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1.
Acta Pharmacol Sin ; 45(10): 2119-2133, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38811775

RESUMEN

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the epidermal growth factor precursor homologous domain A (EGF-A) of low-density lipoprotein receptor (LDLR) in the liver and triggers the degradation of LDLR via the lysosomal pathway, consequently leading to an elevation in plasma LDL-C levels. Inhibiting PCSK9 prolongs the lifespan of LDLR and maintains cholesterol homeostasis in the body. Thus, PCSK9 is an innovative pharmacological target for treating hypercholesterolemia and atherosclerosis. In this study, we discovered that E28362 was a novel small-molecule PCSK9 inhibitor by conducting a virtual screening of a library containing 40,000 compounds. E28362 (5, 10, 20 µM) dose-dependently increased the protein levels of LDLR in both total protein and the membrane fraction in both HepG2 and AML12 cells, and enhanced the uptake of DiI-LDL in AML12 cells. MTT assay showed that E28362 up to 80 µM had no obvious toxicity in HepG2, AML12, and HEK293a cells. The effects of E28362 on hyperlipidemia and atherosclerosis were evaluated in three different animal models. In high-fat diet-fed golden hamsters, administration of E28362 (6.7, 20, 60 mg·kg-1·d-1, i.g.) for 4 weeks significantly reduced plasma total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and PCSK9 levels, and reduced liver TC and TG contents. In Western diet-fed ApoE-/- mice (20, 60 mg·kg-1·d-1, i.g.) and human PCSK9 D374Y overexpression mice (60 mg·kg-1·d-1, i.g.), administration of E28362 for 12 weeks significantly decreased plasma LDL-C levels and the area of atherosclerotic lesions in en face aortas and aortic roots. Moreover, E28362 significantly increased the protein expression level of LDLR in the liver. We revealed that E28362 selectively bound to PCSK9 in HepG2 and AML12 cells, blocked the interaction between LDLR and PCSK9, and induced the degradation of PCSK9 through the ubiquitin-proteasome pathway, which finally resulted in increased LDLR protein levels. In conclusion, E28362 can block the interaction between PCSK9 and LDLR, induce the degradation of PCSK9, increase LDLR protein levels, and alleviate hyperlipidemia and atherosclerosis in three distinct animal models, suggesting that E28362 is a promising lead compound for the treatment of hyperlipidemia and atherosclerosis.


Asunto(s)
Aterosclerosis , Hiperlipidemias , Inhibidores de PCSK9 , Proproteína Convertasa 9 , Receptores de LDL , Animales , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Humanos , Hiperlipidemias/tratamiento farmacológico , Hiperlipidemias/metabolismo , Proproteína Convertasa 9/metabolismo , Receptores de LDL/metabolismo , Masculino , Células Hep G2 , Ratones , Células HEK293 , Ratones Endogámicos C57BL , Mesocricetus , Dieta Alta en Grasa , Cricetinae
2.
J Asian Nat Prod Res ; 25(8): 796-802, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36272140

RESUMEN

In this paper, we present the discovery of a novel salicylic acid derivative, moldavica acid A (1), and a new natural dibenzo[b,f]oxepin, moldavica acid B (2), together with four known phenylpropionic acids (3-6) and protocatechuic acid (7) that were isolated from Dracocephalum moldavica L. Their structures were elucidated by comprehensive spectroscopic methods, including infrared and nuclear magnetic resonance. Compound 1 is the first example of salicylic acid linking a carboxylated α-pyrone via an ethyl bridge. Beyond expanding the knowledge of the chemical diversity of D. moldavica, both compounds 1 and 2 were shown to upregulate the expression of Kruppel-like factor 2, which could serve as a prospective therapeutic target for the treatment of atherosclerosis.

