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1.
Int J Nanomedicine ; 14: 8345-8360, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695371

RESUMO

Background: The protective role of puerarin (PUE) against myocardial infarction is closely related to its regulation on mitochondria. However, free PUE can hardly reach the mitochondria of ischemic cardiomyocytes due to the lack of mitochondrial targeting of PUE. Here PUE was loaded into mitochondria-targeted micelles (PUE@TPP/PEG-PE) for precisely delivering PUE into mitochondria with the aim of enhancing the anti-apoptosis effect. Methods: The mitochondriotropic polymer TPP-PEG-PE was synthesized for the preparation of PUE@TPP/PEG-PE micelles modified with triphenylphosphonium (TPP) cation. The physicochemical properties and anti-apoptosis effect of PUE@TPP/PEG-PE micelles were investigated. The coumarin 6 (C6)-labeled TPP/PEG-PE (C6@TPP/PEG-PE) micelles were used to observe the enhanced cellular uptake, mitochondrial targeting and lysosomes escape. Moreover, in vivo and ex vivo biodistribution of lipophilic near-infrared dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR)-labeled PUE@TPP/PEG-PE (DiR@TPP/PEG-PE) micelles were detected through fluorescence imaging. Results: The successful synthesis of TPP-PEG-PE conjugate was confirmed. PUE@TPP/PEG-PE micelles had a particle size of 17.1 nm, a zeta potential of -6.2 mV, and a sustained-release behavior. The in vitro results showed that the intracellular uptake of C6@TPP/PEG-PE micelles was significantly enhanced in H9c2 cells. C6@TPP/PEG-PE micelles could deliver C6 to mitochondria and reduce the capture of lysosomes. In addition, compared with the PUE@PEG-PE micelles and free PUE, the PUE@TPP/PEG-PE micelles exerted an enhanced protective effect against isoprenaline-induced H9c2 cell apoptosis, as evident by the decreased percentage of apoptotic cells, Caspase-3 activity, ROS level, Bax expression, and increased Bcl-2 expression. The in vivo detecting results of the targeting effect using DiR probe also indicated that TPP/PEG-PE micelles could accumulate and retain in the ischemic myocardium. Conclusion: The results of this study demonstrate the promising potential of applying PUE@TPP/PEG-PE micelles in mitochondria-targeted drug delivery to achieve maximum therapeutic effects of PUE.

2.
Vascul Pharmacol ; 117: 35-44, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30610955

RESUMO

High mobility group box 1 (HMGB1), a critical nonclassical inflammatory cytokine, has been found up-regulated in patients with idiopathic pulmonary arterial hypertension (IPAH), but its role in vascular remodeling of pulmonary hypertension (PH) is still unknown. In present study, we demonstrated that the plasma level of inflammatory cytokine including HMGB1, interleukin 1ß (IL-1ß), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) were elevated in hypoxia-induced pulmonary hypertension rats model. Moreover, expressions of HMGB1 and Toll like receptor-4 (TLR4) in pulmonary arteries were obviously up-regulated accompanied with down-regulation of bone morphogenetic protein receptor 2 (BMPR2) signaling, characterized by decline of phosphorylated Smad1/5/8 (p-Smsd1/5/8) and inhibitor of differention 1 (Id1) expression. In cultured primary pulmonary arterial smooth muscle cells (PASMCs), we found that HMGB1 incubation significantly promoted proliferation and migration of PASMCs, down-regulated p-Smsd1/5/8 and Id1 expression, which can be abrogated by HMGB1 inhibitors saquinavir, glycyrrhizn and TLR4 inhibitors TAK-242. Furthermore, saquinavir, glycyrrhizn and TAK-242 treatment significantly attenuated the development of PH in rats by recovering homodynamic parameters, pulmonary vascular remodeling and BMPR2 signaling pathway. In summary, our results suggest that HMGB1/TLR4 signaling promotes hypoxia-induced pulmonary hypertension via suppressing BMPR2 signaling.

