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1.
Analyst ; 146(20): 6170-6177, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34522939

RESUMO

Triphenyltin chloride (TPhT) is an organotin compound that causes intensive toxicological risk to the environment and humans. A detection method with high sensitivity and stability is therefore desired to better detect TPhT. In this study, a novel SERS substrate was prepared by sputtering an ultra-thin Au layer on a honeycomb-like silver nanoarray fabricated via the nanosphere lithography method. The ultra-thin Au layer was formed by sputtering the intermittent Au nanoparticles on the silver nanoarray, resulting in bimetallic coupling with dramatically increased hotspots and extremely high SERS enhancement with an analytical enhancement factor (AEF) of 6.08 × 109 using Rhodamine 6G (R6G) as the probe molecule. Based on density functional theory (DFT) simulations, the Raman characteristic peaks of TPhT at 999 cm-1 and 655 cm-1 were selected for TPhT detection. The AEF of the SERS substrate HC5-AgAu was calculated to be 3.38 × 106 with the detection concentration of TPhT down to 10-10 M. The as-prepared honeycomb-like silver-gold bimetallic SERS substrate demonstrated great stability and sensitivity for TPhT detection, which might also be applied in monitoring many other environmental pollutants.

2.
Nat Commun ; 12(1): 4876, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385436

RESUMO

While the printed circuit board (PCB) has been widely considered as the building block of integrated electronics, the world is switching to pursue new ways of merging integrated electronic circuits with textiles to create flexible and wearable devices. Herein, as an alternative for PCB, we described a non-printed integrated-circuit textile (NIT) for biomedical and theranostic application via a weaving method. All the devices are built as fibers or interlaced nodes and woven into a deformable textile integrated circuit. Built on an electrochemical gating principle, the fiber-woven-type transistors exhibit superior bending or stretching robustness, and were woven as a textile logical computing module to distinguish different emergencies. A fiber-type sweat sensor was woven with strain and light sensors fibers for simultaneously monitoring body health and the environment. With a photo-rechargeable energy textile based on a detailed power consumption analysis, the woven circuit textile is completely self-powered and capable of both wireless biomedical monitoring and early warning. The NIT could be used as a 24/7 private AI "nurse" for routine healthcare, diabetes monitoring, or emergencies such as hypoglycemia, metabolic alkalosis, and even COVID-19 patient care, a potential future on-body AI hardware and possibly a forerunner to fabric-like computers.


Assuntos
Técnicas Biossensoriais/instrumentação , Medicina de Precisão/instrumentação , Têxteis , Dispositivos Eletrônicos Vestíveis , Tecnologia sem Fio/instrumentação , Técnicas Biossensoriais/métodos , COVID-19/diagnóstico , COVID-19/prevenção & controle , COVID-19/virologia , Desenho de Equipamento , Humanos , Monitorização Fisiológica/instrumentação , Monitorização Fisiológica/métodos , Medicina de Precisão/métodos , SARS-CoV-2/fisiologia , Suor/fisiologia
3.
J Pharm Pharmacol ; 73(2): 161-168, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33793798

RESUMO

OBJECTIVES: The quassinoids eurycomanone (EN) and 13α,21-dihydroeurycomanone (DHY) of Eurycoma longifolia Jack are reported to enhance spermatogenesis. This study aims to profile the pharmacokinetics of DHY, a minor and hitherto unstudied constituent, evaluate its spermatogenesis enhancement property and compare these attributes with that of the predominant EN. METHODS: Crude Eurycoma longifolia extract was chromatographed into a DHY-enriched extract (DHY-F) and an EN-enriched extract (EN-F). Male Sprague-Dawley rats were administered intravenously and orally with both extracts and their plasma levels of both quassinoids were determined. The extracts were then tested for their spermatogenesis augmentation ability in normal rats and an andrographolide-induced oligospermia model. KEY FINDINGS: Chromatographic enrichment resulted in a 28-fold increase of DHY in DHY-F and a 5-fold increase of EN in EN-F compared with non-chromatographed crude extracts. DHY showed better oral bioavailability (1.04 ± 0.58%) than EN (0.31 ± 0.19%). At 5 mg/kg, EN exhibited higher efficacy in spermatogenesis enhancement in normal rats and restoration of oligospermia to normal sperm profile versus DHY. CONCLUSIONS: Despite the better pharmacokinetic profile of DHY, EN remains the main chemical contributor to plant bioactivity. DHY-F and EN-F represent improvements in developing Eurycoma longifolia as a potential phytomedicine for male infertility particularly oligospermia.

