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1.
Curr Med Chem ; 2020 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-33372864

RESUMO

BACKGROUND: We have previously reported that a quinolizidine natural product, aloperine, and its analogs can inhibit influenza virus and/or HIV-1 at low µM concentrations. OBJECTIVE: The main goal of this study was to further optimize aloperine for improved anti-influenza virus activity. METHODS: Structural modifications have been focused on the N12 position of aloperine scaffold. Conventional chemical synthesis was used to obtain derivatives with improved antiviral activities. The anti-HIV and anti-influenza virus activities of the synthesized compounds were determined using an MT4 cell-based HIV-1 replication assay and an anti-influenza virus infection of MDCK cell assay, respectively. RESULTS: Aloperine derivatives can be classified into three activity groups: those that exhibit anti-HIV activity only, anti- influenza virus only, or activity against both viruses. Aloperine optimized for potent anti-influenza activity often lost antiHIV-1 activity, and vice versa. Compound 19 inhibited influenza virus PR8 replication with an IC50 of 0.091 µM, which is approximately 160- and 60-fold more potent than aloperine and the previously reported aloperine derivative compound 3, respectively. CONCLUSION: The data suggest that aloperine is a privileged scaffold that can be modified to become a selective antiviral compound with markedly improved potency against influenza virus or HIV-1.

2.
Bioorg Chem ; 105: 104388, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33130343

RESUMO

A phytochemical investigation on the stems and leaves of Wikstroemia chuii resulted in the isolation of three new daphnane diterpenes, wikstroechuins A-C (1-3), together with eight known analogues (4-11). The structures of new daphnane diterpenes (1-3) were determined on the basis of extensive spectroscopic methods and the known daphnane diterpenes (4-11) were identified by comparing their observable spectroscopic data with those reported spectral data in the literature. The anti-inflammatory effects as well as anti-HIV activities in vitro of all isolated daphnane diterpenes 1-11 were assessed. As a consequence, daphnane diterpenes 1-11 displayed remarkable inhibitory activities on NO (nitric oxide) production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells showing IC50 values in the range of 0.12 ± 0.03 to 10.58 ± 0.16 µM. Meanwhile, daphnane diterpenes 1-11 displayed significant anti-HIV-1 reverse transcriptase (RT) effects showing EC50 values ranging from 0.09509 to 8.62356 µM. These research results indicated that the discovery of these new daphnane diterpenes with remarkable anti-inflammatory and anti-HIV activities from W. chuii, especially these new ones, could be extremely meaningful to the discovery of new anti-inflammatory agents and anti-HIV drugs as well as their potential practical values in the health and pharmaceutical products.

3.
Org Lett ; 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-33253584

RESUMO

The electrophilic alkylthiolation of alkenes, initiated by dimethyl(methylthio)sulfonium salts and the subsequent addition of various heteronucleophilies has been well-established. Regarding the use of carbon nucleophiles, however, only carefully designed sp-type carbon sources have been successfully applied. We herein present our findings on the methylthiolation of alkenes with dimethyl(methylthio)sulfonium trifluoromethanesulfonate, followed by carbon-carbon bond formation in the presence of organozinc reagents, thus achieving a catalyst-free protocol toward to the carbosulfenylation of alkenes.

5.
Kaohsiung J Med Sci ; 2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32783381

RESUMO

Acute promyelocytic leukemia (APL), a biologically and clinically distinct variant of acute myelogenous leukemia, is characterized by the fusion of the N-terminus of promyelocytic leukemia protein to the C terminus of retinoic acid receptor alpha, mostly due to chromosomal translocation t(15;17). Chidamide, a synthetic analogue of MS-275 identified from a group of benzamide-type compounds, has been found to have efficient anticancer activity in basic and clinical research studies. However, the concrete role and underlying mechanism of Chidamide in the treatment of APL has not been well characterized. Our data demonstrate that Chidamide inhibited the expression of histone deacetylase (HDAC) to induce apoptosis and suppress proliferation in NB4 cells. Mechanistically, Chidamide increases the expression of miR-34a by suppressing HDAC. Furthermore, B-cell lymphoma-2 (Bcl-2) is a direct target of miR-34a, the expression of which is regulated by miR-34a. Functionally, Chidamide inhibits cell proliferation and promotes apoptosis through miR-34a/Bcl-2. Chidamide exerts its anticancer effect via the HDAC-mediated miR-34a/Bcl-2 axis, providing potential targets for APL therapy.