3.
Eur J Pharmacol ; 843: 96-103, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30352200

RESUMO

It has been documented cardiac fibroblasts as the predominant cell population undergoing senescence in heart. Calcitonin gene-related peptide (CGRP) exhibits a wide range of cardiovascular protective effects. Whether CGRP protects against cardiac fibroblasts senescence in cardiac fibrosis remains unknown. Here, we detected the down-regulation of CGRP concomitant with senescence in fibrotic myocardium, both hypertension- induced left ventricular fibrosis in SHR rats and hypoxia-induced right ventricular fibrosis in pulmonary artery hypertension rats. Exogenous CGRP inhibited the cardiac fibroblasts senescence and senescence-associated secretory phenotype (SASP) induced by TGF-ß1, which was abolished by CGRP8-37, a selective CGRP receptor antagonist. Moreover, the expression of klotho, an anti-senescence protein, was down-regulated in fibrotic myocardium, and CGRP up-regulated the klotho expression in TGF-ß1-treated cardiac fibroblasts. Klotho knockdown by siRNA reversed the inhibition of CGRP on senescence and SASP induced by TGF-ß1 in cardiac fibroblasts. These results suggested that CGRP inhibited the cardiac fibroblasts senescence and SASP in cardiac fibrosis via up-regulating klotho expression.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Senescência Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Glucuronidase/metabolismo , Animais , Animais Recém-Nascidos , Fibroblastos/fisiologia , Fibrose , Glucuronidase/genética , Masculino , Miocárdio/citologia , Miocárdio/metabolismo , Miocárdio/patologia , RNA Interferente Pequeno , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1/farmacologia , Regulação para Cima
4.
Pharmacol Res ; 142: 294-302, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30553824

RESUMO

Stress response refers to the systemic nonspecific response upon exposure to strong stimulation or chronic stress, such as severe trauma, shock, infection, burn, major surgery or improper environment, which disturb organisms and damage their physical and psychological health. However, the pathogenesis of stress induced disorder remains complicated and diverse under different stress exposure. Recently, studies have revealed a specific role of microRNAs (miRNAs) in regulating cellular function under different types of stress, suggesting a significant role in the treatment and prevention of stress-related diseases, such as stress ulcer, posttraumatic stress disorder, stress-induced cardiomyopathy and so on. This paper have reviewed the literature on microRNA related stress diseases in different databases including PubMed, Web of Science, and the MiRbase. It considers only peer-reviewed papers published in English between 2004 and 2018. This review summarizes new advances in principles and mechanisms of miRNAs regulating stress signalling pathway and the role of miRNAs in human stress diseases. This comprehensive review is to provide an integrated account of how different stresses affect miRNAs and how stress-miRNA pathways may, in turn, be linked with disease, which offers some potential strategies for stress disorder treatment. Furthermore, the limitation of current studies and challenges for clinical use are discussed.

5.
Front Pharmacol ; 9: 530, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29872398

RESUMO

It has been observed that many phytochemicals, frequently present in foods or beverages, show potent chemopreventive or therapeutic properties that selectively affect cancer cells. Numerous studies have demonstrated the anticancer activity of xanthohumol (Xn), a prenylated flavonoid isolated from hops (Humulus lupulus L.), with a concentration up to 0.96 mg/L in beer. This review aims to summarize the existing studies focusing on the anticancer activity of Xn and its effects on key signaling molecules. Furthermore, the limitations of current studies and challenges for the clinical use of Xn are discussed.