4.
Daru ; 29(1): 125-132, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33538999

RESUMO

BACKGROUND: Millions worth of unused drugs particularly those indicated for chronic diseases such as diabetes were returned and disposed leading to substantial wastage. Use of patients' own medications (POMs) in the inpatient setting has reduced wastage and saved cost. The impact of utilizing POMs in the outpatient setting has hitherto not been determined. PURPOSE: This study aims to compare the cost, medication adherence and glycaemic control of utilizing POMs versus usual dispensing. METHODS: Prospective randomized controlled study was conducted among diabetic patients that required monthly medication refill in the Outpatient Pharmacy in 2017. Patients who consented were equally divided into POMs and control groups. Both groups brought excess medications from home at week-0 and week-12. Patients in the POMs group brought excess medications monthly and sufficient amount of drugs were added until the next refill date. Drugs were dispensed as usual in the control group. Total cost consisting of the cost of drugs, staff and building was calculated. Glycosylated haemoglobin (HbA1c) was measured at baseline and week-12. Adherence was measured based on pill counting. RESULTS: Thirty patients aged 56.77 ± 14.67 years with 13.37 ± 7.36 years of diabetes participated. Baseline characteristics were similar between the groups. POMs minimized the total cost by 38.96% which translated to a cost saving of USD 42.76 ± 6.98, significantly different versus USD 0.02 ± 0.52 in the control group, p = 0.025. Mean HbA1c reduced significantly (-0.79%, p = 0.016) in the POMs group but not significant in the control group (-0.11%, p = 0.740). Medication adherence improved significantly in both groups at week-12 (p < 0.010). Nevertheless, patients in the POMs group were more adherent, 87.20% vs. 66.32%, p = 0.034. CONCLUSION: Utilizing POMs resulted in cost saving, improved adherence and better glycaemic control. Use of POMs should be practiced in the outpatient pharmacy to reduce wastage and cost.

5.
J Pharm Biomed Anal ; 194: 113758, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33248861

RESUMO

A simple, rapid, sensitive, and reproducible LC-MS/MS method was developed for simultaneous quantification of flavoxate and 3-methyl-flavone-8-carboxylic (MFCA) in human plasma, using diphenhydramine HCl as internal standard (IS). The chromatographic separation was achieved using Agilent Poroshell 120 EC-C18 - Fast LC column (100 × 2.1mmID, 2.7 µm) fitted with UHPLC Guard Poroshell 120 EC-C18 (5 × 2.1 mmID, 2.7 µm). The mobile phase consisted of 0.1 % v/v formic acid and acetonitrile (30:70, v/v) run at a flow rate of 0.40 mL/min. The standard calibration curve was linear over the concentration range of 2.00 - 2,000.31 ng/mL and 240.00 - 24,000.04 ng/mL for flavoxate and MFCA. For flavoxate and MFCA, the within-run precision was 0.81-6.67 % and 1.68-4.37 %, while accuracy was 100.21-108.25 % and 103.99-110.28 %. The between-run precision was 2.01-9.14 % and 2.31-11.11 %, and accuracy was 96.09-103.33 % and 102.37-109.52 %. The extended run precision was 7.78-11.04 % and 2.22-3.33 %, while accuracy was 100.72-101.88 % and 102.34-105.60 %. Flavoxate and MFCA in plasma were stable 4 h at bench top (short term), 24 h in autosampler and instrumentation room (post-preparative), after 7 freeze-thaw cycles, and 89 days in the freezer. Both analytes and IS stock solutions were stable for 31 days when kept at room temperature (25 ± 4 °C) and refrigerated (2-8 °C). The validated method was successfully applied to a bioequivalence study of two flavoxate formulations involving 24 healthy volunteers.