3.
J Exp Bot ; 73(10): 3205-3220, 2022 05 23.
Artículo en Inglés | MEDLINE | ID: mdl-34758079

RESUMEN

Whether photosynthesis has improved with increasing yield in major crops remains controversial. Research in this area has often neglected to account for differences in light intensity experienced by cultivars released in different years. Light intensity is expected to be positively associated with photosynthetic capacity and the resistance of the photosynthetic apparatus to high light but negatively associated with light-utilization efficiency under low light. Here, we analyzed the light environment, photosynthetic activity, and protein components of leaves of 26 winter wheat cultivars released during the past 60 years in China. Over time, light levels on flag leaves significantly decreased due to architectural changes, but photosynthetic rates under high or low light and the resistance of the photosynthetic apparatus to high light remained steady, contrary to expectations. We propose that the difference between the actual and expected trends is due to breeding. Specifically, breeding has optimized photosynthetic performance under high light rather than low light. Moreover, breeding selectivity altered the stoichiometry of several proteins related to dynamic photosynthesis, canopy light distribution, and photoprotection. These results indicate that breeding has significantly altered the photosynthetic mechanism in wheat and its response to the light environment. These changes likely have helped increase wheat yields.


Asunto(s)
Fitomejoramiento , Triticum , Luz , Fotosíntesis/fisiología , Hojas de la Planta/fisiología , Triticum/metabolismo
4.
Yao Xue Xue Bao ; 51(4): 563-72, 2016 04.
Artículo en Zh | MEDLINE | ID: mdl-29859525

RESUMEN

This study was designed to identify inducers of ATP-binding cassette transporter A1(ABCA1) and CD36 and lysosomal integral membrane protein-II analogous-1(CLA-1) and to evaluate the in vitro effect of the active compound on lipid metabolism. Among 20 000 compounds screened, E23869 was found as a positive hit using cell-based high throughput screening models. The up-regulating activities of E23869 in ABCA1p-LUC and CLA-1p-LUC Hep G2 cells were 196% and 198%, respectively. The EC(50) values of E23869 in ABCA1p- LUC and CLA-1p-LUC Hep G2 cells were 0.25 µmol·L(-1) and 0.66 µmol·L(-1), respectively. E23869 significantly upregulated the protein levels of ABCA1, scavenger receptor class B type I(SR-BI)/CLA-1 and ATP-binding cassette transporter G1(ABCG1) in both macrophages RAW264.7 and L02 cells by Western blotting analysis. Foam cell assay showed that E23869 inhibited lipids accumulations in macrophages RAW264.7. Cholesterol efflux assay showed that E23869 induced HDL-mediated cholesterol efflux in macrophages RAW264.7. Moreover, E23869 up-regulated ABCA1, SR-BI/CLA-1 and ABCG1 expressions through activation of PPARα and PPARγ. In addition, E23869 weakly promoted in vitro differentiation of mouse preadipocytes 3T3-L1. In conclusion, E23869 up-regulated ABCA1, SR-BI/CLA-1 and ABCG1 expressions to promote cholesterol efflux, which is a good leading compound for regulation of lipid metabolism.


Asunto(s)
Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Receptores Depuradores de Clase B/metabolismo , Animales , Transporte Biológico , Antígenos CD36 , Línea Celular , Colesterol/metabolismo , Células Espumosas/efectos de los fármacos , Células Hep G2 , Humanos , Macrófagos/efectos de los fármacos , Ratones , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Células RAW 264.7 , Activación Transcripcional , Regulación hacia Arriba
5.
J Asian Nat Prod Res ; 17(6): 676-82, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25977996

RESUMEN

A new trichostatin analog (1) and two known analogs (2, 3) have been isolated from the rice fermentation of the Streptomyces sp. CPCC 203909. Their structures were determined by spectroscopic and chemical methods. The absolute configurations of 1 were assigned by Marfey's method, combined with comparing the NMR and circular dichroism spectroscopic data of 2 and 3. Compound 1 showed cytotoxicity against human embryonic kidney 293 cell line with IC50 value of 39.2 µM.


Asunto(s)
Ácidos Hidroxámicos/aislamiento & purificación , Streptomyces/química , Fermentación , Humanos , Ácidos Hidroxámicos/química , Concentración 50 Inhibidora , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular
6.
Yao Xue Xue Bao ; 50(4): 440-6, 2015 Apr.
Artículo en Zh | MEDLINE | ID: mdl-26223125

