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1.
Pestic Biochem Physiol ; 158: 112-120, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31378345

RESUMO

Cytochrome P450s (P450s) confer resistance against herbicides, and this is increasingly becoming a concern for weed control. As a widespread Gramineae weed in paddy fields, Echinocloa glabrescens has become resistant to the acetolactate synthase (ALS)-inhibiting triazolopyrimidine herbicide penoxsulam. In this study, we found that the GR50 of the resistant population (SHQP-R) decreased substantially from 25.6 to 5.0 and 6.2 g a.i. ha-1 after treatment with the P450 inhibitors piperonyl butoxide (PBO) and malathion, respectively. However, P450 inhibitors almost had no effects on the susceptibility of the sensitive population (JYJD-S) to penoxsulam. To investigate the mechanisms of metabolic resistance, transcriptome sequencing analysis was performed to find candidate genes that may confer resistance to penoxsulam in E. glabrescens. A total of 233 P450 differentially expressed genes (DEGs) were identified by transcriptome sequencing. We found that the metabolic process and metabolic pathways were the most highly enriched in DEGs. Further, twenty-seven candidate P450 DEGs were selected for qPCR validation analyses. After penoxsulam treatment, the relative expression levels were significantly higher in SHQP-R than in JYJD-S. Among these, the relative expression of twenty-three P450 DEGs (eighteen from the CYP72A-71C-74A-96A-734A subfamily; five from CYP81E1-94C1-94B3-714C1-714C2) were upregulated and four P450 DEGs (from CYP724B1-711A1-707A7-97B2) were downregulated. Changes in the expression of these candidate P450 genes in E. glabrescens were in response to penoxsulam, which provides preliminary evidence for the role of P450s in herbicide metabolism in E. glabrescens. However, further functional studies on metabolic resistance to penoxsulam in a resistant E. glabrescens population are required.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Echinochloa/efeitos dos fármacos , Echinochloa/metabolismo , Perfilação da Expressão Gênica/métodos , Sulfonamidas/farmacologia , Uridina/análogos & derivados , Sistema Enzimático do Citocromo P-450/genética , Echinochloa/genética , Resistência a Herbicidas/genética , Malation/farmacologia , Butóxido de Piperonila/farmacologia , Uridina/farmacologia
2.
J Enzyme Inhib Med Chem ; 34(1): 1388-1399, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31392901

RESUMO

Fourteen novel dipeptide carboxamide derivatives bearing benzensulphonamoyl propanamide were synthesized and characterized using 1H NMR, 13C NMR, FTIR and MS spectroscopic techniques. In vivo antimalarial and in vitro antimicrobial studies were carried out on these synthesized compounds. Molecular docking, haematological analysis, liver and kidney function tests were also evaluated to assess the effect of the compounds on the organs. At 200 mg/kg body weight, 7i inhibited the multiplication of the parasite by 81.38% on day 12 of post-treatment exposure. This was comparable to the 82.34% reduction with artemisinin. The minimum inhibitory concentration (MIC) in µM ranged from 0.03 to 2.34 with 7h having MIC of 0.03 µM against Plasmodium falciparium. The in vitro antibacterial activity of the compounds against some clinically isolated bacteria strains showed varied activities with some of the new compounds showing better activities against the bacteria and the fungi more than the reference drug ciprofloxacin and fluconazole.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antimaláricos/química , Antimaláricos/farmacologia , Dipeptídeos/química , Dipeptídeos/farmacologia , Sulfonamidas/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antimaláricos/síntese química , Bactérias/efeitos dos fármacos , Dipeptídeos/síntese química , Fungos/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Ratos , Sulfonamidas/química
3.
J Enzyme Inhib Med Chem ; 34(1): 1380-1387, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31401884

RESUMO

Novel sulfonamide-dithiocarbamate hybrids were designed and synthesised via the molecular hybridisation strategy. Among them, compound 13d displayed a potent activity with IC50 values of 0.9, 0.7, 1.9 and 2.6 µM against UM-UC-3, RT-112, RT4 and T24. Compound 13d inhibited the migration and regulated the migration-related markers (E-cadherin, N-cadherin, Vimentin, Snail and Slung) against RT-112 cells in a concentration dependent manner. By the tubulin polymerisation assay in vitro and immunostaining assay, compound 13d was identified as a novel tubulin polymerisation inhibitor. Intragastric administration of compound 13d could inhibit the growth of RT-112 cells in vivo in a xenograft mouse model with the low toxicity, indicating that it may be a leading candidate with antitumor properties to treat bladder cancer.