6.
J Hematol Oncol ; 13(1): 101, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32703317

RESUMO

MicroRNAs (miRNAs) play important roles in cell proliferation, differentiation, and survival and may be useful for acute myeloid leukemia (AML) diagnosis and prognosis. In this study, we defined a novel miRNA, hsa-miR-12462, through small RNA sequencing of the bone marrow (BM) cells from 128 AML patients. Overexpression of hsa-miR-12462 in AML cells (U937 and HL-60) significantly decreased their growth rate when compared with those of the wild-type and MOCK controls. In a xenograft mouse model, tumor weight and size in the mice bearing the U937 cells with hsa-miR-12462 overexpression were significantly reduced when compared with those bearing the mock cells. The AML cells overexpressing hsa-miR-12462 had increased sensitivity to cytarabine chemotherapy. Combining the data from the MiRDB, an online microRNA database ( http://mirdb.org ), with the RNA-sequencing results, SLC9A1 was predicted to be one of the targets of hsa-miR-12462. hsa-miR-12462 was further confirmed to bind exclusively to the 3'UTR of SLC9A1 in U937 cells, leading to downregulation of SLC9A1. In summary, a higher level of hsa-miR-12462 in AML cells is associated with increased sensitivity to cytarabine chemotherapy via downregulation of SLC9A1.

7.
Spectrochim Acta A Mol Biomol Spectrosc ; 242: 118750, 2020 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-32731144

RESUMO

Simultaneous high sensitivity detection of biomolecules is important for research in medicine, living cells and environmental samples. In this work, a water stable coordination polymer, [Cd2(bptc)(4,4'-bpy)(H2O)3]ˑH2O 1 (H4bptc = 2,3,3',4'-biphenyl tetracarboxylic acid, 4,4'-bpy = 4,4'-bipyridine), was designed and successfully synthesized as a luminescent sensor for simultaneous recognition of Ascorbic Acid (AA) and L-Tryptophan (L-Trp) based on luminescent -OFF and -ON, respectively. Importantly, the proposed sensing system showed an excellent performance with high KSV values of 4.85 × 104 M-1, 9.60 × 107 M-1 and low limit of detection (LOD) of 0.28 nM, 63 nM, respectively. In addition, the probable mechanisms are also discussed. The luminescent quenching behavior by AA can be mainly attributed to the static resonance energy transfer between complex 1 and the analytes. Whereas the enhancing effect of L-Trp comes from the intrinsic strong luminescence for L-Trp itself and photo-competitive mechanism between CP 1 sensor and L-Trp, supposedly. In addition, the repeatability of both systems were also investigated.

8.
Lipids Health Dis ; 19(1): 151, 2020 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-32586390

RESUMO

BACKGROUND: Coronary artery stenosis induces heart diseases including acute coronary syndrome (ACS). Some studies reported the ceramide species are associated with the ACS and major adverse cardia and cerebrovascular events (MACE). However, few studies investigated the association between plasma ceramide levels and the severity of stenosis, together with the onset of diseases. This aim of the present study was to investigate the association betweencertain ceramide species, coronary artery stenosis and acute coronary syndrome. METHODS: Five hundred fifty-three patients with definite or suspected CAD were recruited and received angiography. Subjects were assigned into 4 groups according to the severity of coronary artery stenosis. The measurements of 4 plasma ceramide species, namely, Cer (d18:1/16:0), Cer (d18:1/18:0), Cer (d18:1/24:1), Cer (d18:1/24:0) were carried out by Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and the ratio of Cer (d18:1/16:0), Cer (d18:1/18:0) and Cer (d18:1/24:1) to Cer (18:1/24:0), respectively, were calculated as index to evaluate the association between plasma ceramides levels and coronary artery stenosis. Multiple logistic regression analysis was used to establish the prognostic model for the prediction of ACS risk. RESULTS: After the adjustment by multiple clinical risk factors including age, gender, pre-existing myocardial/cerebral infarction, hemoglobin A1c% (HbA1c%), smoking and the diagnosis during index hospitalization, multiple logistic regression analysis showed that the high ratio of Cer (d18:1/24:1) to Cer (d18:1/24:0), female gender, HbA1c%, unstable angina (UAP) and acute myocardial infarction (AMI) diagnosis (compared with atherosclerosis) during index hospitalization were associated with more severe coronary artery stenosis. Furthermore, the prognostic model was established after adjustment of risk factors and the area under curve (AUC) of receiver operating characteristics (ROC) for the prognostic model was 0.732 and 95% CI was 0.642-0.822. CONCLUSION: The severity of coronary artery stenosis is associated with high ratio of Cer (d18:1/24:1) to Cer (d18:1/24:0), female gender, HbA1c% and AMI. Although the reported prognostic model showed a good discrimination, further investigation on long term MACE is needed to evaluate the role of ceramide for the prediction of MACE risk.