Assuntos
Flavoxato , Espectrometria de Massas em Tandem , Ácidos Carboxílicos , Cromatografia Líquida , Humanos , Reprodutibilidade dos Testes , Equivalência Terapêutica
6.
Mol Med Rep ; 22(5): 3645-3658, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32901880

RESUMO

Eurycoma (E.) longifolia Jack (Tongkat Ali) is a widely applied medicine that has been reported to boost serum testosterone and increase muscle mass. However, its actual biological targets and effects on an in vitro level remain poorly understood. Therefore, the present study aimed to investigate the effects of a standardised E. longifolia extract (F2) on the growth and its associated gene expression profile in mouse Leydig cells. F2, even at lower doses, was found to induce a high level of testosterone by ELISA. The level was as high as the levels induced by eurycomanone and formestane in Leydig cells. However, Leydig cells treated with F2 demonstrated reduced viability, which was likely due to the diminished cell population at the G0/G1 phase and increased cell population arrested at the S phase in the cell cycle, as assessed by MTT assay and flow cytometry, respectively. Cell viability was revived when the treatment time­point was prolonged to 96 h. Genome­wide gene analysis by reverse transcription­quantitative PCR of F2­treated Leydig cells at 72 h, when the cell growth was not revived, and 96 h, when the cell growth had started to revive, revealed cyclin­dependent kinase­like 2 (CDKL2) to be a potential target in regulating the viability of F2­treated Leydig cells. Functional analysis, as analysed using GeneMANIA Cytoscape program v.3.6.0 (https://genemania.org/), further suggested that CDKL2 could act in concert with Casitas B­lineage lymphoma and sphingosine kinase 1 interactor­A­kinase anchoring protein domain­containing genes to regulate the viability of F2­treated Leydig cells. The findings of the present study provide new insights regarding the potential molecular targets associated with the biological effect of E. longifolia extract on cell growth, particularly on the cell cycle, which could aid in enhancing the bioefficacy and reducing the toxicity of this natural product in the future.


Assuntos
Eurycoma/química , Redes Reguladoras de Genes/efeitos dos fármacos , Células Intersticiais do Testículo/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Androstenodiona/análogos & derivados , Androstenodiona/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Quinases Ciclina-Dependentes/genética , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Células Intersticiais do Testículo/metabolismo , Masculino , Camundongos , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-cbl/genética , Testosterona/metabolismo
7.
Heliyon ; 5(7): e02156, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31388587

RESUMO

Whilst the potential of neural stem cell (NSC)-based treatment is recognized worldwide and seems to offer a promising therapeutic option for stroke treatments, there is currently no full understanding regarding the effects of hypoxic and baicalein-enriched fraction (BEF) preconditioning approaches on the therapeutic potential of these cells for stroke. The potential of preconditioned NSC can be determined based on the expression of several key neuroprotective genes using qRT-PCR technique. However, prior to that, it is imperative and extremely important to carefully select reference gene(s) for accurate qRT-PCR data normalization to avoid error in data interpretation. This study aimed to evaluate the stability of ten candidate reference genes via comprehensive analysis using three algorithms software: geNorm, NormFinder and BestKeeper. Our results revealed that HPRT1 and RPL13A were the most reliable reference genes for BEF-preconditioned NSCs, but ironically, HPRT1 was ranked as the least stable reference gene for hypoxic-preconditioned NSCs. On the other hand, RPLP1 and RPL13A were selected as the most stably expressed pair of reference genes for hypoxic-preconditioned NSCs. In conclusion, this study has pointed out the importance of identifying valid reference genes and has presented the first significant validation on best reference genes recommended for qRT-PCR study involves NSC preconditioned with hypoxia or with BEF extracted from Oroxylum indicum medicinal plant.