Assuntos
Antineoplásicos/farmacologia , Sulfonamidas/farmacologia , Moduladores de Tubulina/farmacologia , Neoplasias da Bexiga Urinária/patologia , Animais , Antineoplásicos/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectrometria de Massas , Camundongos , Camundongos Nus , Espectroscopia de Prótons por Ressonância Magnética , Sulfonamidas/química , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Enzyme Inhib Med Chem ; 34(1): 1457-1464, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31411080

RESUMO

Carbonic anhydrases (CAs, EC 4.2.1.1) are crucial metalloenzymes that are involved in diverse bioprocesses. We report the synthesis and biological evaluation of novel series of benzenesulfonamides incorporating un/substituted ethyl quinoline-3-carboxylate moieties. The newly synthesised compounds were in vitro evaluated as inhibitors of the cytosolic human (h) isoforms hCA I and II. Both isoforms hCA I and II were inhibited by the quinolines reported here in variable degrees: hCA I was inhibited with KIs in the range of 0.966-9.091 µM, whereas hCA II in the range of 0.083-3.594 µM. The primary 7-chloro-6-flouro substituted sulphfonamide derivative 6e (KI = 0.083 µM) proved to be the most active quinoline in inhibiting hCA II, whereas, its secondary sulfonamide analog failed to inhibit the hCA II up to 10 µM, confirming the crucial role of the primary sulphfonamide group, as a zinc-binding group for CA inhibitory activity.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica I/antagonistas & inibidores , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Inibidores da Anidrase Carbônica/química , Humanos , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade , Sulfonamidas/química
5.
Pestic Biochem Physiol ; 159: 17-21, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400779

RESUMO

Capsella bursa-pastoris is a serious broadleaf weed in winter wheat fields in China. It has evolved high levels of resistance to acetolactate synthase (ALS) inhibiting herbicides and has caused substantial losses of wheat yield in recent years. We monitored the herbicide resistance of Capsella bursa-pastoris collected from 18 regions of Shandong Province in 2009, 2013 and 2017, respectively. Compared with the 2009 populations, the number of populations resistant to florasulam had increased in 2013 and 2017. Resistance to tribenuron-methyl increased in 2013, but decreased in 2017. The 2009 and 2013 populations developed resistance only to tribenuron-methyl, but some 2017 populations developed cross-resistance to imazethapyr and florasulam as well. Mutations in ALS (Pro-197-Thr/Ser/His/Arg/Leu/Gln) were identified in the 2009 and 2013 populations; however, two ALS mutations (Pro197 and/or Trp574) were identified in 2017 plants. Meanwhile, plants containing both point mutations (Pro197 + Trp574) were identified in the 2017 populations. This study demonstrated that target site gene mutations were the main reason for Capsella bursa-pastoris resistance to ALS-inhibiting herbicides. Although target-site mutation is the reason for resistance to ALS-inhibiting herbicides in Capsella bursa-pastoris, the resistance patterns and mutations identified have changed over time.


Assuntos
Acetolactato Sintase/genética , Capsella/efeitos dos fármacos , Resistência a Herbicidas/genética , Herbicidas/farmacologia , Proteínas de Plantas/genética , Sulfonatos de Arila/farmacologia , Capsella/enzimologia , Capsella/genética , Mutação/genética , Ácidos Nicotínicos/farmacologia , Mutação Puntual/genética , Pirimidinas/farmacologia , Sulfonamidas/farmacologia
6.
J Agric Food Chem ; 67(29): 8085-8095, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31265279