9.
Comput Struct Biotechnol J ; 18: 1121-1136, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32489526

RESUMO

As one of the classical traditional Chinese medicine (TCM) prescriptions in treating gynecological tumors, Guizhi Fuling Decoction (GFD) has been used to treat breast cancer (BRCA). Nonetheless, the potential molecular mechanism remains unclear so far. Therefore, systems pharmacology was used in combination with high throughput sequencing-based high throughput screening (HTS2) assay and bioinformatic technologies in this study to investigate the molecular mechanisms of GFD in treating BRCA. By computationally analyzing 76 active ingredients in GFD, 38 potential therapeutic targets were predicted and significantly enriched in the "pathways in cancer". Meanwhile, experimental analysis was carried out to examine changes in the expression levels of 308 genes involved in the "pathways in cancer" in BRCA cells treated by five herbs of GFD utilizing HTS2 platform, and 5 key therapeutic targets, including HRAS, EGFR, PTK2, SOS1, and ITGB1, were identified. The binding mode of active compounds to these five targets was analyzed by molecular docking and molecular dynamics simulation. It was found after integrating the computational and experimental data that, GFD possessed the anti-proliferation, pro-apoptosis, and anti-angiogenesis activities mainly through regulating the PI3K and the MAPK signaling pathways to inhibit BRCA. Besides, consistent with the TCM theory about the synergy of Cinnamomi Ramulus (Guizhi) by Cortex Moutan (Mudanpi) in GFD, both of these two herbs acted on the same targets and pathways. Taken together, the combined application of computational systems pharmacology techniques and experimental HTS2 platform provides a practical research strategy to investigate the functional and biological mechanisms of the complicated TCM prescriptions.

10.
Biomed Pharmacother ; 127: 110146, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32334376

RESUMO

Emerging in vivo and vitro data suggest that white tea extract (WTE) is capable of favourably modulating metabolic syndrome, especially by ameliorating abnormal lipid metabolism. Microarray-based gene expression profiling was performed in HepG2 cells to analyze the effects of WTE from a systematic perspective. Gene Ontology and pathway analysis revealed that WTE significantly affected pathways related to lipid metabolism. WTE significantly downregulated apolipoprotein B (APOB) and microsomal triglyceride transfer protein (MTTP) expression and thereby reduced the production of very-low-density lipoprotein. In the meanwhile, WTE stimulated low-density lipoprotein-cholesterol (LDL-c) uptake through targeting low-density lipoprotein receptor (LDLR), as a consequence of the activation of sterol regulatory element-binding protein 2 (SREBP2) and peroxisome proliferator-activated receptor δ (PPARδ). Furthermore, WTE significantly downregulated triglycerides synthetic genes and reduced intracellular triglycerides accumulation. Besides, we demonstrated that the tea catechins epigallocatechin-3-gallate (EGCG) and epicatechin-3-gallate (ECG) are abundant in WTE and contribute to the regulation of cholesterol metabolism related genes, including LDLR, MTTP and APOB. Our findings suggest white tea plays important roles in ameliorating abnormal lipid metabolism in vitro.

11.
Rev Cardiovasc Med ; 21(1): 113-118, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32259909

RESUMO

Patients with heart failure (HF) are prone to combine with renal insufficiency. Recently, LCZ696 has been used in the treatment of HF, but whether LCZ696 is better than angiotensin converting enzyme inhibitors/angiotensin receptor antagonists (ACEI/ARB) in renal protection for HF patients has not been investigated. Therefore, we conducted a meta-analysis focusing on LCZ696 and its role in preservation of renal function in HF patients. Embase, PubMed, the Cochrane Library and ClinicalTrials.gov databases were electronically searched for available randomized controlled trials (RCTs). HF patients taking LCZ696 or ACEI/ARB were assessed for renal adverse events. The last search date was Sep 20, 2019. A total of 14959 patients from 6 trials were included in this meta-analysis. As compared to ACEI/ARB, LCZ696 significantly reduced the risk of renal function deterioration (odds ratio 0.77, 95% confidence interval 0.61-0.97, P = 0.02). In summary, LCZ696 may have superior renal protection in HF patients compared with ACEI/ARB.


