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1.
Metabolism ; 128: 154958, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34958817

RESUMO

BACKGROUND: With metabolic dysfunction-associated fatty liver disease (MAFLD) incidence and prevalence increasing, it is necessary to identify patients with advanced fibrosis (F3-F4 stages). We evaluated the performance of new biomarkers and algorithms for diagnosing advanced fibrosis in an Asian population. METHODS: Data from two Asian cohorts (including 851 biopsy-proven MAFLD [578 from Wenzhou, 273 from Hong Kong]) were studied. The association between N-terminal propeptide of type 3 collagen (PRO-C3) and the histologic stage of liver fibrosis was analyzed by multivariable linear regression. The area under the receiver operating characteristic curve (AUROC) was used to test the diagnostic performance of serum PRO-C3 and the ADAPT score for advanced fibrosis and compared them to other established non-invasive tests. RESULTS: Serum PRO-C3 levels increased progressively across liver fibrosis stages and correlated with advanced fibrosis (P < 0.001). The ADAPT score had an AUROC of 0.865 (95% confidence interval 0.829-0.901) for advanced fibrosis; the accuracy, sensitivity and negative predictive values were 81.4%, 82.2% and 96.1%, respectively. This result was better compared to that of PRO-C3 alone or other non-invasive fibrosis biomarkers (aspartate aminotransferase-to-platelet ratio index, Fibrosis-4, BARD, and NAFLD fibrosis score). In subgroup analyses (including sex, age, diabetes, NAFLD activity score, body mass index or serum alanine aminotransferase levels), the ADAPT score had good diagnostic performance. CONCLUSION: PRO-C3 and the ADAPT score reliably exclude advanced fibrosis in MAFLD patients and reduce the need for liver biopsy.

2.
Bioorg Chem ; 94: 103487, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31831161

RESUMO

Based on the structural characteristics of aztreonam (AZN) and its target PBP3, a series of new monobactam derivatives bearing various substituents on oxime residue were prepared and evaluated for their antibacterial activities against susceptible and resistant Gram-negative bacteria. Among them, compounds 8p and 8r displayed moderate potency with MIC values of 0.125-32 µg/mL against most tested Gram-negative strains, comparable to AZN. Meanwhile, the combination of 8p and 8r with avibactam as a ß-lactamases inhibitor, in a ratio of 1:16, showed a promising synergistic effect against both ESBLs- and NDM-1-producing K. pneumoniae, with significantly reduced MIC values up to 8-fold and >256-fold respectively. Furthermore, both of them demonstrated excellent safety profiles both in vitro and in vivo. The results provided powerful information for further structural optimization of monobactam antibiotics to fight ß-lactamase-producing resistant Gram-negative bacteria.


Assuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Monobactamas/farmacologia , Oximas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Monobactamas/síntese química , Monobactamas/química , Oximas/química , Relação Estrutura-Atividade
3.
Org Biomol Chem ; 16(15): 2639-2642, 2018 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-29611862

RESUMO

An unprecedented and efficient [4 + 3] cycloaddition of N-(ortho-chloromethyl)aryl amides with nitrones has been developed. This approach provides easy access to a series of seven-membered benzooxadiazepine derivatives in good to excellent yields (up to 99% yield) under mild reaction conditions.

4.
Eur J Med Chem ; 149: 45-55, 2018 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-29494844

RESUMO

Preventing filoviruses in the entry stage is an attractive antiviral strategy. Taking aloperine, a Chinese natural herb with an endocyclic skeleton, as the lead, 23 new aloperine derivatives were synthesized and evaluated for their anti-filovirus activities including ebola virus (EBOV) and marburg virus (MARV) using pseudotyped virus model. Structure-activity relationship (SAR) analysis indicated that the introduction of a 12N-dichlorobenzyl group was beneficial for the potency. Compound 2e exhibited the most potent anti-EBOV and anti-MARV effects both in vitro and in vivo. It also displayed a good pharmacokinetic and safety profile in vivo, indicating an ideal druglike feature. The primary mechanism study showed that 2e could block a late stage of viral entry, mainly through inhibiting cysteine cathepsin B activity of host components. We consider compound 2e to be a promising broad-spectrum anti-filovirus agent with the advantages of a unique chemical scaffold and a specific biological mechanism.