RESUMO

Herbicide resistance identification is essential for effective chemical weed control. In this study, we quantified the differences in growth response between penoxsulam resistant (R) and sensitive (S) Echinochloa crus-galli populations, explored the changes in ALS, and performed genetic analyses to identify metabolic genes that are up-regulated by the application of penoxsulam and other common herbicides. The R population showed a 26.0-fold higher resistance to penoxsulam and varied resistance to most tested herbicides with indices ranging from 4.9 to 145.9. A Trp-574-Arg amino acid mutation in ALS and low penoxsulam ALS sensitivity were the main mechanisms underlying herbicide resistance. The penoxsulam resistance can be significantly reversed by two P450s inhibitors and one GST inhibitor. By RNA-Seq, thirty-six highly expressed contigs were selected, and 30 of them were up-regulated in the R population treated by penoxsulam. Many of these genes were significantly expressed when treated with pyroxsulam, metamifop, and quinclorac. These upregulated genes appear to be complementary for plant resistance to penoxsulam and other common herbicides.


Assuntos
Echinochloa/efeitos dos fármacos , Resistência a Herbicidas , Herbicidas/farmacologia , Sulfonamidas/farmacologia , Uridina/análogos & derivados , Acetolactato Sintase/genética , Acetolactato Sintase/metabolismo , Echinochloa/genética , Echinochloa/crescimento & desenvolvimento , Echinochloa/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Uridina/farmacologia
7.
Expert Opin Ther Pat ; 29(8): 595-603, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31280615

RESUMO

Introduction: As a key element in arguably the most important pathway MAPK signaling, the BRAF kinase gives rise to severe diseases including cancers when pathologically activated. Extensive research on BRAFi (BRAF inhibitor) has been carried out to profile the characters for optimized agents and to elaborate the therapeutic strategies for the related cancer treatment. Areas covered: This review gives an overview of recently approved BRAF agents on function mode, therapeutic efficacy, and deficiency, based on which current challenges and corresponding strategies were presented. New entities as BRAFi for medical purpose in patent literature during the period 2013-2018 were also briefly introduced. Expert opinion: With the disclosure of paradox-breaker BRAFi PLX7904 crystal in complex with BRAF, the rational design for next-generation BRAFi is becoming ever more feasible. Accompanying therapeutic strategies in BRAFi elaboration may also provide flexible choice in the future 'personal medicine'. Further digging in the greatly enriched BRAFi pool will greatly benefit the drug design processes such as FBDD- and SBDD-driven development.


Assuntos
Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/farmacologia , Desenho de Drogas , Compostos Heterocíclicos com 2 Anéis/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias/patologia , Patentes como Assunto , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Sulfonamidas/farmacologia
8.
J Agric Food Chem ; 67(31): 8459-8467, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31339701

RESUMO

Novel purine nucleoside derivatives containing a sulfonamide moiety were prepared, as well as their antiviral activities against potato virus Y (PVY), cucumber mosaic virus (CMV), and tobacco mosaic virus (TMV) were evaluated. The antiviral mechanisms of the compounds were investigated. Results showed that most of the compounds had good antiviral activities. Compound 5 at 500 µg/mL exhibited excellent curative and protective activities of 52.5% and 60.0% and of 52.0% and 60.2% for PVY and CMV, respectively, which are higher than those of ningnanmycin (48.1%, 49.6%; 45.3%, 47.7%), ribavirin (38.3%, 48.2%; 40.8%, 45.5%), and chitosan oligosaccharide (32.5%, 33.8%; 35.1%, 34.6%). Moreover, compound 5 displayed good inactivating activity against TMV, with an EC50 value of 48.8 µg/mL, which is better than that of ningnanmycin (84.7 µg/mL), ribavirin (150.4 µg/mL), and chitosan oligosaccharide (521.3 µg/mL). The excellent antiviral activity of compound 5 is related to its immune induction effect which can regulate the physiological and biochemical processes in plants, including defense-related enzyme activities, defense-related genes, and photosynthesis-related proteins. These results indicate that purine nucleoside derivatives containing a sulfonamide moiety are worthy of further research and development as new antiviral agents.


