suitable channel size and shape. In addition, a plausible mechanism for these catalytic reactions was proposed, and the reactivity-structure relationship was further clarified.
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In our continuing quest to develop a metal-organic framework (MOF)-catalyzed tandem pyrrole acylation-Nazarov cyclization reaction with α,ß-unsaturated carboxylic acids for the synthesis of cyclopentenone[b]pyrroles, which are key intermediates in the synthesis of natural product (±)-roseophilin, a series of template-induced Zn-based (1-3) metal-organic frameworks (MOFs) have been solvothermally synthesized and characterized. Structural conversions from non-porous MOF 1 to porous MOF 2, and back to non-porous MOF 3 arising from the different concentrations of template guest have been observed. The anion-π interactions between the template guests and ligands could affect the configuration of ligands and further tailor the frameworks of 1-3. Futhermore, MOFs 1-3 have shown to be effective heterogeneous catalysts for the tandem acylation-Nazarov cyclization reaction. In particular, the unique structural features of 2, including accessible catalytic sites and suitable channel size and shape, endow 2 with all of the desired features for the MOF-catalyzed tandem acylation-Nazarov cyclization reaction, including heterogeneous catalyst, high catalytic activity, robustness, and excellent selectivity. A plausible mechanism for the catalytic reaction has been proposed and the structure-reactivity relationship has been further clarified. Making use of 2 as a heterogeneous catalyst for the reaction could greatly increase the yield of total synthesis of (±)-roseophilin.
Assuntos
Compostos Organometálicos/química , Zinco/química , Acilação , Catálise , Ciclização , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/química , Compostos Organometálicos/síntese química , Pirróis/síntese química , Pirróis/químicaRESUMO
A concise synthetic approach to the unnatural 5-epi-taiwaniaquinone G has been developed via a Lewis acid catalyzed tandem acylation-Nazarov cyclization reaction to construct the tricyclic skeleton, followed by installation of the isopropyl group through a strategy involving coumarin formation and its subsequent hydrolysis.
Assuntos
Cumarínicos/síntese química , Diterpenos/síntese química , Ácidos de Lewis/química , Compostos Policíclicos/síntese química , Catálise , Cumarínicos/química , Ciclização , Diterpenos/química , Estrutura Molecular , Compostos Policíclicos/química , EstereoisomerismoRESUMO
P2Y14 receptor (P2Y14R) is activated by uridine 5'-diphosphate-glucose, which is involved in many human inflammatory diseases. Based on the molecular docking analysis of currently reported P2Y14R antagonists and the crystallographic overlap study between the reported P2Y14R antagonist compounds 6 and 9, a series of N-substituted-acetamide derivatives were designed, synthesized, and identified as novel and potent P2Y14R antagonists. The most potent antagonist, compound I-17 (N-(1H-benzo[d]imidazol-6-yl)-2-(4-bromophenoxy)acetamide, IC50 = 0.6 nM) without zwitterionic character, showed strong binding ability to P2Y14R, high selectivity, moderate oral bioactivity, and improved pharmacokinetic profiles. In vitro and in vivo evaluation demonstrated that compound I-17 had satisfactory inhibitory activity on the inflammatory response of monosodium urate (MSU)-induced acute gouty arthritis. I-17 decreased inflammatory factor release and cell pyroptosis through the NOD-like receptor family pyrin domain-containing 3 (NLRP3)/gasdermin D (GSDMD) signaling pathway. Thus, compound I-17, with potent P2Y14R antagonistic activity, in vitro and in vivo efficacy, and favorable bioavailability (F = 75%), could be a promising lead compound for acute gouty arthritis.