8.
Biomed Pharmacother ; 110: 118-128, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30466001

RESUMO

Previously, a series of aurones bearing amine and carbamate functionalities was synthesized and evaluated for their cholinesterase inhibitory activity and drug-like attributes. In the present study, these aurones were evaluated for their multi-targeting properties in two Alzheimer's disease (AD)-related activities namely, monoamine oxidase (MAO) and amyloid-beta (Aß) inhibition. Evaluation of the aurones for MAO inhibitory activity disclosed several potent selective inhibitors of MAO-B, particularly those with 6-methoxyl group attached at ring A. Of the different amine moieties attached as side chains, pyrrolidine-bearing aurones were prominent as represented by 2-2, the most potent inhibitor. Evaluation on the Aß aggregation inhibition identified 4-3 as the best inhibitor with a percentage inhibition comparable to that of a known Aß inhibitor curcumin. Examination on the neuroprotective ability of the more drug-like aurone 4-3 in two Caenorhabditis elegans neurodegeneration models showed 4-3 to protect the nematodes against both Aß- and 6-hydroxydopamine-induced toxicities. These new activities further support 4-3 as a promising lead to develop the aurones as potential multipotent agents for neurodegenerative diseases.


Assuntos
Benzofuranos/administração & dosagem , Inibidores da Colinesterase/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Inibidores da Monoaminoxidase/administração & dosagem , Monoaminoxidase/metabolismo , Neuroproteção/efeitos dos fármacos , Animais , Benzofuranos/química , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/antagonistas & inibidores , Proteínas de Caenorhabditis elegans/metabolismo , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Inibidores da Monoaminoxidase/química , Neuroproteção/fisiologia , Relação Estrutura-Atividade
9.
J Pharm Pharmacol ; 71(5): 860-868, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30515807

RESUMO

OBJECTIVES: This study aims to investigate the blood-brain barrier (BBB) permeability of curcumin analogues with shortened linkers and their ability to protect against amyloid-beta toxicity in a whole organism model. METHOD: Four curcumin analogues were synthesized. These analogues and curcumin were evaluated for their BBB permeability in the parallel artificial membrane permeability assay. The transgenic Caenorhabditis elegansGMC101 that expresses human Aß1-42 was treated with the compounds to evaluate their ability to delay Aß-induced paralysis. Expression of skn-1mRNA was examined on nematodes treated with selected efficacious compounds. In vitro Aß aggregation in the presence of the compounds was performed. KEY FINDINGS: The four analogues showed improved BBB permeability vs curcumin in the PAMPA with the hemi-analogue C4 having the highest permeability coefficient. At 100 µm, analogues C1 and C4 as well as curcumin significantly prolonged the survival of the nematodes protecting against Aß toxicity. However, only curcumin and C4 showed protection at lower concentrations. skn-1mRNA was significantly elevated in nematodes treated with curcumin and C4 indicating SKN-1/Nrf activation as a possible mode of action. CONCLUSIONS: Analogue C4 provides a new lead for the development of a curcumin-based compound for protection against Aß toxicity with an improved BBB permeability.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Barreira Hematoencefálica/metabolismo , Curcumina/química , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans , Curcumina/análogos & derivados , Curcumina/farmacocinética , Proteínas de Ligação a DNA , Modelos Animais de Doenças , Paralisia/induzido quimicamente , Permeabilidade , Substâncias Protetoras , Fatores de Transcrição
10.
J Pharm Sci ; 106(2): 502-510, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27855959

RESUMO

Previously, several aurone derivatives were identified with promising neuroprotective activities. In developing these compounds to target the central nervous system (CNS), an assessment of their blood-brain barrier (BBB) permeability was performed using in vitro BBB models: parallel artificial membrane permeability assay-BBB which measures passive permeability and primary porcine brain endothelial cell model which enables determination of the involvement of active transport mechanism. Parallel artificial membrane permeability assay-BBB identified most compounds with high passive permeability, with 3 aurones having exceptional Pe values highlighting the importance of basic amine moieties and optimal lipophilicity for good passive permeability. Bidirectional permeability assays with porcine brain endothelial cell showed a significant net influx permeation of the aurones indicating a facilitated uptake mechanism in contrast to donepezil, a CNS drug included in the evaluation which only displayed passive permeation. From pH-dependent permeability assay coupled with data analysis using pCEL-X software, intrinsic transcellular permeability (Po) of a representative aurone 4-3 was determined, considering factors such as the aqueous boundary layer that may hinder accurate in vitro to in vivo correlation. The Po value determined supported the in vivo feasibility of the aurone as a CNS-active compound.