Assuntos
Antivirais/farmacologia , Filoviridae/efeitos dos fármacos , Piperidinas/síntese química , Piperidinas/uso terapêutico , Internalização do Vírus/efeitos dos fármacos , Antivirais/síntese química , Catepsina B/antagonistas & inibidores , Clorobenzenos , Humanos , Piperidinas/farmacologia , Quinolizidinas , Relação Estrutura-Atividade
5.
Protoplasma ; 252(4): 1135-48, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25547962

RESUMO

In this paper, we explored the protective effect and physiochemical mechanism of He-Ne laser preillumination in enhancement of tall fescue seedlings tolerance to high salt stress. The results showed that salt stress greatly reduced plant growth, plant height, biomass, leaf development, ascorbate acid (AsA) and glutathione (GSH) concentration, the enzymatic activities, and gene expression levels of antioxidant enzymes such as catalase (CAT) and glutathione reductase (GR) and enhanced hydrogen peroxide (H2O2) content, superoxide radical (O2 (·-)) generation rates, membrane lipid peroxidation, relative electrolyte leakage, the enzymatic activities, and gene expression levels of superoxide dismutase (SOD), ascorbate peroxidase (APX), and peroxidase (POD), compared with controls. However, He-Ne laser preillumination significantly reversed plant growth retardation, biomass loss, and leaves development decay induced by salt stress. And the values of the physiochemical parameters observed in salt-stressed plants were partially reverted or further increased by He-Ne laser. Salt stress had no obvious effect on the transcriptional activity of phytochromeB, whereas He-Ne laser markedly enhanced its transcriptional level. Preillumination with white fluorescent lamps (W), red light (RL) of the same wavelength, or RL, then far-red light (FRL) had not alleviated the inhibitory effect of salt stress on plant growth and antioxidant enzymes activities, suggesting that the effect of He-Ne laser on improved salt tolerance was most likely attributed to the induction of phytochromeB transcription activities by the laser preillumination, but not RL, FRL or other light sources. In addition, we also utilized sodium nitroprusside (SNP) as NO donor to pre-treat tall fescue seedlings at the same conditions, and further evaluated the differences of physiological effects between He-Ne laser and NO in increasing salt resistance of tall fescue. Taken together, our data illustrated that He-Ne laser preillumination contributed to conferring an increased tolerance to salt stress in tall fescue seedlings due to alleviating oxidative damage through scavenging free radicals and inducing transcriptional activities of some genes involved in plant antioxidant system, and the induction of phytochromeB transcriptional level by He-Ne laser was probably correlated with these processes. Moreover, this positive physiochemical effect seemed more effective with He-Ne laser than NO molecule.


Assuntos
Festuca/metabolismo , Festuca/efeitos da radiação , Lasers , Luz , Plântula/metabolismo , Plântula/efeitos da radiação , Antioxidantes/metabolismo , Ascorbato Peroxidases/metabolismo , Ácido Ascórbico/metabolismo , Catalase/metabolismo , Festuca/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Redutase/metabolismo , Peróxido de Hidrogênio/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos da radiação , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Peroxidase/metabolismo , Peroxidases/metabolismo , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/metabolismo , Folhas de Planta/efeitos da radiação , Plântula/efeitos dos fármacos , Cloreto de Sódio/farmacologia , Superóxido Dismutase/metabolismo
6.
ChemMedChem ; 8(9): 1545-53, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23881611