RESUMEN

ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-BI/CLA-1) are the key proteins in reverse cholesterol transport (RCT). The high expression of ABCA1 and SR-BI/CLA-1 can decrease the danger of atherosclerosis. The purpose of the study is to find ABCA1 and CLA-1up-regulators for treating atherosclerosis by using cell-based high throughput screening models. Among 20 000 compounds screened, E0869 [1-(3, 4-dimethylphenyl)-1-oxopropan-2-yll4-((methylsulfonyl)methyl)benzoate] was found as the positive hit. The up-regulated activities of E0869 in ABCAl1-LUC and bCA-l1-LUC HepG2 cell were 160% and 175%, respectively. The EC50 values of E0869 in ABCAl1-LUC and CLA-l1-LUC HepG2 cell were 3.79 and 1.42 pµol- x ,(-1) respectively. E0869 could upregulate the mRNA and protein levels of ABCA1, SR-BI/CLA-1 and ABCGJ1genes in HepG2 and RAW264.7 cells by Real-Time Quantitative PCR and Western blotting analysis, but could not influence the expression of FAS, SREBP-l1 and CD36. Foam cell assay showed that E0869 could inhibit lipids accumulation in mouse peritoneal macrophages RAW264.7. Cholesterol efflux assay showed that E0869 could induce HDL-mediated cholesterol efflux in mouse peritoneal macrophages RAW264.7. In conclusion, E0869 could up-regulate ABCA1 and CLA-1 activity, and had good anti-atherosclerotic activity in vitro.


Asunto(s)
Transportador 1 de Casete de Unión a ATP/metabolismo , Aterosclerosis/tratamiento farmacológico , Receptores Depuradores de Clase B/metabolismo , Animales , Transporte Biológico , Colesterol , Células Hep G2 , Ensayos Analíticos de Alto Rendimiento , Humanos , Macrófagos Peritoneales/efectos de los fármacos , Ratones , ARN Mensajero , Regulación hacia Arriba
7.
Zhongguo Zhong Yao Za Zhi ; 40(9): 1751-4, 2015 May.
Artículo en Zh | MEDLINE | ID: mdl-26323142

RESUMEN

By using a cell-based high throughput screening model for the CLA-1 up-regulator, Streptomyces 203909 was found to produce up-regulator of CLA-1. A novel trichostatin analogue was isolated from the rice fermentation of Streptomyces sp. CPCC 203909by a combination of various chromatographic techniques including column chromatography (CC) over silica gel, flash C18 CC, and reversed-phase HPLC. Its structure was identified as (-)-(R,2E,4Z)-7-[(4'-dimethylamino) phenyl]-4,6-dimethyl-7-oxohepta-2,4-dienoyl-L-glutamine (1) by the spectroscopic and chemical methods, and combination with the CD spectroscopy and Marfey's method. In the prelimi- nary assays, Compound 1 showed cytotoxicity against human embryonic kidney 293 cell line with IC50 value 35.3 [µmol · L(-1).


Asunto(s)
Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/metabolismo , Streptomyces/metabolismo , Supervivencia Celular/efectos de los fármacos , Fermentación , Células Hep G2 , Humanos , Ácidos Hidroxámicos/aislamiento & purificación , Ácidos Hidroxámicos/farmacología , Estructura Molecular , Streptomyces/química
8.
Yao Xue Xue Bao ; 49(5): 602-7, 2014 May.
Artículo en Zh | MEDLINE | ID: mdl-25151728

RESUMEN

In the previous study, a high-throughput screening method was established to find the antagonists of CD36. In the present study, a new compound named IMB-1680 was found using this method. The anti-atherosclerotic activities of IMB-1680 were then evaluated. Dose-dependent activities of IMB-1680 were detected by using Sf9 [hCD36] and CHO [hCD36] models. Fluorescence microscopic photography and flow cytometry were used to analyze uptake of mLDL. Foam cell test with RAW264.7 macrophages was used to examine lipid accumulation. The results showed that IMB-1680 inhibited CD36 activity with IC50 of 2.80 and 8.79 micromol x L(-1) in Sf9[hCD36] and CHO [hCD36] cells, respectively. Fluorescence microscopic photography and flow cytometry revealed that IMB-1680 could significantly reduce DiI-AcLDL uptake. Meanwhile, IMB-1680 also could reduce lipids accumulation in RAW264.7 macrophages. In all, the data indicated that IMB-1680 might be a potent effective anti-atherosclerotic leading compound.


