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We describe a synthetic approach for a set of fluorescent thieno[3,2- b]pyridine-5(4 H)-one derivatives and their photophysical properties. These fluorophores are prepared by a series of reactions employing the Suzuki-Miyaura cross-coupling reaction and a regioselective aza-[3 + 3] cycloaddition of 3-aminothiophenes with α,ß-unsaturated carboxylic acids. Our findings revealed that the photophysical properties are chemically tunable by an appropriate choice of functional group on the thieno[3,2- b]pyridine-5(4 H)-one scaffold.
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This corrects the article DOI: 10.1038/srep23472.
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Efficient and concise approaches for the synthesis of three bioactive natural products, isohericerin, isohericenone, and erinacerin A, are described in this paper. The key reactions employed include a Mannich reaction with commercially available hydroxybenzoate and subsequent one-pot lactamization to afford the common precursor isoindolinone in 3 steps and a Suzuki-Miyaura coupling reaction to connect geranyl side chains to the isoindolinone core. In addition, the mild and efficient synthesis of the C5'-oxidized geranyl side unit of isohericenone is enabled by developing a highly regioselective and efficient method for the Cu-catalyzed methylboronation of functionalized terminal alkynes.
Assuntos
Alcinos/química , Compostos de Boro/síntese química , Cobre/química , Compostos Heterocíclicos com 3 Anéis/síntese química , Alcaloides Indólicos/síntese química , Compostos de Boro/química , Catálise , Compostos Heterocíclicos com 3 Anéis/química , Alcaloides Indólicos/química , Estrutura MolecularRESUMO
The high level of interest in the cyclodepsipeptides family in the natural products stems from their diverse range of biological activities. One of the cyclodepsipeptides, (-)-bassianolide, represents rich pharmacophores with diverse biological activities including potential cytotoxicity to various cancer cells. Efficient total synthesis of (-)-bassianolide was designed and achieved in nine steps, with significant improvements in the overall yield of 46.8% (vs. 7.2% yield in previous synthesis) using Ghosez's chloroenamine reagent under mild conditions. The cytotoxicity of the (-)-bassianolide was evaluated against five human tumor cells, and the results showed that the (-)-bassianolide displayed significant cytotoxicity against A549, SK-OV-3, HepG2, HCT-15, MCF-7 and MDA-MB 231 cell lines with IC50 values of 7.24, 8.44, 15.39, 6.40, 11.42 and 3.98 µg/mL respectively. Specifically, (-)-bassianolide induced G0/G1 arrest associated with a decrease of cyclin A, D1 and an increase of p53, MDM2, and p21 expression in MDA-MB 231 cells. These results demonstrate that (-)-bassianolide possesses antitumor activities via arresting of the cell cycle and the synthetic approach features an efficient and mild method for the formation of amide bonds through three inter- and intramolecular coupling reactions.
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Antineoplásicos/farmacologia , Peptídeos Cíclicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Genetic ablation of BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), an essential regulator of cardiac cell death, is an effective way to prevent cardiac cell death triggered by pathologic conditions. However, currently there exists no known means, such as inhibitors, to down-regulate BNIP3 in mature heart. Here, we report that a small molecule inducer of microRNA-182 (miR-182) suppressed ischemia/reperfusion (I/R)-induced cardiac cell death by down-regulating BNIP3. We first selected miR-182 as a potent BNIP3-targeting miRNA based on miRNA-target prediction databases and empirical data. The subsequent screening of small molecules for inducing miR-182 expression identified Kenpaullone as a hit compound. Both exogenous miR-182 and Kenpaullone significantly suppressed hypoxia-induced cardiomyocyte death in vitro. To investigate the effect of changing substituents of Kenpaullone on miR-182 expression, we synthesized 9 derivatives of Kenpaullone. Among these derivatives, compound 5 showed significantly improved ability to induce miR-182 expression. The results of the in vivo study showed that compound 5 significantly improved heart function following I/R-injury in rats. Our study provides strong evidence that the small molecule-mediated up-regulation of miRNAs is a viable strategy to down-regulate target proteins with no known chemical inhibitor and that compound 5 may have potential to prevent I/R-inflicted cardiac cell death.