RESUMO

A series of novel N-substituted sophocarpinic acid derivatives was designed, synthesized, and evaluated for their anti-enteroviral activities against coxsackievirus type B3 (CVB3) and coxsackievirus type B6 (CVB6) in Vero cells. Structure-activity relationship analysis revealed that the introduction of a benzenesulfonyl moiety on the 12-nitrogen atom in (E)-ß,γ-sophocarpinic acid might significantly enhance anti-CVB3 activity. Among the derivatives, (E)-12-N-(m-cyanobenzenesulfonyl)-ß,γ-sophocarpinic acid (11 m), possessing a meta-cyanobenzenesulfonyl group, exhibited potent activity against CVB3 with a selectivity index (SI) of 107. Furthermore, compound 11 m also showed a good oral pharmacokinetic profile, with an AUC value of 7.29 µM h⁻¹ in rats, and good safety through the oral route in mice, with an LD50 value of >1000 mg kg⁻¹; these values suggest a druggable characteristic. Therefore, compound 11 m was selected for further investigation as a promising CVB3 inhibitor. We consider (E)-ß,γ-N-(benzenesulfonyl)sophocarpinic acids to be a novel class of anti-CVB3 agents.


Assuntos
Alcaloides/química , Alcaloides/síntese química , Antivirais/farmacologia , Enterovirus Humano B/efeitos dos fármacos , Administração Oral , Alcaloides/farmacocinética , Animais , Antivirais/síntese química , Antivirais/química , Área Sob a Curva , Benzenossulfonatos/química , Chlorocebus aethiops , Feminino , Meia-Vida , Masculino , Camundongos , Curva ROC , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Células Vero
7.
Chem Cent J ; 7(1): 117, 2013 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-23837573

RESUMO

BACKGROUND: The emergence of multi-drug resistant tuberculosis (MDR-TB) has heightened the need for new chemical classes and innovative strategies to tackle TB infections. It is urgent to discover new classes of molecules without cross-resistance with currently used antimycobacterial drugs. RESULTS: Eighteen new 8-substituted protoberberine derivatives were synthesized and evaluated for their anti-mycobacterial activities against Mycobacterium tuberculosis (M. tuberculosis) strain H37Rv. Among them, compound 7g was the most effective antitubercular agent with minimum inhibitory concentration (MIC) of 0.5 µg/mL. Moreover, it also afforded a potent antitubercular effect against clinically isolated MDR strains of M. tuberculosis with MICs ranging from 0.25 to 1.0 µg/mL, suggesting a novel mode of action. CONCLUSIONS: The structure-activity relationship (SAR) analysis revealed that introduction of a substituent at the 8-position in pseudoprotoberberine, especially an n-decyl, could significantly enhance the anti-TB activity. We consider 8-n-decylberberines to be a novel family of anti-tubercular agents with an advantage of inhibiting MDR strains of M. tuberculosis.

8.
Eur J Med Chem ; 52: 151-8, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22503208

RESUMO

Twenty-eight new 13-n-octylberberine derivatives were synthesized and evaluated for their activities against drug-susceptible Mycobacterium tuberculosis (M. tuberculosis) strain H(37)Rv. Among these compounds, compound 16e was the most effective anti-tubercular agent with a MIC value of 0.125 µg/mL. Importantly, compound 16e exhibited more potent effect against rifampicin (RIF)- and isoniazid (INH)-resistant M. tuberculosis strains than both RIF and INH, suggesting a new mechanism of action. Therefore, it has been selected as a drug candidate for further investigation, or as a chemical probe for identifying protein target and studying tuberculosis biology. We consider 13-n-octylberberine analogs to be a promising novel class of antituberculars against multi-drug-resistant (MDR) strains of M. tuberculosis.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Berberina/análogos & derivados , Berberina/síntese química , Berberina/farmacologia , Técnicas de Química Sintética , Mycobacterium tuberculosis/efeitos dos fármacos , Antibacterianos/química , Berberina/química , Farmacorresistência Bacteriana/efeitos dos fármacos , Relação Estrutura-Atividade
9.
Bioorg Med Chem Lett ; 21(19): 5787-90, 2011 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-21880491