Asunto(s)
Antígenos CD36/antagonistas & inhibidores , Antígenos CD36/metabolismo , Lipoproteínas LDL/metabolismo , Receptores Depuradores/antagonistas & inhibidores , Animales , Antígenos CD36/genética , Células CHO , Células Cultivadas , Cricetulus , Relación Dosis-Respuesta a Droga , Células Espumosas/citología , Ensayos Analíticos de Alto Rendimiento , Humanos , Macrófagos/citología , Macrófagos/metabolismo , Ratones , Estructura Molecular , Plásmidos , Células Sf9 , Spodoptera , Transfección
9.
Yao Xue Xue Bao ; 47(4): 446-51, 2012 Apr.
Artículo en Zh | MEDLINE | ID: mdl-22799025

RESUMEN

ATP-binding cassette transporter A1 (ABCA1) promotes cholesterol and phospholipid efflux from cells to lipid-poor apolipoprotein A-I (apoA-I), and plays a key role in the initial steps of the whole process of reverse cholesterol transport (RCT). Upregulation of ABCA1 is beneficial for atherosclerosis (AS) prevention and/or therapy, which indicated that ABCA1 was a target for anti-AS drug development. In the previous study, a high-throughput screening method was established using ABCA1p-LUC HepG2 cell line to find the upregulators of ABCA1. In the present study, compound 2030421B was found using this method, with EC50 of 0.50 microg x mL(-1). The compound was further identified as an upregulator of ABCA1 expression by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting analysis. Studies also showed that the 2030421B could induce apoA-I-mediated cholesterol efflux and inhibit lipids uptake into mouse peritoneal macrophages RAW264.7.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Anticolesterolemiantes/farmacología , Apolipoproteína A-I/metabolismo , Benzaldehídos/farmacología , Colesterol/metabolismo , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/genética , Animales , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/química , Benzaldehídos/administración & dosificación , Benzaldehídos/química , Transporte Biológico , Células Cultivadas , Relación Dosis-Respuesta a Droga , Células Hep G2 , Ensayos Analíticos de Alto Rendimiento , Humanos , Metabolismo de los Lípidos , Lípidos/análisis , Macrófagos Peritoneales/citología , Macrófagos Peritoneales/metabolismo , Ratones , Estructura Molecular , ARN Mensajero , Regulación hacia Arriba/efectos de los fármacos
10.
Yao Xue Xue Bao ; 45(9): 1128-33, 2010 Sep.
Artículo en Zh | MEDLINE | ID: mdl-21351569

RESUMEN

Scavenger receptor CD36 could bind and endocytose oxLDL into macrophages which were then differentiated into foam cells that constitute the atherosclerotic lesion core, and was considered to be a potential target to treat atherosclerosis. In the establishment of the compound library of berberine (BBR, 1) analogues, we discovered that 13-hexylberberine (2) showed an antagonistic activity against CD36. Taking 2 as the lead compound, 21 derivatives were synthesized and their antagonistic activities were evaluated via an ELISA-like high-throughput screening (HTS) model. The primary structure-activity relationships were studied. It was indicated that the introduction of suitable groups at the 2- and 3-position of the aromatic ring A or at the 9-position of the aromatic ring D could enhance the activity. Among the 21 studied compounds, 7g bearing a benzyloxyl group at the 9-position provided a highest CD36 antagonistic activity with the IC50 value of 7.7 micromol L(-1). Besides, its antagonistic activity was further verified with Sf9 insect cell HTS model. So berberine analogues are a new family of CD36 receptor antagonists and worthy to be studied further.


Asunto(s)
Berberina/análogos & derivados , Berberina/síntesis química , Antígenos CD36/metabolismo , Receptores Depuradores/antagonistas & inhibidores , Animales , Berberina/química , Berberina/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Ensayo de Inmunoadsorción Enzimática , Ensayos Analíticos de Alto Rendimiento , Spodoptera/citología , Spodoptera/virología , Relación Estructura-Actividad
11.
Int J Clin Exp Pathol ; 13(12): 3044-3051, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33425105