Assuntos
Benzofuranos/química , Benzofuranos/farmacocinética , Barreira Hematoencefálica/metabolismo , Permeabilidade Capilar , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacocinética , Animais , Encéfalo/metabolismo , Linhagem Celular , Células Endoteliais/metabolismo , Membranas Artificiais , Suínos
11.
Eur J Med Chem ; 94: 195-210, 2015 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-25768702

RESUMO

A series of novel aurones bearing amine and carbamate functionalities at various positions (rings A and/or B) of the scaffold was synthesized and evaluated for their acetylcholinesterase and butyrylcholinesterase inhibitory activities. Structure-activity relationship study disclosed several potent submicromolar acetylcholinesterase inhibitors (AChEIs) particularly aurones bearing piperidine and pyrrolidine moieties at ring A or ring B. Bulky groups particularly methoxyls, and carbamate to a lesser extent, at either rings were also prominently featured in these AChEI aurones as exemplified by the trimethoxyaurone 4-3. The active aurones exhibited a lower butyrylcholinesterase inhibition. A 3'-chloroaurone 6-3 originally designed to improve the metabolic stability of the scaffold was the most potent of the series. Molecular docking simulations showed these AChEI aurones to adopt favourable binding modes within the active site gorge of the Torpedo californica AChE (TcAChE) including an unusual chlorine-π interaction by the chlorine of 6-3 to establish additional bondings to hydrophobic residues of TcAChE. Evaluation of the potent aurones for their blood-brain barrier (BBB) permeability and metabolic stability using PAMPA-BBB assay and in vitro rat liver microsomes (RLM) identified 4-3 as an aurone with an optimal combination of high passive BBB permeability and moderate CYP450 metabolic stability. LC-MS identification of a mono-hydroxylated metabolite found in the RLM incubation of 4-3 provided an impetus for further improvement of the compound. Thus, 4-3, discovered within this present series is a promising, drug-like lead for the development of the aurones as potential multipotent agents for Alzheimer's disease.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Relação Estrutura-Atividade , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Benzofuranos/química , Domínio Catalítico , Técnicas de Química Sintética , Avaliação Pré-Clínica de Medicamentos/métodos , Estabilidade de Medicamentos , Microssomos Hepáticos/efeitos dos fármacos , Simulação de Acoplamento Molecular , Permeabilidade , Ratos , Torpedo
12.
Food Technol Biotechnol ; 53(3): 278-285, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27904359

RESUMO

A series of propionylated starches with different degrees of substitution (DS) was synthesised and their physicochemical properties and application as a stabiliser were investigated. Starch propionates with moderate DS were prepared by esterification of native corn starch with propionic anhydride. By varying the reaction times of the esterification process, twelve starch propionates with DS of 0.47 to 0.94 were prepared. FTIR and NMR confirmed the introduction of propionyl groups to the starch. X-ray diffraction pattern showed reduced crystallinity in the starch propionates. The contact angle was found to increase proportionately with the increase in DS. Swelling power results showed that starch propionates were able to swell more than native corn starch at low temperature (40 °C). Oil-in- -water (O/W) emulsions prepared using starch propionates (DS of 0.64 to 0.86) showed exceptional stability when challenged by centrifugation stress test. These stable O/W emulsions had viscosities in the range of 1236.7-3330.0 mPa·s. In conclusion, moderately substituted short-chain (propionylated) starches could be a promising cold swelling starch, thickener and O/W emulsion stabiliser in food, pharmaceutical and cosmetic industries.