Assuntos
Aminobutiratos/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Rim/efeitos dos fármacos , Inibidores de Proteases/uso terapêutico , Tetrazóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Aminobutiratos/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Combinação de Medicamentos , Medicina Baseada em Evidências , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Humanos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Neprilisina/antagonistas & inibidores , Inibidores de Proteases/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Tetrazóis/efeitos adversos , Resultado do Tratamento
12.
J Pharm Pharm Sci ; 23(1): 1-9, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32027818

RESUMO

PURPOSE: We investigated the relationship between imatinib trough concentrations and genetic polymorphisms with efficacy of imatinib in Chinese patients with chronic myeloid leukemia (CML). METHODS: There were 171 eligible patients. Peripheral blood samples were collected from 171 eligible patients between 21 and 27 hours after the last imatinib administration. Complete cytogenetic response (CCyR), major molecular response (MMR) and complete molecular response (CMR) were used as metrics for efficacy. Nine single nucleotide polymorphisms in 5 genes, SLC22A4 (917 T>C, -248 C>G and -538 C>G), SLC22A5 (-945 T>G and -1889 T>C), SLCO1A2 (-361 G>A), SLCO1B3 (334 T>G and 699 G>A) and ABCG2 (421C>A) were selected for genotyping. RESULTS: Patients with CCyR achieve higher trough concentrations than those without CCyR (1478.18±659.83 vs 984.89±454.06 ng mL-1, p<0.001). Patients with MMR and CMR achieve higher trough concentrations than those without MMR and CMR, respectively (1486.40±703.38 vs 1121.17±527.14 ng mL-1, p=0.007; 1528.00±709.98 vs 1112.67±518.35 ng mL-1, p=0.003, respectively). Carriers of A allele in SLCO1A2 -361G>A achieve higher CCyR and MMR rates (p=0.047, OR=4.320, 95% CI: 0.924-20.206; p=0.042, OR=2.825, 95% CI: 1.016-7.853, respectively). Both trough concentrations and SLCO1A2 -361G>A genotypes are independent factors affecting imatinib efficacy. The positive and negative predictive values for CCyR are 71.01% and 68.75%, respectively. The positive and negative predictive values for MMR are 62.86% and 69.70%, respectively. CONCLUSION: Imatinib trough concentrations and SLCO1A2 -361G>A genotypes are associated with imatinib efficacy in Chinese patients with CML.

13.
Life Sci ; 248: 117467, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32105706

RESUMO

BACKGROUND: NQO1 protein acts as a cellular protective system, on account of its role as a quinone reductase and redox regulator. Nonetheless, new NQO1 roles are emerging-including its regulation of the cellular proliferation of many tumor cells-and this enzyme has been found to relate to the incidence of various diseases, including chronic myeloid leukemia. However, the mechanisms through which NQO1 influences leukemia progression remain unclear. MARTIAL AND METHODS: The current study looks to name NQO1 as a novel molecular target that modulates DNA synthesis and chronic myeloid leukemia growth. RESULTS AND CONCLUSION: Our results indicate that the frequency of the T allele of NQO1 polymorphism in chronic myeloid leukemia patients is higher than that among healthy East Asian individuals (0.492 vs. 0.419) and much higher than the average level of the general population (0.492 vs. 0.289) (1000 Genomes). Functionally, NQO1 knockdown increases the protein expression of the TOP2A and MCM complex, and consequently promotes DNA synthesis and K562 cell growth. NQO1 knockdown also promotes tumorigenesis in a xenograft model. NQO1 overexpression, on the other hand, was found to have the opposite effects. SIGNIFICANCE: Our results show that NQO1 downregulation promotes K562 cellular proliferation via the elevation of DNA synthesis.


