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Palladium catalyzed tandem reaction represents a one-pot synthetic approach to efficiently synthesize complex functionalized molecules while reducing synthetic steps, aligning with the principles of green chemistry. However, achieving a direct cascade of the aza-Wacker and Povarov reactions in one-pot synthesis presents a challenge due to substrate compatibility issues between the two reactions. In this work, we describe an aza-Wacker/Povarov reaction employing a highly electrophilic palladium catalyst, which effectively converts anilines and 1,6-dienes into hexahydro-cyclopenta[b]quinolines. The optimized conditions yield up to 79%, with a diastereoselectivity > 20:1. Substrate range testing reveals compatibility with various sensitive functional groups, and successful late-stage modifications are performed on several natural products and drug molecules, demonstrating the versatility and practicality of the method. Additionally, a preliminary investigation into the reaction mechanism suggests an aza-Wacker process followed by a Povarov process.
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Pd-catalyzed regioselective amination of unactivated alkene remains a challenge and is of great interest. Herein, a palladium-catalyzed and ligand-controlled strategy for the Markovnikov selective oxidative amination of 4-pentenoic acid has been described. The protocol effectively reverses the carboxylic acid-directed anti-Markovnikov selectivity in oxidative amination of 4-pentenoic acid, successfully constructing γ-ketoamide derivatives.
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BACKGROUND: Neoadjuvant chemoradiotherapy (NCRT) followed by total mesorectal excision (TME) is the standard treatment for locally advanced rectal cancer (LARC). Mucinous adenocarcinoma (MAC) is a potential poor prognosis subgroup of rectal cancer. However, the predictive value of MAC in NCRT treatment of LARC is controversial. METHODS: A comprehensive literature search of PubMed, Embase, and the Cochrane Library was performed. All studies examining the effect of MAC on CRT response in LARC were included. Outcomes of MAC were compared with non-specific adenocarcinoma (AC) by using random-effects methods. Data were presented as odds ratios (ORs) with 95% confidence intervals (CIs). The main outcomes were the rates of pathological complete response (pCR), tumor and nodal down-staging, positive resection margin rate, local recurrence, and overall mortality. RESULTS: Fifteen studies containing comparative data on outcomes in a total of 9,238 patients receiving NCRT for LARC were eligible for inclusion. MAC had a reduced rate of pCR (OR, 0.38; 95% CI, 0.18-0.78) and tumor down-staging (OR, 0.31; 95% CI, 0.22-0.44) following NCRT compared with AC. MAC did not significantly affect nodal down-staging (OR, 0.42; 95% CI, 0.16-1.12) after NCRT. CONCLUSION: MAC of LARC was found to be a negative predictor of response to NCRT with lower rates of pCR and tumor down-staging for LARC. The nodal down-staging of MAC was relatively lower than that of AC, although the differences were not statistically significant.
Asunto(s)
Adenocarcinoma Mucinoso , Terapia Neoadyuvante , Neoplasias del Recto , Neoplasias del Recto/terapia , Neoplasias del Recto/patología , Neoplasias del Recto/mortalidad , Humanos , Adenocarcinoma Mucinoso/terapia , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Mucinoso/mortalidad , Estadificación de Neoplasias , Adenocarcinoma/terapia , Adenocarcinoma/patología , Adenocarcinoma/mortalidad , Recurrencia Local de Neoplasia , Pronóstico , Resultado del Tratamiento , Quimioradioterapia , Quimioradioterapia Adyuvante , Márgenes de EscisiónRESUMEN
Herein, a palladium-catalyzed 1,1-aminoxylation of 3-butenoic acid and 2-alkynylanilines has been developed, achieving the installation of two distinct heteroatom motifs across an olefin skeleton. The strategy features a high step and atom economy and good functional group tolerance, which outlines an efficient approach for simultaneously building up γ-butylactone and indole skeletons. Notably, an external ligand, 2,9-dimethyl-1,10-phenanthroline, has been used to succeed in this protocol to effectively suppress the production of indole byproducts.