13.
Eur J Med Chem ; 71: 67-80, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24275249

RESUMO

Osteosarcoma is a primary bone malignancy with aggressive metastatic potential and poor prognosis rates. In our earlier work we have investigated the therapeutic potential of curcumin as an anti-invasive agent in osteosarcoma by its ability to regulate the Wnt/ß-catenin signaling pathway. However, the clinical use of curcumin is limited owing to its low potency and poor pharmacokinetic profile. In this study, an attempt was made to achieve more potent Wnt inhibitory activity in osteosarcoma cells by carrying out synthetic chemical modifications of curcumin. We synthesized a total of five series consisting of 43 curcumin analogs and screened in HEK293T cells for inhibition of ß-catenin transcriptional activity. Six promising analogs, which were 6.5- to 60-fold more potent than curcumin in inhibiting Wnt activity, were further assessed for their anti-invasive activity and Wnt inhibitory mechanisms. Western blot analysis showed disruption of ß-catenin protein nuclear translocation following treatment with analogs 2f, 3c and 4f. Using transwell assays, we also found that these compounds were more potent than 1a (curcumin) in impeding the invasion of osteosarcoma cells, possibly through suppressing MMP-9 activity. Structure-activity-relationship studies revealed that Wnt inhibitory effects could be enhanced by shortening and restraining the flexibility of the 7-carbon linker moiety connecting the terminal aromatic rings of curcumin and substituting both rings with appropriate substituents. Our results demonstrate that the synthesized curcumin analogs are more potent Wnt inhibitors in osteosarcoma cell lines as compared to parental curcumin and are good lead compounds for further development. Future in vivo tests with these compounds will define their therapeutic potentials as promising drug candidates for clinical treatment of osteosarcoma.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Curcumina/farmacologia , Osteossarcoma/tratamento farmacológico , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Antineoplásicos/química , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Curcumina/análogos & derivados , Células HEK293 , Humanos , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Osteossarcoma/metabolismo , Osteossarcoma/patologia
14.
ChemMedChem ; 6(4): 713-24, 2011 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-21302361

RESUMO

The ability of aurones to modulate the efflux activities of ABCG2 and ABCB1 was investigated by quantifying their effects on the accumulation of pheophorbide A (PhA) in ABCG2-overexpressing MDA-MB-231/R cells and calcein AM in ABCB1-overexpressing MDCKII/MDR1 cells. Key structural features for interactions at both ABCG2 and ABCB1 are a methoxylated ring A, an intact exocyclic double bond, and the location of the carbonyl bond on ring C. Modifications on rings B and C were less critical and served primarily to moderate activity and selectivity for one or both transporters. These SAR trends were quantified by Free-Wilson analyses and are reflected in a pharmacophore model for PhA accumulation. Several compounds were found to be equipotent with fumitremorgin C (FTC) in promoting PhA accumulation, and they also demonstrated strong affinities for ABCB1. These compounds were disubstituted on ring B with methoxy or a combination of methoxy and hydroxy groups. Taken together, our findings highlight the versatility of the aurone template as a lead scaffold for the design of dual-targeting ABCG2 and ABCB1 modulators.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia , Benzofuranos/farmacologia , Proteínas de Neoplasias/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Antineoplásicos/síntese química , Antineoplásicos/química , Benzofuranos/síntese química , Benzofuranos/química , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Relação Estrutura-Atividade
15.
Eur J Med Chem ; 45(7): 2957-71, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20392544

RESUMO

The chemopreventive potential of functionalized aurones and related compounds as inducers of NAD(P)H:quinone oxidoreductase 1 (NQO1, EC 1.6.99.2) are described. Several 4,6-dimethoxy and 5-hydroxyaurones induced NQO1 activity of Hepa1c1c7 cells by 2-fold at submicromolar concentrations, making these the most potent inducers to be identified from this class. Mechanistically, induction of NQO1 was mediated by the activation of AhR/XRE and Nrf2/ARE pathways, indicating that aurones may be mixed activators of NQO1 induction or agents capable of exploiting the proposed cross-talk between the AhR and Nrf2 gene batteries. QSAR analysis by partial least squares projection to latent structures (PLS) identified size parameters, in particular those associated with non-polar surface areas, as an important determinant of induction activity. These were largely determined by the substitution on rings A and B. A stereoelectronic role for the exocyclic double bond as reflected in the E(LUMO) term was also identified. The electrophilicity of the double bond or its effect on the conformation of the target compound are possible key features for induction activity.