Assuntos
Antivirais/química , Antivirais/farmacologia , Nucleosídeos de Purina/química , Nucleosídeos de Purina/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Antivirais/síntese química , Cucumovirus/efeitos dos fármacos , Desenho de Drogas , Estrutura Molecular , Potyvirus/efeitos dos fármacos , Relação Estrutura-Atividade , Vírus do Mosaico do Tabaco/efeitos dos fármacos
9.
Chem Biol Interact ; 309: 108723, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31228469

RESUMO

Ischemic preconditioning and pharmacological preconditioning are common strategies to prevent lethal myocardial injury, especially nutritional preconditioning (NPC). In this study, we investigated the effects of astragaloside IV (Ast), as an NPC agent, on myocardium suffered anoxia/reoxygenation (A/R) injury. Rats received 5 mg/kg Ast daily for 3 weeks by intragastric administration. Then, hearts were harvested and underwent A/R treatment using a Langendorff apparatus. Ast- pretreatment significantly promoted functional recovery of the myocardium, reduced infarct size, and oxidative stress, and decreased the apoptotic index. Similar findings were demonstrated in H9c2 cardiomyocytes that were pretreated with Ast for 24 h. Moreover, Ast-pretreatment significantly upregulated Bcl-2 expression, especially in mitochondria. The effects of Ast treatment against A/R injury were also reflected by increased antioxidant potential, inhibited reactive oxygen species (ROS) burst, increased oxygen consumption rate, maintained mitochondrial membrane potential (MMP), inhibited mitochondrial permeability transition pore (mPTP) opening, and prevented apoptosis. Selective inhibition of Bcl-2 by ABT-737 decreased myocardial injury protection of Ast. Ast-pretreatment resulted in NPC- related effects against A/R, and mitochondria may be the target of a cascade of events elicited by upregulating Bcl-2 expression, promoting translocation of Bcl-2 into mitochondria, maintaining MMP, inhibiting ROS bursts, thereby leading to recovery of mitochondrial respiration, preventing mPTP opening, decreasing cytochrome C release, preventing apoptosis, and ultimately alleviating myocardial injury.


Assuntos
Mitocôndrias/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Antioxidantes/química , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Caspase 3/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocromos c/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/efeitos dos fármacos , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Nitrofenóis/farmacologia , Nitrofenóis/uso terapêutico , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Superóxido Dismutase/metabolismo
10.
Expert Opin Ther Pat ; 29(7): 487-496, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31154862

RESUMO

INTRODUCTION: Studies presented in patents show that a novel chemotherapeutic agent, venetoclax, might be useful in additional therapeutic indications. Venetoclax is approved in America for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Venetoclax selectively inhibits the B-cell lymphoma-2 (Bcl-2) protein, an anti-apoptotic protein that can be overexpressed in most B-cell lymphoid malignancies. AREAS COVERED: This is a review of all the patents granted until November 2018, with venetoclax in the examples or claim section of the patent document. The patents include the synthesis, polymorphism, formulations, in vitro and in vivo efficacy as well as the therapeutic application of venetoclax. EXPERT OPINION: The approved indications for treatment with venetoclax are limited but expanding rapidly. Studies suggest that venetoclax might be useful in several other therapeutic indications, mostly other hematological malignancies. Numerous studies use venetoclax in combinations with other therapeutic agents. Such combinational treatment shows promising results in additional indications as well as drug-resistant cancers. Venetoclax is an interesting new therapeutic involved in a variety of clinical research. Patent applications in recent years even include venetoclax in somewhat exotic fields such as type 1 diabetes, asthma, and Zika virus treatment.


Assuntos
Antineoplásicos/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Sulfonamidas/administração & dosagem , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Patentes como Assunto , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacologia
11.
Ecotoxicol Environ Saf ; 181: 43-48, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31158722

RESUMO

More and more antibacterial agents are used together to treat bacterial infections in diverse fields, but the overuse of antibacterial agents may cause the environmental pollution of antibiotic resistance genes (ARGs). In order to reduce the use of antimicrobial agents, the potential joint effects of quorum-sensing inhibitors (QSIs) and traditional antimicrobial agents have been proposed to be effective. In this study, the joint effects of traditional antimicrobial agents, represented by sulfonamides (SAs) and silver antibacterial agents (silver nitrate (AgNO3) and nanosilver (AgNP, 5 nm)), and five potential QSIs, were investigated using B. subtilis. It was found that AgNP showed higher toxicity than AgNO3, whereas the joint effects on B. subtilis showed no difference between AgNO3 and AgNP when they combined with SAs or QSIs, respectively. In general, AgNO3 and AgNP presented synergetic and additive effects with QSIs, but additive and antagonistic effects with SAs; SAs exhibited synergetic, additive and antagonistic effects with different QSIs whether in binary or ternary mixed system. Moreover, it was found that the use of antimicrobials was reduced and the synergistic combined toxicity of antimicrobial agents on B. subtilis was increased through the addition of the QSIs. This study can offer a valuable reference for the combined medication of the different antimicrobial agents, which will benefit the environmental and human health.