Assuntos
DNA de Neoplasias/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucócitos/metabolismo , NAD(P)H Desidrogenase (Quinona)/genética , Adulto , Alelos , Animais , Grupo com Ancestrais do Continente Asiático , Linhagem Celular Tumoral , Proliferação de Células , DNA Topoisomerases Tipo II/genética , DNA Topoisomerases Tipo II/metabolismo , DNA de Neoplasias/biossíntese , Feminino , Xenoenxertos , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/etnologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucócitos/patologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , NAD(P)H Desidrogenase (Quinona)/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Polimorfismo Genético , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais
14.
ACS Med Chem Lett ; 11(1): 83-89, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31938468

RESUMO

Scaffold hopping-driven lead optimizations were performed based on our prior lead 7-methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one (2a) by C-ring expansion and isometric replacement of the A/B-ring, successively, aimed at finding new potential alternative drug candidates with different scaffold(s), high antitumor activity, and other improved properties to replace prior, once promising drug candidates that failed in further studies. Two series of new compounds 7 (a-d) and 13 (a-j) were synthesized and evaluated for antitumor activity, leading to the discovery of three highly potent compounds 13c, 13d, and 13e with different scaffolds. They exhibited similar high antitumor activity with single digital low nanomolar GI50 values (4.6-9.6 nM) in cellular assays, comparable to lead 2a, clinical drug candidate CA-4, and paclitaxel in the same assays. Further biological evaluations identified new active compounds as tubulin polymerization inhibitors targeting the colchicine binding site. Moreover, 13d showed better aqueous solubility than 2a and a similar log P value.

15.
Materials (Basel) ; 13(2)2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31963389

RESUMO

Building novel functional nanomaterials with a polymer is one of the most dynamic research fields at present. Here, three amphiphilic block copolymers of 8-hydroxyquinoline derivative motifs (MQ) with excellent coordination function were synthesized by Reversible Addition-Fragmentation Chain Transfer Polymerization (RAFT) polymerization. The coordination micelles were prepared through the self-assembly process, which the MQ motifs were dispersed in the hydrophobic polystyrene (PSt) blocks and hydrophilic Poly(N-isopropylacrylamide (PNIPAM)) blocks, respectively. The dual-emission micelles including the intrinsic red light emission of quantum dots (QDs) and the coordination green light emission of Zn2+-MQ complexes were built by introducing the CdSe/ZnS and CdTe/ZnS QDs in the core and shell precisely in the coordination micelles through the coordination-driven self-assembly process. Furthermore, based on the principle of three primary colors that produce white light emission, vinyl carbazole units (Polyvinyl Carbazole, PVK) with blue light emission were introduced into the hydrophilic PNIPAM blocks to construct the white light micelles that possess special multi-emission properties in which the intrinsic red light emission of QDs, the coordination green light of Zn2+-MQ complexes, and the blue light emission of PVK were synergized. The dual and multi-emission hybrid micelles have great application prospects in ratiometric fluorescent probes and biomarkers.

16.
Phytomedicine ; 64: 153072, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31480012

RESUMO

BACKGROUND: Breast cancer is one of the most lethal cancers in women when it reaches the metastatic stage. The plant Carpesium cernuum has been used as an anti-inflammatory, analgesic, and detoxifying agent in Chinese folk medicine. However, the inhibitory activity and molecular mechanisms of Carpesium cernuum in breast cancer cells have not been investigated. METHODS: RNA sequencing experiments were performed to elucidate the cellular pathways affected by Carpesium cernuum extract (CCE). Cell viability and EdU incorporation assays were conducted to determine the effect of CCE on cell proliferation. The inhibitory effects of CCE on the expression levels of target genes were confirmed by qRT-PCR and Western blot. Cell migration and invasion were analysed with transwell chamber assays. RESULTS: Proliferation assays indicated that CCE inhibited cell proliferation in multiple cancer cell lines and the IC50 value of CCE was the smallest in MDA-MB-231 cells. Transcriptome analysis showed that CCE significantly affected the cell adhesion pathway. Further experiments revealed that CCE suppressed cell migration and invasion. The inhibitory effect on migration was likely mediated by targeting TIMP1, MMP9, CD44 and COL4A2. The main active components of CCE were isolated, and CCE-derived sesquiterpene lactone substances could reproduce the inhibitory effect of CCE on cell migration and invasion. CONCLUSIONS: Overall, both molecular and phenotypic assays showed that CCE has potential in the treatment of breast cancer, especially for the treatment of breast cancer metastasis. CCE-derived sesquiterpene lactone substances are the foundation for the tumor inhibitory effect of CCE.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Asteraceae/química , Neoplasias da Mama/tratamento farmacológico , Extratos Vegetais/farmacologia , Antineoplásicos Fitogênicos/química , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Extratos Vegetais/química
17.
Org Lett ; 21(17): 6663-6667, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31397155