Assuntos
Benzofuranos/química , Benzofuranos/farmacologia , Relação Quantitativa Estrutura-Atividade , Quinona Redutases/biossíntese , Elementos de Resposta , Transdução de Sinais/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Benzofuranos/síntese química , Linhagem Celular Tumoral , Citocromo P-450 CYP1A1/metabolismo , Indução Enzimática/efeitos dos fármacos , Camundongos , Mutação , Fator 2 Relacionado a NF-E2/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Xenobióticos/metabolismo
16.
Eur J Pharm Sci ; 35(4): 293-306, 2008 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-18725288

RESUMO

A series of 4,6-dimethoxyaurones were synthesized by reacting 4,6-dimethoxybenzofuran-3(2H)-one with various benzaldehydes in a base-catalyzed aldol reaction. A Z configuration was assigned to the aurones based on spectroscopic and crystallographic data. The aurones were tested for their ability to modulate ABCG2 (breast cancer resistance protein)-mediated multidrug resistance in vitro. Several members (0.5 microM) increased the accumulation of mitoxantrone (MX) in human breast cancer cells (MDA-MB-231) transfected with ABCG2 and re-sensitized these cells to the cytotoxic effects of MX. In the re-sensitization assay, aurones at 0.5 microM reduced the resistance of the transfected cells to MX to just twice that of the parental cells, exceeding fumitremorgin C (FTC) tested at the same concentration. The aurones (10 microM) also increased calcein-AM accumulation in MDCKII/MDR1 cells that were transfected with ABCB1 (P-glycoprotein), at levels comparable to verapamil tested at the same concentration. Structure-activity analysis showed that substitution of the benzylidene ring B of the aurone template was less important for ABCG2 inhibition, with little variation in activity noted for compounds with an unsubstituted ring B or one that was substituted. In contrast, substitution of ring B gave rise to better inhibitors of ABCB1. A preference for the 3' position of ring B was noted. There was also some indication from the data that aurones with good ABCG2 inhibitory activity were poor ABCB1 inhibitors and vice versa, but further confirmation would be required. Limited antiproliferative activity (>70% cell survival) was observed for many aurones on four different cell lines. Thus, functionalized 4,6-dimethoxyaurones are promising ABCG2 inhibitors that combine good activity at submicromolar concentrations with limited antiproliferative activity.


Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzofuranos/síntese química , Benzofuranos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Neoplasias/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Animais , Antineoplásicos/metabolismo , Benzofuranos/metabolismo , Western Blotting , Neoplasias da Mama/patologia , Proliferação de Células , Sobrevivência Celular , Cristalografia por Raios X , DNA Complementar/biossíntese , DNA Complementar/genética , Cães , Feminino , Citometria de Fluxo , Fluoresceínas/metabolismo , Humanos , Indicadores e Reagentes , Mitoxantrona/metabolismo , Modelos Moleculares , Relação Estrutura-Atividade , Sais de Tetrazólio , Tiazóis , Células Tumorais Cultivadas
17.
Bioorg Med Chem ; 16(14): 6737-46, 2008 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-18556207

RESUMO

A library of functionalized 6-chloro-2-methoxy-(N(9)-substituted)acridin-9-amines structurally related to quinacrine were synthesized and evaluated for antiprion activity on four different cell models persistently infected with scrapie prion strains (ScN2a, N167, Ch2) or a human disease prion strain (F3). Most of the compounds were distinguished by the side chain attached to 9-amino of the acridine ring. These were dialkylaminoalkyl and phenyl with basic groups on the phenyl ring. The most promising compound was 6-chloro-2-methoxy-N-(4-(4-methylpiperazin-1-yl)phenyl)acridin-9-amine (15) which had submicromolar EC(50) values (0.1-0.7microM) on all cell models, was able to clear PrP(Sc) at non-toxic concentrations of 1.2-2.5microM, and was more active than quinacrine in terms of EC(50) values. Other promising compounds were 14 (a regioisomer of 15) and 17 which had a 1-benzylpiperidin-4-yl substituent attached to the 9-amino function. Activity was strongly dependent on the presence of a substituted acridine ring, which in this library comprised 6-chloro-2-methoxy substituents on the acridine ring. The side chains of 14, 15, and 17 have not been previously associated with antiprion activity and are interesting leads for further optimization of antiprion activity.


Assuntos
Aminoacridinas/síntese química , Aminoacridinas/farmacologia , Príons/antagonistas & inibidores , Quinacrina/química , Aminoacridinas/química , Linhagem Celular , Humanos , Doenças Priônicas/tratamento farmacológico , Relação Estrutura-Atividade
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