RESUMO

Currently, there is no approved antiviral drug for the infection caused by enteroviruses. A series of novel N-arylethyl isoquinoline derivatives defined with substituents on the ring A and C were designed, synthesized and evaluated in vitro for their activities against Coxsackievirus B3 (CVB3). The primary structure-activity relationship revealed that substituents on the ring A were not beneficial for the activity. Among these analogs synthesized, compound 7f bearing a methylenedioxy at the R(4) and R(5) positions afforded an anti-CVB3 activity and a reasonable selectivity index (SI=26.8); furthermore, 7f exhibited a moderate activity against enterovirus 71 (EV71) with SI value of 9.0. Thus it has been selected as an anti-enteroviral lead compound for further investigation.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Desenho de Fármacos , Enterovirus Humano B/efeitos dos fármacos , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Animais , Antivirais/química , Chlorocebus aethiops , Enterovirus Humano B/fisiologia , Concentração Inibidora 50 , Isoquinolinas/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Células Vero , Replicação Viral/efeitos dos fármacos
10.
Bioorg Med Chem Lett ; 21(16): 4732-5, 2011 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-21757347

RESUMO

Oxymatrine (1) is a natural anti-hepatitis B virus (HBV) drug that down-regulates host heat-stress cognate 70 (Hsc70) expression through a mechanism different from that of nucleosides. Taking Hsc70 as a target against HBV, 26 novel N-substituted matrinic acid analogs were designed, synthesized and evaluated for their regulation of Hsc70 mRNA expression with 1 as the lead. The SAR analysis revealed that (i) the carboxyl group at the 11-position was required for activity; (ii) introducing of a substituent on the nitrogen atom at the 12-position of 3, especially substituted benzyl, might significantly improve the activity. Among these analogs, compound 9p possessing N-p-methoxylbenzyl afforded an increased anti-HBV effect in comparison with 1. We consider 9p a promising anti-HBV candidate.


Assuntos
Antibacterianos/farmacologia , Butiratos/farmacologia , Proteínas de Choque Térmico HSC70/antagonistas & inibidores , Quinolizinas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Butiratos/síntese química , Butiratos/química , Regulação para Baixo/efeitos dos fármacos , Proteínas de Choque Térmico HSC70/metabolismo , Hepacivirus/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , Conformação Molecular , Quinolizinas/síntese química , Quinolizinas/química , RNA Mensageiro/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade
11.
J Med Chem ; 54(3): 869-76, 2011 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-21218816

RESUMO

Heat-stress cognate 70 (Hsc70) is a host protein required for hepatitis B virus (HBV) replication, and oxymatrine (1) suppresses Hsc70 expression. Taking Hsc70 as a target against HBV, 22 analogues of 1 defined with substituents at position 1, 13, or 14 were synthesized and evaluated for their activity on Hsc70 mRNA expression. The SAR revealed that (i) the oxygen atom at the 1-position was not essential, (ii) increasing electron density on the ring D reduced the activity, and (iii) introducing a proper substituent at the 13- and/or 14-position(s), especially electron-withdrawing groups, might enhance the activity. Among the analogues, 6b possessing 13-ethoxyl afforded an increased activity in respect to 1. Importantly, it was active for either wild-type or lamivudine-resistant HBV, as its target is host Hsc70 but not viral enzymes. LD(50) of 6b in mice was over 750 mg/kg in oral route. We consider compound 6b promising for further investigation.