6.
Naunyn Schmiedebergs Arch Pharmacol ; 389(7): 757-67, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27052575

RESUMO

Rutaecarpine has been shown to exhibit wide pharmacological effects in the cardiovascular system via stimulation of calcitonin gene-related peptide (CGRP) release. In the present study, the effect of rutaecarpine on hypoxia-induced right ventricular (RV) remodeling and the underlying mechanisms were evaluated. RV remodeling was induced by hypoxia (10 % O2, 3 weeks) in rats. Rats were treated with rutaecarpine (20 or 40 mg/kg) by intragastric administration. Proliferation of cardiac fibroblasts was induced by TGF-ß1 (5 ng/mL) and determined by MTS and EdU incorporation method. Cardiac fibroblasts were treated with exogenous CGRP (10 or 100 nM). The concentrations of CGRP and TGF-ß1 in plasma were measured by ELISA. The expression of eIF3a, p27, α-SMA, collagen-I/III, ANP, and BNP were measured by real-time PCR or western blot. Hypoxia induced an increase of right ventricle systolic pressure (RVSP), ration of RV/LV+S, and RV/tibial length in rats, while cardiac hypertrophy, apoptosis, and fibrosis were detected. The expression of ANP, BNP, α-SMA, collagen-I, collagen-III, eIF3a, and TGF-ß1 was up-regulated, and the expression of p27 was down-regulated in the right ventricle of hypoxia-treated rats. The plasma concentration of CGRP was decreased and TGF-ß1 was increased in hypoxia-treated rats. All of these effects induced by hypoxia were attenuated by rutaecarpine in a dose-dependent manner. In cultured cardiac fibroblasts, TGF-ß1 significantly promoted the proliferation and up-regulated the expression of α-SMA and collagen-I/III, while the expression of eIF3a was up-regulated and the expression of p27 was down-regulated. The effects of TGF-ß1 were attenuated by CGRP. CGRP8-37, a selective CGRP receptor antagonist, abolished the effects of CGRP. Rutaecarpine attenuates hypoxia-induced RV remodeling via stimulation of CGRP release, and the effects of rutaecarpine involve the eIF3a/p27 pathway.


Assuntos
Hipertrofia Ventricular Direita/prevenção & controle , Hipóxia/tratamento farmacológico , Alcaloides Indólicos/farmacologia , Quinazolinas/farmacologia , Disfunção Ventricular Direita/prevenção & controle , Função Ventricular Direita/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fator de Iniciação 3 em Eucariotos/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/metabolismo , Hipertrofia Ventricular Direita/fisiopatologia , Hipóxia/complicações , Hipóxia/metabolismo , Hipóxia/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/metabolismo , Disfunção Ventricular Direita/fisiopatologia , Pressão Ventricular/efeitos dos fármacos
7.
Eur J Pharmacol ; 773: 42-50, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26821114

RESUMO

Fluorofenidone is a novel derivative of l-mimosine. It has remarkable anti-fibrotic properties. In this study, we established that fluorofenidone ameliorates pulmonary fibrosis (PF) both in vivo and in vitro by specifically inhibiting the expression of eukaryotic translation initiation factor 3a (eIF3a). eIF3a plays an important role in the development and progression of PF. An animal model of PF was induced by intratracheal instillation of bleomycin (5mg/kg) in rats. Rats were orally administered with fluorofenidone (250, 500 mg/kg/d·[i.g.]) and pirfenidone (500 mg/kg/d·[i.g.]) for 28 days. Primary pulmonary fibroblasts were cultured to determine the effect of fluorofenidone on TGF-ß1-induced (5 ng/ml) proliferation and differentiation of fibroblasts. The expression/level of eIF3a, TGF-ß1, α-SMA, collagen I, and collagen III were analyzed by ELISA, real-time PCR, and western blot. The cell proliferation rate was determined by MTS assay. The results indicate that fluorofenidone significantly improves the pathological changes in lung tissues and reduces the deposition of collagen by inhibiting eIF3a in rats with bleomycin-induced PF. Moreover, in a culture of pulmonary fibroblasts, fluorofenidone decreased the up-regulation of TGF-ß1-induced eIF3a by inhibiting the proliferation of cells and reducing the expression of α-SMA, collagen I, and collagen III. These findings suggest that eIF3a is a new and special target of fluorofenidone, which could be potentially used in the development of a drug that treats PF.