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Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. The unlimited proliferation of tumor cells is one of the key features resulting in the malignant development and progression of CRC. Consequently, understanding the potential proliferation and growth molecular mechanisms and developing effective therapeutic strategies have become key in CRC treatment. Pyroptosis is an emerging type of regulated cell death (RCD) that has a significant role in cells proliferation and growth. For the last few years, numerous studies have indicated a close correlation between pyroptosis and the occurrence, progression, and treatment of many malignancies, including CRC. The development of effective therapeutic strategies to inhibit tumor growth and proliferation has become a key area in CRC treatment. Thus, this review mainly summarized the different pyroptosis pathways and mechanisms, the anti-tumor (tumor suppressor) and protective roles of pyroptosis in CRC, and the clinical and prognostic value of pyroptosis in CRC, which may contribute to exploring new therapeutic strategies for CRC.
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Neoplasias Colorrectales , Piroptosis , Piroptosis/efectos de los fármacos , Humanos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/tratamiento farmacológico , Animales , Proliferación Celular , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacologíaRESUMEN
Herein, we describe a novel approach to the synthesis of benzocycloheptene derivatives via base-promoted (5 + 2) annulation between 2-(alkynylaryl)acetonitriles and arylalkynes. In this chemistry, 2-(alkynylaryl)acetonitriles are employed as a new C5 synthon to construct various benzocycloheptene(s) derivatives by building two C-C bonds in one single step. This method features excellent regioselectivity, the use of readily available starting materials, and good functional group tolerance. The practicality of the strategy was further demonstrated by gram-scale synthesis, late-stage functionalizations, and the post-modification of natural products such as probenecid and tetrahydrofurfuryl alcohol.
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Catalytic cyclization via dual C-H bond activation has evolved as a powerful strategy for building bi- and polycyclic molecules. Herein, a palladium-catalyzed annulation of tertiary anilines with 3-butenoic acid via N-α-C(sp3)-H and ortho-C(sp2)-H activation is described. The remarkable characteristics of this reaction include excellent diastereoselectivity, broad substrate scope, and good tolerance for some highly sensitive groups. In addition, the KIE experiment suggested that the C-H bond abscission is not the turnover-limiting step.
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Catalytic 1,1-difunctionalization of unactivated alkenes with two nucleophiles has attracted a great deal of interest but remains a challenge in synthetic chemistry. Here, palladium(II)-catalyzed Nu/Nu'-type 1,1-oxamidation and 1,1-diamination of unactivated alkenyl carbonyl compounds followed by amination are described. The distinguishing features of this reaction include the lack of a directing group, good functional group tolerance, and easily operational catalytic reaction conditions. Mechanistic investigations support a unique route involving two consecutive nucleopalladations for this 1,1-difunctionalization.
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A novel and expedient cascade strategy has been demonstrated for the synthesis of fused benzo-aza-oxa-[5-6-5] tetracycles in high yields and diastereoselectivities (up to 20 : 1 dr). The strategy was fulfilled through palladium-catalyzed oxidative convergent assembly of functionally divergent anilines and 3-butenoic acid with five chemical bonds constructed. Coupled with control experiments and deuterium labelled studies, DFT calculations were performed for the proposed mechanism. The utility of the illustrated strategy is emphasized by gram-scale syntheses, late-stage functionalization, and the transformation to a key core of natural products such as martinellic acid and seneciobipyrrolidine.
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Paladio , Paladio/química , Catálisis , CiclizaciónRESUMEN
Efficient hepatocellular carcinoma (HCC) therapy remains a significant challenge due to the unsatisfactory targeting efficiency of nanoparticles (NPs) with either a passive targeting or a single active targeting property. Although a dual-targeting mechanism-based strategy can promote the partial targeting efficiency, most of the reported NPs with dual-targeting properties generally suffer from sophisticated chemical design, multistep synthesis, and purification procedures, leading to batch-to-batch variation and difficulties in scalable production. To develop a facile yet efficient strategy toward dual-targeting ligand-functionalized NPs for precise HCC therapy and potential clinical translation, folic acid (FA) was readily introduced as a hydrophobic and targeting component to a hydrophilic macromolecular prodrug, galactosylated chitosan-5-fluorouracil acetic acid (GC-FU), to afford FA-GC-FU formulation that can self-assemble into NPs driven by the solubility variation of FA and GC-FU without the necessity of previously used physical cross-linking. The resulting nanoparticles of FA-GC-FU can target the overexpressed asialoglycoprotein receptors (ASGPRs) and folate receptors (FRs) on the surface of HCC cells, respectively, via the FA and lactobionic acid (LA) residues exposed on the surface of the NPs, leading to the maximized targeting efficiency of HCC and minimized nonspecific uptake by normal hepatocytes in vitro and in vivo. Therefore, this study not only developed a simple yet efficient strategy toward a facile fabrication of NPs with dual-targeting ligands but also presented a precise therapeutic platform for HCC with great potential for clinical translation.