RESUMO

The catalytic reductive transformation of carboxylic esters into α-branched ethers is described. The procedure pivots on the chemoselective iridium-catalyzed hydrosilylation of ester and lactone functionality to afford a silyl acetal intermediate. Upon treatment with a Lewis acid, these hemilabile intermediates dissociate to form reactive oxocarbenium ions, which can be intercepted by allyltributyltin nucleophiles, resulting in the formation of valuable α-branched alkyl-alkyl ether derivatives. This reductive allylation procedure was found to be amenable to a range of carboxylic ester starting materials, and good chemoselectivity for ethyl over tert-butyl esters was demonstrated. Furthermore, downstream synthetic manipulation of α-amino acid-derived products led to the efficient formation of pyrrolidine, piperidine, and azepane frameworks.

18.
Front Pharmacol ; 10: 859, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31427969

RESUMO

The combination of three or more antiviral agents that act on different targets is known as highly active antiretroviral therapy (HAART), which is widely used to control HIV infection. However, because drug resistance and adverse effects occur after long-term administration, an increasing number of HIV/AIDS patients do not tolerate HAART. It is necessary to continue developing novel anti-HIV drugs, particularly HIV entry/fusion inhibitors. Our group previously identified a small-molecule compound, NB-64, with weak anti-HIV activity. Here, we found that N-substituted pyrrole derivative 12m (NSPD-12m), which was derived from NB-64, had strong anti-HIV-1 activity, and NSPD-12m-treated cells showed good viability. The mechanism of action of NSPD-12m might be targeting the gp41 transmembrane subunit of the HIV envelope glycoprotein, thus inhibiting HIV entry. Site-directed mutagenesis confirmed that a positively charged lysine residue (K574) located in the gp41 pocket region is pivotal for the binding of NSPD-12m to gp41. These findings suggest that NSPD-12m can serve as a lead compound to develop novel virus entry inhibitors.

19.
J Transl Med ; 17(1): 220, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291961

RESUMO

BACKGROUND: The influence of DNMT3A R882 mutations on adult acute myeloid leukemia (AML) prognosis is still controversial presently. The influence of R882 allele ratio on drug response and prognosis of AML is unknown yet. Besides, it is obscure whether anthracyclines are involved in chemoresistance resulted from R882 mutations. METHODS: DNMT3A R882 mutations in 870 adult AML patients receiving standard induction therapy were detected by pyrosequencing. Associations of the mutants with responses to induction therapy and disease prognosis were analyzed. RESULTS: DNMT3A R882 mutations were detected in 74 (8.51%) patients and allele ratio of the mutations ranged from 6 to 50% in the cohort. After the first and second courses of induction therapy including aclarubicin, complete remission rates were significantly lower in carriers of the DNMT3A R882 mutants as compared with R882 wildtype patients (P = 0.022 and P = 0.038, respectively). Compared with R882 wild-type patients, those with the R882 mutations showed significantly shorter overall survival (OS) and disease-free survival (DFS) (P = 1.92 × 10-4 and P = 0.004, respectively). Patients with higher allele ratio of R882 mutations showed a significantly shorter OS as compared with the lower allele ratio group (P = 0.035). CONCLUSION: Our results indicate that the impact of DNMT3A R882 mutations on AML prognosis was determined by the mutant-allele ratio and higher allele ratio could predict a worse prognosis, which might improve AML risk stratification. In addition, DNMT3A R882 mutations were associated with an inferior response to induction therapy with aclarubicin in Chinese AML patients.


Assuntos
Alelos , Grupo com Ancestrais do Continente Asiático/genética , DNA (Citosina-5-)-Metiltransferases/genética , Leucemia Mieloide Aguda/genética , Mutação/genética , Adolescente , Adulto , Idoso , Antraciclinas/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Adulto Jovem
20.
R Soc Open Sci ; 6(4): 190142, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31183150

RESUMO

A novel reference film was characterized to improve the oxygen gas transmission measurement accuracy of plastic materials for pharmaceutical packaging. The material processing, homogeneity, stability, jointly determined value and uncertainty evaluation were discussed. The film is the first reference film characterized by multiple laboratories using both manometric and coulometric methods. The oxygen transmission rate of the reference film was 20.53 with the expanded uncertainty of 1.36. The newly characterized reference film can be used in the calibration and self-calibration of oxygen transmission measurement equipment and analytical method verification to improve the measurement accuracy and achieve traceable data.

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