Assuntos
Bleomicina/efeitos adversos , Fator de Iniciação 3 em Eucariotos/antagonistas & inibidores , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Piridonas/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colágeno/metabolismo , Fator de Iniciação 3 em Eucariotos/genética , Fator de Iniciação 3 em Eucariotos/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Fibrose Pulmonar/induzido quimicamente , Piridonas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1/sangue , Fator de Crescimento Transformador beta1/metabolismo
8.
Life Sci ; 144: 61-8, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26612348

RESUMO

AIM: Eukaryotic translation initiation factors 3a (eIF3a) is involved in regulating cell cycle, cell division, growth and differentiation. Previous studies suggest a role of eIF3a on fibrosis disease and cellular proliferation and differentiation of fibroblasts. The present study aims to investigate the role of eIF3a on hypoxia-induced right ventricular (RV) remodeling and underlying mechanism. MAIN METHODS: RV remodeling was induced by hypoxia (10% O2, 3 weeks) in rats. Primary cardiac fibroblasts were cultured in vitro and their proliferation was investigated by MTS and EdU incorporation method. eIF3a knockdown was conducted by eIF3a siRNA. The expression/level of TGF-ß1, eIF3a, p27 and α-SMA, collagen-I, collagen-III, ANP and BNP were analyzed by ELISA, real-time PCR or Western blot. KEY FINDINGS: The expression of eIF3a was obviously increased in right ventricle of RV remodeling rats accompanied by up-regulation of α-SMA and collagens. In cultured cardiac fibroblasts, application of exogenous TGF-ß1-induced cellular proliferation and differentiation concomitantly with up-regulation of eIF3a expression and down-regulation of p27 expression. The effects of TGF-ß1-induced proliferation and up-regulation of α-SMA and collagen in cardiac fibroblasts were abolished by eIF3a siRNA. eIF3a siRNA reversed TGF-ß1 induced down-regulation of p27 expression. SIGNIFICANCE: The eIF3a plays a crucial role in hypoxia-induced RV remodeling by regulating TGF-ß1-induced proliferation and differentiation of cardiac fibroblasts, which is mediated via eIF3a/p27 pathway.


Assuntos
Fatores de Iniciação em Eucariotos/genética , Hipertrofia Ventricular Direita/genética , Hipertrofia Ventricular Direita/patologia , Hipóxia/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Remodelação Ventricular/genética , Actinas/biossíntese , Actinas/genética , Animais , Diferenciação Celular/genética , Proliferação de Células , Células Cultivadas , Colágeno/biossíntese , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Fibroblastos , Técnicas de Silenciamento de Genes , Masculino , RNA Interferente Pequeno/farmacologia , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1/farmacologia
9.
Eur J Pharmacol ; 765: 565-73, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26409044

RESUMO

Mammalian Target of Rapamycin (mTOR) is involved in the proliferation and survival of pulmonary artery smooth muscle cells (PASMCs) in human pulmonary hypertension (PH) and animal PH models, and miRNAs are reported to play a key role in modulation of the proliferation of PASMCs. The purposes of this study are to determine the functions of miR-100 and mTOR in cardiovascular remodeling of the hypoxic PH rats and to clarify the correlation between them. We established a rat model of hypoxic PH, which showed an increase in right ventricle systolic pressure, right ventricular and pulmonary vascular remodeling, accompanied by an up-regulation of mTOR and a down-regulation of miR-100. Next, we established an in vitro model of hypoxia-induced proliferation of PASMCs. Consistent with the in vivo findings, hypoxia induced proliferation of PASMCs, accompanied by a down-regulation of miR-100 and an up-regulation of mTOR; these phenomena were reversed by miR-100 mimics or the antagonist of mTOR. Finally, the dual-luciferase reporter gene assay was utilized to reveal the direct interaction between miR-100 and the 3 '-UTR region of mTOR gene. Based on these observations, we conclude that miR-100 can modulate the proliferation of PASMCs in hypoxic PH rats through suppressing the mTOR expression.


Assuntos
Hipertensão Pulmonar/metabolismo , Hipóxia/metabolismo , MicroRNAs/metabolismo , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/biossíntese , Animais , Proliferação de Células/fisiologia , Hipertensão Pulmonar/patologia , Hipóxia/patologia , Masculino , Ratos , Ratos Sprague-Dawley
10.
PLoS One ; 10(6): e0130806, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26120832