Assuntos
Alcaloides/síntese química , Antivirais/síntese química , Farmacorresistência Viral , Proteínas de Choque Térmico HSC70/metabolismo , Vírus da Hepatite B/efeitos dos fármacos , Quinolizinas/síntese química , Administração Oral , Alcaloides/química , Alcaloides/farmacologia , Animais , Antivirais/química , Antivirais/farmacologia , Regulação para Baixo , Desenho de Fármacos , Proteínas de Choque Térmico HSC70/genética , Células Hep G2 , Vírus da Hepatite B/metabolismo , Humanos , Lamivudina/farmacologia , Dose Letal Mediana , Camundongos , Conformação Molecular , Quinolizinas/química , Quinolizinas/farmacologia , RNA Mensageiro/metabolismo , Relação Estrutura-Atividade
13.
Hepatology ; 52(3): 845-53, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20593456

RESUMO

UNLABELLED: Host heat shock cognate 70 (Hsc70) protein is packaged into hepatitis C viral (HCV) particles as a structural component of the virus in the assembly process. It helps HCV RNA release into the cytoplasm in the next infection cycle. The goal of this study is to investigate whether chemically down-regulating host Hsc70 expression could be a novel strategy to interrupt HCV replication. Compounds were screened with an Hsc70 messenger RNA (mRNA) assay. IMB-DM122 was found to be an effective and safe inhibitor for Hsc70 mRNA/protein expression in human hepatocytes. IMB-DM122 inhibited HCV replication through destabilization of Hsc70 mRNA, and the half-life of host Hsc70 mRNA was reduced by 78% after the compound treatment. The Hsc70 mRNA 3' untranslated region sequence is the element responsible for the effect of IMB-DM122 on Hsc70 mRNA. The compound appears to be highly efficient in inhibiting Hsc70-related HCV replication. Treatment of the HCV-infected hepatocytes with IMB-DM122 reduced the virion encapsidation of Hsc70, and therefore disrupted HCV replication and the infection cycle. IMB-DM122 showed considerable good safety in vitro as well as in vivo with no indication of harmful effect on liver and kidney functions. CONCLUSION: Hsc70 might be a new drug target and mechanism to inhibit HCV proliferation.


Assuntos
Proteínas de Choque Térmico HSC70/genética , Hepacivirus/fisiologia , RNA Mensageiro/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Feminino , Proteínas de Choque Térmico HSC70/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/virologia , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos , Modelos Animais , Naftiridinas/farmacologia , RNA Mensageiro/metabolismo
14.
Yao Xue Xue Bao ; 45(4): 462-6, 2010 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-21355210

RESUMO

Ten pharmacophore models of beta-tubulin inhibitors were established from the training set of seventeen beta-tubulin inhibitors (two categories) with comformer analysis by using the Catalyst software. The optimal pharmacophore model with two hydrophobic units and two hydrogen bond acceptor units were confirmed (RMS = 0.43, Correl = 0.98, Weight = 2.06, Config = 15.97). This pharmacophore model is able to predict the activity of known beta-tubulin inhibitors and can be further used to identify structurally diverse compounds with higher activity.


Assuntos
Benzamidas/química , Moduladores de Tubulina/química , Ureia/análogos & derivados , Desenho Assistido por Computador , Desenho de Fármacos , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Software , Relação Estrutura-Atividade , Ureia/química
15.
J Med Chem ; 52(2): 492-501, 2009 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-19090767

RESUMO

Twenty-nine derivatives of berberine (1) or pseudoberberine (2) were designed, semisynthesized, and evaluated for their up-regulatory activity on the low-density-lipoprotein receptor (LDLR) expression. SAR analysis revealed that (i) the methylenedioxy group at the 2- and 3-position is an essential element to keep the activity, (ii) the 7-position quaternary ammonium and planar structure of the compound are activity-required, and (iii) addition of electron-donating groups at the 7- or 13-position reduced the activity. Of the compound 1 analogues, compound 2 exhibited an increased activity on LDLR expression compared to 1. In the hyperlipidemic rats, compound 2 (100 (mg/kg)/day) reduced blood CHO and LDL-c by 42.6% and 49.4%, respectively, more efficient than 1 did (p < 0.01 for both). The results were confirmed in the hyperlipidemic mice. LD(50) of 2 in mice was over 5000 mg/kg (oral). We consider compound 2 a promising cholesterol-lowering drug candidate.