RESUMEN

Chemotherapy treatment of acute myeloid leukemia (AML) can be compromised due to the multidrug resistance (MDR) of leukemia cells. HOTAIR, a long noncoding RNA (LncRNA), is involved in MDR development of various solid tumors. However, whether it functions in MDR development of leukemia remains unclear. In this study, expressions of HOTAIR in leukemia cell line K562/A02 and bone marrow samples from 10 patients with refractory and relapsed AML were detected by qRT-PCR. The apoptosis, proliferation, and susceptibility of K562/A02 cells to Adriamycin (ADR) were analyzed by flow cytometry and CCK8 assay, respectively. The expression of cell cycle regulator P21 and Notch1 in the K562/A02 cells was examined by qRT-PCR. The accumulation of total AKT and the phosphorylated AKT (pAKTS473) were detected by western blotting. We found that the expression of HOTAIR in drug-resistant cells and patient samples was increased. Inhibition of HOTAIR expression could suppress the proliferation, increase the apoptosis, and promote the doxorubicin sensitivity of K562/A02 cells. Moreover, inhibiting expression of HOTAIR could attenuate the expression of P21 and Notch1 and inhibit the phosphorylation of AKT in drug-resistant cells. In conclusion, our results demonstrated that LncRNA-HOTAIR is involved in MDR development of leukemia cells by regulating the expression of P21 and the AKT/Notch1 signaling pathway.

12.
SLAS Discov ; 25(4): 397-408, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31858876

RESUMEN

Atherosclerosis is the pathological basis of most cardiovascular diseases. Reverse cholesterol transport (RCT) is a main mechanism of cholesterol homeostasis and involves the direct transport of high-density lipoprotein (HDL) cholesteryl ester by selective cholesterol uptake. Hepatic scavenger receptor class B member 1 (SR-BI) overexpression can effectively promote RCT and reduce atherosclerosis. SR-BI may be an important target for prevention or treatment of atherosclerotic disease. In our study, we inserted human SR-BI mRNA 3' untranslated region (3'UTR) downstream of the luciferase reporter gene, to establish a high-throughput screening model based on stably transfected HepG2 cells and to screen small-molecule compounds that can significantly enhance the mRNA stability of the SR-BI gene. Through multiple screenings of 25 755 compounds, the top five active compounds that have similar structures were obtained, with a positive rate of 0.19%. The five positive compounds could enhance the SR-BI expression and uptake of DiI-HDL in the hepatocyte HepG2. E238B-63 could also effectively extend the half-life of SR-BI mRNA and enhance the SR-BI mRNA and protein level and the uptake of DiI-HDL in hepatocytes in a time-dependent and dose-dependent manner. The structure-activity relationship analysis showed that the structure N-(3-hydroxy-2-pyridyl) carboxamide is possibly the key pharmacophore of the active compound, providing reference for acquiring candidate compounds with better activity. The positive small molecular compounds obtained in this study might become new drug candidates or lead compounds for the treatment of cardiovascular diseases and contribute to the further study of the posttranscriptional regulation mechanism of the SR-BI gene.


Asunto(s)
Aterosclerosis/tratamiento farmacológico , Ensayos Analíticos de Alto Rendimiento , Receptores Depuradores de Clase B/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Aterosclerosis/genética , Aterosclerosis/metabolismo , Ésteres del Colesterol/genética , Ésteres del Colesterol/metabolismo , HDL-Colesterol/genética , Células Hep G2 , Hepatocitos/metabolismo , Humanos , Lipoproteínas HDL/genética , Lipoproteínas HDL/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Estabilidad Proteica/efectos de los fármacos , Receptores Depuradores de Clase B/genética
13.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 25(2): 471-475, 2017 Apr.
Artículo en Zh | MEDLINE | ID: mdl-28446295

RESUMEN

OBJECTIVE: To investigate the diagnostic value of circulating serum miRNA for multiple myeloma. METHODS: Forty blood samples from patients with multiple myeloma were collected from July 2013 to June 2014 in Department of Hematology, Zhongshan Hospital Affiliated to Xiamen University. The real-time quantitative PCR was performed to detect the serum expression levels of miRNAs (miR-29a, miR-155, miR-16 and miR-92a) circulating in the different stages of patients with multiple myeloma and evaluate the diagnostic value for patients with multiple myeloma. RESULTS: The serum level of miR-29a significantly increased in newly diagnosed patients as compared to healthy donor (P<0.01), serum miR-155 levels were significantly lower as compared with healthy donor(P<0.001); The ratio of miR-29a and miR-155 was an effective biomarker for distinguishing multiple myeloma from healthy donor, their sensitivity and specificity were 80.8% and 83.3% respectively for myeloma diagnosis. the change of miR-29a expression was consistent with the changes of bone marrow plasma cells and M protein levels. CONCLUSION: These circulating serum microRNA, such as miR-29a, miR-155 and miR-16, may serve as potential diagnostic biomarkers for multiple myeloma, and the ratio of miR-29a/miR-155 may serve as a most useful biomarker for myeloma diagnosis.