RESUMO

Enhanced proliferation of pulmonary arterial vascular smooth muscle cells (PASMCs) is a key pathological component of vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Mammalian targeting of rapamycin (mTOR) signaling has been shown to play a role in protein translation and participate in the progression of pulmonary hypertension. Eukaryotic translation initiation factor-2α (eIF2α) is a key factor in regulation of cell growth and cell cycle, but its role in mTOR signaling and PASMCs proliferation remains unknown. Pulmonary hypertension (PH) rat model was established by hypoxia. Rapamycin was used to treat rats as an mTOR inhibitor. Proliferation of primarily cultured rat PASMCs was induced by hypoxia, rapamycin and siRNA of mTOR and eIF2α were used in loss-of-function studies. The expression and activation of eIF2α, mTOR and c-myc were analyzed. Results showed that mTOR/eIF2α signaling was significantly activated in pulmonary arteries from hypoxia exposed rats and PASMCs cultured under hypoxia condition. Treatment with mTOR inhibitor for 21 days attenuated vascular remodeling, suppressed mTOR and eIF2α activation, inhibited c-myc expression in HPH rats. In hypoxia-induced PASMCs, rapamycin and knockdown of mTOR and eIF2α by siRNA significantly abolished proliferation and increased c-myc expression. These results suggest a critical role of the mTOR/eIF2αpathway in hypoxic vascular remodeling and PASMCs proliferation of HPH.


Assuntos
Fator de Iniciação 2 em Eucariotos/metabolismo , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Hipóxia/complicações , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Hipóxia/patologia , Hipóxia/fisiopatologia , Masculino , Miócitos de Músculo Liso/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Artéria Pulmonar/patologia , RNA Interferente Pequeno/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Regulação para Cima/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos
11.
Med Res Rev ; 35(4): 753-89, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25808858

RESUMO

Camptothecins (CPTs) are cytotoxic natural alkaloids that specifically target DNA topoisomerase I. Research on CPTs has undergone a significant evolution from the initial discovery of CPT in the late 1960s through the study of synthetic small-molecule derivatives to investigation of macromolecular constructs and formulations. Over the past years, intensive medicinal chemistry efforts have generated numerous CPT derivatives. Three derivatives, topotecan, irinotecan, and belotecan, are currently prescribed as anticancer drugs, and several related compounds are now in clinical trials. Interest in other biological effects, besides anticancer activity, of CPTs is also growing exponentially, as indicated by the large number of publications on the subject during the last decades. Therefore, the main focus of the present review is to provide an ample but condensed overview on various biological activities of CPT derivatives, in addition to continued up-to-date coverage of anticancer effects.


Assuntos
Camptotecina/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Camptotecina/química , Humanos
12.
Biochem Biophys Res Commun ; 450(1): 135-41, 2014 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-24866234

RESUMO

Large-dose or long-term use of aspirin tends to cause gastric mucosa injury, which is recognized as the major side effect of aspirin. It has been demonstrated that glutamate exerts a protective effect on stomach, and the level of glutamate is critically controlled by cystine/glutamate transporter (Xc(-)). In the present study, we investigated the role of glutamate-cystine/glutamate transporter system in aspirin-induced acute gastric mucosa injury in vitro and in vivo. Results showed that in human gastric epithelial cells, aspirin incubation increased the activity of LDH and the number of apoptotic cells, meanwhile down-regulated the mRNA expression of Xc(-) accompanied with decreased glutamate release. Similar results were seen in a rat model. In addition, exogenous l-glutamate attenuated the gastric mucosa injury and cell damage induced by aspirin both in vitro and in vivo. Taken together, our results demonstrated that acute gastric mucosa injury induced by aspirin is related to reduction of glutamate-cystine/glutamate transporter system activity.