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Antineoplásicos/química , Antineoplásicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Nanopartículas/química , Células A549 , Apoptosis/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Quitosano/química , Fluorouracilo/química , Fluorouracilo/farmacología , Ácido Fólico/química , Hepatocitos/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ligandos , Medicina de Precisión/métodos , Profármacos/química , Profármacos/farmacología , SolubilidadRESUMEN
A novel type of macromolecular prodrug delivery system is reported in this research. The N-galactosylated-chitosan-5-fluorouracil acetic acid conjugate (GC-FUA) based nanoparticle delivery system was evaluated in vitro and in vivo. Biocompatibility of GC-FUA-NPs was screened by BSA adsorption test and hemolysis activity examination in vitro. Cytotoxicity and cellular uptake study in HepG2 and A549 cells demonstrated that compared to free 5-Fu, the GC-FUA-NPs play great function in killing cancer cells for the cell endocytosis mediated by asialoglycoprotein receptor (ASGPR), which overexpresses on the cell surface. Pharmacokinetics study further illustrated that the drug-loaded nanoparticles has a much longer half-time than free 5-Fu in blood circulation in Sprague-Dawley (SD) rats. Tissue distribution was investigated in Kunming mice, and the result showed that the GC-FUA-NPs have a long circulation effect. The obtained data suggested that GC-FUA-NP is a very promising drug delivery system for efficient treatment of hepatocellular carcinoma.
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Antimetabolitos Antineoplásicos/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Quitosano/análogos & derivados , Quitosano/administración & dosificación , Portadores de Fármacos/administración & dosificación , Fluorouracilo/análogos & derivados , Fluorouracilo/administración & dosificación , Nanopartículas/química , Profármacos/administración & dosificación , Células A549 , Absorción Fisiológica , Animales , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/farmacocinética , Antimetabolitos Antineoplásicos/farmacología , Carcinoma Hepatocelular/metabolismo , Supervivencia Celular/efectos de los fármacos , Quitosano/efectos adversos , Quitosano/farmacocinética , Quitosano/farmacología , Portadores de Fármacos/efectos adversos , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacología , Fluorouracilo/efectos adversos , Fluorouracilo/farmacocinética , Fluorouracilo/farmacología , Glicosilación , Semivida , Hemólisis/efectos de los fármacos , Células Hep G2 , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Ratones , Nanopartículas/efectos adversos , Nanopartículas/ultraestructura , Profármacos/efectos adversos , Profármacos/farmacocinética , Profármacos/farmacología , Conejos , Distribución Aleatoria , Ratas Sprague-Dawley , Distribución TisularRESUMEN
Inflammatory bowel disease (IBD) correlates with oxidative stress, inflammation, and alteration in several signal pathways, including nuclear transcription factor-kappaB (NF-κB). Pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB, has been widely demonstrated to exhibit an antioxidant and anti-inflammatory function. This study aimed to test the hypothesis that NF-κB inhibitor PDTC confers a beneficial role in a colitis model induced by dextran sodium sulfate (DSS) in mouse. The results showed that DSS decreased daily weight gain, induced colonic inflammation, suppressed the expression of antioxidant enzymes and tight junctions, and activated NF-κB and nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) signaling pathways. PDTC significantly upregulated (P < 0.05) Gpx1, Gpx4, occludin, and ZO-1 expressions in the DSS-induced colitis model. Meanwhile, PDTC reversed (P < 0.05) the activation of NF-κB signal pathway caused by DSS treatment. In conclusion, PDTC could serve as an adjuvant therapy for the patient with IBD.