Asunto(s)
Biomarcadores de Tumor/sangre , MicroARN Circulante/sangre , Mieloma Múltiple/diagnóstico , Biomarcadores , Neoplasias Colorrectales , Humanos , MicroARNs
14.
Clin Cancer Res ; 23(8): 2038-2049, 2017 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-27683179

RESUMEN

Purpose: Antiproliferative, antiviral, and immunomodulatory activities of endogenous type I IFNs (IFN1) prompt the design of recombinant IFN1 for therapeutic purposes. However, most of the designed IFNs exhibited suboptimal therapeutic efficacies against solid tumors. Here, we report evaluation of the in vitro and in vivo antitumorigenic activities of a novel recombinant IFN termed sIFN-I.Experimental Design: We compared primary and tertiary structures of sIFN-I with its parental human IFNα-2b, as well as affinities of these ligands for IFN1 receptor chains and pharmacokinetics. These IFN1 species were also compared for their ability to induce JAK-STAT signaling and expression of the IFN1-stimulated genes and to elicit antitumorigenic effects. Effects of sIFN-I on tumor angiogenesis and immune infiltration were also tested in transplanted and genetically engineered immunocompetent mouse models.Results: sIFN-I displayed greater affinity for IFNAR1 (over IFNAR2) chain of the IFN1 receptor and elicited a greater extent of IFN1 signaling and expression of IFN-inducible genes in human cells. Unlike IFNα-2b, sIFN-I induced JAK-STAT signaling in mouse cells and exhibited an extended half-life in mice. Treatment with sIFN-I inhibited intratumoral angiogenesis, increased CD8+ T-cell infiltration, and robustly suppressed growth of transplantable and genetically engineered tumors in immunodeficient and immunocompetent mice.Conclusions: These findings define sIFN-I as a novel recombinant IFN1 with potent preclinical antitumorigenic effects against solid tumor, thereby prompting the assessment of sIFN-I clinical efficacy in humans. Clin Cancer Res; 23(8); 2038-49. ©2016 AACR.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Interferón-alfa/química , Interferón-alfa/farmacología , Animales , Femenino , Citometría de Flujo , Humanos , Immunoblotting , Interferón alfa-2 , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Neoplasias Experimentales/tratamiento farmacológico , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacología , Resonancia por Plasmón de Superficie , Ensayos Antitumor por Modelo de Xenoinjerto
15.
Eur J Med Chem ; 46(4): 1066-73, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21295889

RESUMEN

By using human scavenger receptor CD36 as the target, twenty-five N-(2-arylethyl) isoquinoline derivatives were designed, synthesized and evaluated for their antagonistic activities for CD36-oxidatively low density lipoprotein (oxLDL) binding. The primary analysis of structure-activity relationship (SAR) indicated a methoxyl at the 7-position and a hydroxyl at the 6- or 8-position could afford good activities. Among these analogs, compounds 7e and 7t showed the potential CD36 antagonistic activities with IC(50) values of 0.2 and 0.8 µg/mL, respectively. Furthermore, both of them could effectively inhibit oxLDL uptake in insect Sf9 cells overexpressing human CD36, and thus have been selected for further investigation. We consider N-(2-arylethyl) isoquinoline analogs to be a family of novel CD36 antagonists.


Asunto(s)
Antígenos CD36/metabolismo , Isoquinolinas/química , Isoquinolinas/farmacología , Animales , Línea Celular , Diseño de Fármacos , Humanos , Isoquinolinas/síntesis química , Lipoproteínas LDL/metabolismo , Microscopía Fluorescente , Relación Estructura-Actividad
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