Assuntos
Sistema X-AG de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Aspirina/administração & dosagem , Mucosa Gástrica/metabolismo , Ácido Glutâmico/metabolismo , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/metabolismo , Animais , Anti-Inflamatórios não Esteroides , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Humanos , Masculino , Ratos , Ratos Sprague-Dawley
13.
Pest Manag Sci ; 70(4): 667-73, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23861305

RESUMO

BACKGROUND: Benzophenone hydrazone derivatives are among the most important classes of synthetic insecticides. In an effort to discover new molecules with good insecticidal/acaricidal activities, a series of novel benzophenone hydrazone N-acylated thiourea and urea derivatives was synthesized and bioassayed. RESULTS: All of these compounds exhibited excellent bioactivities against T. cinnabarinus and B. brassicae, especially towards T. cinnabarinus with LC50 values ranging from 0.305 to 2.036 mmol L(-1). Moreover, the acaricidal activities against T. cinnabarinus of compounds 8a-i, 12b-f and 12h were 2.5-5.5-fold that of parent molecule 3 based on the LC50 value. CONCLUSION: Based on the observed bioactivities, the structure-activity relationship of these analogs was also discussed. Structure-activity relationships provided information that could direct further investigation on structure modification. Our studies indicated that benzophenone hydrazone N-acylated thiourea and urea derivatives could be used as potential lead compounds for developing novel acaricides and insecticides.


Assuntos
Acaricidas/síntese química , Inseticidas/síntese química , Acaricidas/toxicidade , Animais , Afídeos/efeitos dos fármacos , Benzofenonas/química , Benzofenonas/toxicidade , Bioensaio , Hidrazonas/química , Hidrazonas/toxicidade , Inseticidas/toxicidade , Relação Estrutura-Atividade , Tetranychidae/efeitos dos fármacos
14.
Med Chem Res ; 23(11): 4926-4931, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25709376

RESUMO

A series of novel spin-labeled 4ß-[(4-substituted)-1,2,3-triazol-1-yl]podophyllotoxin derivatives (17a-h) were firstly designed and synthesized with significant regioselectivity by employing Cu(I) catalyzed click approach, and evaluated for cytotoxicity against four human tumor cell lines (A-549, DU145, KB, and KBvin). Among them, compound 17h displayed the highest cytotoxic activity against the tumor cell lines tested. Significantly, compound 17h showed superior cytotoxic activity compared with etoposide (IC50 6.30 to>10 µM), a clinically available anticancer drug. Significant activity toward the drug resistant KBvin cell line revealed promising future for compound 17h as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidate.

15.
Bioorg Med Chem ; 21(8): 2363-2369, 2013 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-23490151

RESUMO

Twenty new acyl thiourea derivatives of podophyllotoxin and 4'-demethylepipodophyllotoxin were prepared and screened for their cytotoxicity against four human tumor cell lines, A-549, DU-145, KB, and KBvin. With IC50 values of 0.098-1.13 µM, compounds 13b, 13c, and 13o displayed much better cytotoxic activity than the control etoposide. Most importantly, 13b and 13o exhibited promising cytotoxicity against the drug resistant tumor cell line KBvin with IC50 values of 0.098 and 0.13 µM, respectively, while etoposide lost activity completely. Structure-activity relationship (SAR) correlations of the new derivatives have been established. Compounds 13b and 13o merit further development as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidates.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Podofilotoxina/análogos & derivados , Podofilotoxina/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células KB , Podofilotoxina/síntese química , Podofilotoxina/química , Relação Estrutura-Atividade , Tioureia/análogos & derivados , Tioureia/síntese química , Tioureia/química , Tioureia/farmacologia , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia
16.
Bioorg Med Chem Lett ; 22(24): 7659-61, 2012 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-23102893

RESUMO

New 7-acyl camptothecin derivatives were designed and synthesized from camptothecin in a one-pot reaction through a Minisci type-reaction and were evaluated for cytotoxicity against four tumor cell lines, A-549, DU-145, KB, and KB-vin. All of the new compounds showed significant inhibition of human tumor cell growth, with IC(50) values ranging from 0.01538 to 13.342 µM. Most of the derivatives were more cytotoxic than irinotecan, and the (7a) and 7-propionyl (7b) analogs exhibited the highest cytotoxic activity against the tumor cell lines tested. This compound class merits further development as anticancer clinical trial candidates.


Assuntos
Antineoplásicos/farmacologia , Camptotecina/farmacologia , Desenho de Drogas , Antineoplásicos/síntese química , Antineoplásicos/química , Camptotecina/síntese química , Camptotecina/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Células KB , Estrutura Molecular , Relação Estrutura-Atividade
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