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Colitis/tratamiento farmacológico , FN-kappa B/metabolismo , Pirrolidinas/administración & dosificación , Tiocarbamatos/administración & dosificación , Animales , Colitis/inducido químicamente , Colitis/inmunología , Citocinas/genética , Sulfato de Dextran , Modelos Animales de Enfermedad , Glutatión Peroxidasa/genética , Masculino , Ratones , Ratones Endogámicos ICR , Ocludina/genética , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Transducción de Señal , Proteína de la Zonula Occludens-1/genética , Glutatión Peroxidasa GPX1RESUMEN
The fabrication and evaluation of a natural pectin-based drug delivery system are reported in this study. The drug delivery system displays specific active targeting ability to hepatocellular carcinoma due to the presence of excess galactose residues in the polymer structure as the natural targeting ligands. The system was prepared under very mild conditions in an aqueous medium containing Ca(2+) and CO3(2-) ions, generating uniform pectin-based nanoparticles with an average diameter of 300 nm, and the drug-loading content of anticancer drug 5-fluorouracil (5-FU) is around 24.8%. Cytotoxicity study of the 5-FU-loaded nanoparticles (5-FU-NPs) in HepG2 and A549 cell lines demonstrated their greater potency in killing cancer cells with overexpressed asialoglycoprotein receptor (ASGPR) on the cell surface, compared to that of the free drug. Pharmacokinetics study using Sprague-Dawley (SD) rats further confirmed that the drug-loaded nanoparticles showed a much longer half-life in the circulation fluids than the free drug. Tissue distribution was investigated on Kunming mice, and the results also demonstrated that the 5-FU-NPs has a long circulation effect. Taken together, the pectin-based drug delivery systems exhibit size-induced prolonged circulation as well as ASGP receptor-mediated targeting ability to cancer cell lines; therefore, it is a promising platform for the treatment of hepatocellular carcinoma.
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Antineoplásicos , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Nanopartículas/uso terapéutico , Pectinas/farmacología , Pectinas/uso terapéutico , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Bioensayo , Cápsulas/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Humanos , Concentración 50 Inhibidora , Ratones , Microscopía Electrónica de Transmisión , Nanopartículas/química , Tamaño de la Partícula , Pectinas/química , RatasRESUMEN
AIM: To investigate the effect of 5-allyl-7-gen-difluoromethylenechrysin (ADFMChR) on apoptosis of human liver carcinoma HepG2 cell line and the molecular mechanisms involved. METHODS: HepG2 cells and L-02 cells were cultured in vitro and the inhibitory effect of ADFMChR on their proliferation was measured by MTT assay. The apoptosis of HepG2 cells was determined by flow cytometry (FCM) using propidium iodide (PI) fluorescence staining. DNA ladder bands were observed by DNA agarose gel electrophoresis. The influence of ADFMChR on the proxisome proliferator-activated receptor gamma (PPARgamma), NF-kappaB, Bcl-2 and Bax protein expression of HepG2 cells were analyzed by Western blotting. RESULTS: MTT assay showed that ADFMChR significantly inhibited proliferation of HepG2 cells in a dose-dependent manner, with little effect on growth of L-02 cells, and when IC(50) was measured as 8.45 micromol/L and 191.55 micromol/L respectively, the potency of ADFMChR to HepG2 cells, was found to be similar to 5-fluorouracil (5-FU, IC(50) was 9.27 micromol/L). The selective index of ADFMChR cytotoxicity to HepG2 cells was 22.67 (191.55/8.45), higher than 5-FU (SI was 7.05 (65.37/9.27). FCM with PI staining demonstrated that the apoptosis rates of HepG2 cells treated with 3.0, 10.0 and 30.0 micromol/L ADFMChR for 48 h were 5.79%, 9.29% and 37.8%, respectively, and were significantly higher when treated with 30.0 micromol/L ADFMChR than when treated with 30.0 micromol/L ChR (16.0%) (P < 0.05) and were similar to those obtained with 30.0 micromol/L 5-FU (41.0%). DNA agarose gel electrophoresis showed that treatment of HepG2 cells with 10.0 micromol/L ADFMChR for 48 h and 72 h resulted in typical DNA ladders which could be reversed by 10.00 micromol/L GW9662, a blocker of PPARgamma. Western blotting analysis revealed that after 24 h of treatment with 3.0, 10.0, 30.0 micromol/L ADFMChR, PPARgamma and Bax protein expression in HepG2 cells increased but Bcl-2 and NF-kappaB expression decreased; however, pre-incubation with 10.0 micromol/L GW9662 could efficiently antagonize and weaken the regulatory effect of 3.0, 30.0 micromol/L ADFMChR on PPARgamma and NF-kappaB protein expression in HepG2 cells. CONCLUSION: ADFMChR induces apoptosis of HepG2 cell lines by activating PPARgamma, inhibiting protein expression of Bcl-2 and NF-kappaB, and increasing Bax expression.