Assuntos
Berberina/análogos & derivados , Colesterol/sangue , Receptores de LDL/fisiologia , Regulação para Cima/efeitos dos fármacos , Animais , Berberina/farmacologia , Berberina/uso terapêutico , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Hipercolesterolemia/tratamento farmacológico , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , RNA Mensageiro/genética , Ratos , Receptores de LDL/genética , Relação Estrutura-Atividade
16.
Bioorg Med Chem Lett ; 18(16): 4675-7, 2008 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-18644725

RESUMO

Berberine (BBR, 1) is a novel cholesterol-lowering agent that up-regulates low-density-lipoprotein receptor (LDLR) expression through a mechanism different from that of statins. Because of the unique mode of action and good safety record, BBR provoked our interest to do structure modification at different domains for its cholesterol-lowering activity. Nineteen BBR analogues with substituents on the benzene ring D were synthesized in the present study. The analysis of structure-activity relationship (SAR) indicated that the two methoxyl groups in an ortho-distribution on this benzene ring afforded a good activity. Among the 19 analogues, compound 8j bearing a methoxyl at both 10- and 11-position showed an increased LDLR up-regulatory activity in respect to BBR, and therefore has been selected as a promising cholesterol-lowering drug candidate for further evaluation.


Assuntos
Berberina/análogos & derivados , Berberina/síntese química , Química Farmacêutica/métodos , Receptores de LDL/biossíntese , Regulação para Cima , Benzeno , Desenho de Fármacos , Humanos , Hipercolesterolemia/tratamento farmacológico , Íons , Lipídeos , Modelos Químicos , Estabilidade de RNA/efeitos dos fármacos , Receptores de LDL/antagonistas & inibidores , Eletricidade Estática , Relação Estrutura-Atividade
17.
J Med Chem ; 51(11): 3094-103, 2008 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-18457382

RESUMO

Forty-six new compounds were synthesized on the basis of our knowledge of the 3-haloacylamino benzoylurea (HBU) series. Structure-activity relationship (SAR) analysis indicates that (i) the configuration of the chiral center in 1 (JIMB01) is not indispensable for the activity, (ii) the phenyl ring is essential, and (iii) a substitution at the 6-position of the phenyl ring with a halogen enhances the activity. Among the analogues, 11e and 14b bearing 6-fluoro substitution showed potent activities against nine human tumor cell lines, including CEM (leukemia), Daudi (lymphoma), MCF-7 (breast cancer), Bel-7402 (hepatoma), DU-145 (prostate cancer), PC-3 (prostate cancer), DND-1A(melanoma), LOVO (colon cancer), and MIA Paca (pancreatic cancer) with IC 50 values between 0.01 and 0.30 microM. 14b inhibited human hepatocarcinoma by 86% in volume in nude mice. The mechanism of 14b is to inhibit microtubule assembly, followed by the M-phase arrest, bcl-2 inactivation, and then apoptosis. We consider 14b promising for further anticancer investigation.


Assuntos
Acetanilidas/síntese química , Antimitóticos/síntese química , Ureia/análogos & derivados , Acetanilidas/química , Acetanilidas/farmacologia , Animais , Antimitóticos/química , Antimitóticos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Estereoisomerismo , Relação Estrutura-Atividade , Transplante Heterólogo , Ureia/síntese química , Ureia/química , Ureia/farmacologia
19.
Yao Xue Xue Bao ; 40(12): 1122-6, 2005 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-16496677

RESUMO

AIM: To design and synthesize new compounds of prandial glucose regulator with more simple structure. METHODS: The target compounds were synthesized from diethyl succinate and benzaldehyde or 4-fluorobenzaldehyde by four-step reactions. Thus 18 compounds were synthesized. Their structures were comfirmed by NMR, MS and IR. RESULTS: Seventeen compounds had different hypoglycemic activity in mice, among them, 9 compounds had higher hypoglycemic activity and 6 compounds had character of prandial glucose regulator. CONCLUSION: Part of the compounds have higher hypoglycemic activity deserve to be further investigated.


Assuntos
Compostos de Benzilideno/síntese química , Hipoglicemiantes/síntese química , Succinatos/síntese química , Animais , Compostos de Benzilideno/química , Compostos de Benzilideno/farmacologia , Glicemia/metabolismo , Carbamatos/síntese química , Carbamatos/química , Cicloexanos/síntese química , Cicloexanos/química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Indóis/síntese química , Indóis/química , Isoindóis , Camundongos , Estrutura Molecular , Nateglinida , Fenilalanina/análogos & derivados , Fenilalanina/síntese química , Fenilalanina/química , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade , Succinatos/química , Succinatos/farmacologia
20.
Sheng Wu Gong Cheng Xue Bao ; 20(1): 120-5, 2004 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-16108502

RESUMO

Direct DNA delivery procedures (include biolistics method) often resulted in multiple copies of the transgenes in transformants and certain copies of them were rearranged. Integration of multiple copies of the introduced genes was the main reason of gene silencing which meant inhibition or loss of foreign gene expression in filial generations of transformants. In the present work, we compared the influences of maize Ubi-1 promoter and other promoters on copy number of transgenes in maize transgenic plants. Immature embryos from Zea mays L. plants of sib-pollinated of A188 x H99 genotype were used as initial materials. Type- I embryonic calluses derived from preculture of immature embryos were treated on N6 medium containing 0.6 mol/L sucrose for 3 approximately 5 hours and transformed via particle bombardment with PDS1000/He delivery system (Bio-Rad). Bombarded calluses were treated with hyperosmotic N6 medium for 16 approximately 20 hours continuously. Then the cultures were transferred onto normal N6 medium and incubated at 26 degrees C in dark for two weeks and subsequently selected on N6 medium supplemented with 2 or 5 mg/L phosphinothricin (PPT) but without casamino acid for another two weeks. The calluses after selective culture were transferred onto hormone-free MS medium containing 2 or 5 mg/L PPT but without casamino acid, and incubated at 24 degrees C under 16 h illumination for plant regeneration. Regenerated plantlets over 2 cm in height were transferred to Magenta box containing 1/2 hormone-free MS medium. Plantlets over 8 cm in height were transplanted to soil. After growing for one week in greenhouse, the plants were sprayed with 250 mg/L PPT solution. Fertile transgenic maize plants were regenerated and confirmed by Southern blotting and histochemical localization of beta-glucuronidase (GUS) activity. Relations between promoter and copy number of transgenes in transformants were analyzed. Maize transgenic plants possessing an intact copy and another incomplete copy of beta-glucuronidase gene (gus) were obtained in case gus gene under the control of maize Ubi-1 promoter (pUbi:GUS). Simultaneously the co-transformed phosphinothricin acetyltransferase gene (bar) controlled by CaMV 35S promoter in another plasmid (p35S:BAR) also existed with only one copy. When pDB1 and (pUbi:in2) were cobombarded, the regenerated transgenic maize plant exhibited with only one copy of in2 gene too. It suggested that the copy number of transgenes in maize transformants was low if the transgenes controlled by maize Ubi-1 promoter. The possible reason might be that the foreign genes were integrated site-specifically via homologous recombination between Ubi-1 promoter and its endogenous sequences in maize genome, and two cotransformed plasmids had reconstructed as one intact molecule before integrating into maize chromosome. On the contrary, if p35S:BAR was cobom-barded with plasmid pAct:In1 containing rice Act-1 promoter (without maize Ubi-1 promoter), the transgenic maize plants had 4 approximately 8 copies of bar gene. These results reflected that utilization of self gene promoter could reduce the copy number of the transgenes in transgenic plants of certain species itself and avoid the occurrence of gene silencing. T2 seeds have been harvested.


Assuntos
Dosagem de Genes , Proteínas de Plantas/genética , Plantas Geneticamente Modificadas/genética , Regiões Promotoras Genéticas , Ubiquitina C/genética , Zea mays/genética
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