Assuntos
Antibacterianos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Nanopartículas Metálicas/administração & dosagem , Percepção de Quorum/efeitos dos fármacos , Nitrato de Prata/farmacologia , Sulfonamidas/farmacologia , Antibacterianos/administração & dosagem , Sinergismo Farmacológico , Nitrato de Prata/administração & dosagem , Sulfonamidas/administração & dosagem
12.
J Enzyme Inhib Med Chem ; 34(1): 1199-1209, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31237458

RESUMO

The synthesis of a novel series of 3-functionalised benzenesulfonamides incorporating phenyl-1,2,3-triazole with an amide linker was achieved by using the "click-tail" approach. The new compounds, including the intermediates, were assayed as inhibitors of human carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I and II (cytosolic isoforms) and also for hCA IV and IX (transmembrane isoforms) taking acetazolamide as standard drug. Most of these compounds exhibited excellent activity against all these isoforms. hCA I was inhibited with Kis in the range of 50.8-966.8 nM, while the glaucoma associated hCA II was inhibited with Kis in the range of 6.5-760.0 nM. Isoform hCA IV was inhibited with Kis in the range of 65.3-957.5 nM, whereas the tumor associated hypoxia induced hCA IX was inhibited with Kis in the range of 30.8-815.9 nM. The structure activity relationship study for the 3-functionalised-1-phenyl-1,2,3-triazole sulfamoylbenzamides against these isoforms was also inferred from the results.


Assuntos
Inibidores da Anidrase Carbônica/síntese química , Isoenzimas/antagonistas & inibidores , Sulfonamidas/farmacologia , Triazóis/química , Triazóis/farmacologia , Inibidores da Anidrase Carbônica/química , Humanos , Isoenzimas/química , Relação Estrutura-Atividade , Sulfonamidas/química
13.
Pestic Biochem Physiol ; 157: 60-68, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31153478

RESUMO

A series of novel substituted oxazole isoxazole carboxamides derivatives were designed on the basis of active subunit combination. Forty-four novel compounds were synthesized by an efficient one-pot procedure under microwave irradiation. The bioactivity was evaluated as herbicide safener against the injury of chlorsulfuron. It was found that most of the synthesized compounds displayed remarkable protection against chlorsulfuron via enhanced glutathione content and glutathione S transferase activity. Especially compound I-11 exhibited better bioactivity than the safeners isoxadifen-ethyl and R-28725. Molecular docking simulations suggested that the target compounds could compete with chlorsulfuron in the active site of acetolactate synthase, which could explain the protective effects of safeners. The present work demonstrates that the target compounds containing oxazole isoxazole groups could be considered as potential candidates for developing novel safeners in the future.


Assuntos
Herbicidas/química , Herbicidas/farmacologia , Isoxazóis/química , Oxazóis/química , Sulfonamidas/farmacologia , Triazinas/farmacologia , Acetolactato Sintase/genética , Acetolactato Sintase/metabolismo , Ativação Enzimática/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Transferase/metabolismo , Relação Estrutura-Atividade , Zea mays/enzimologia
14.
Life Sci ; 232: 116561, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31247208

RESUMO

AIMS: The poor prognosis of ovarian cancer is mainly caused by chemotherapy resistance. Studies show that the Bcl-2 inhibitor ABT737 can significantly improve the effect of cisplatin and induce mitochondrial pathway apoptosis. However, the mechanism of ABT737 increases sensitivity to cisplatin by regulating mitochondrial function remains unclear in ovarian cancer cells. Sirt3, as a histone deacetylase, is involved in the regulation of mitochondrial function in cancers. In this study, we intend to explore the mechanistic link between Sirt3 and mitochondrial dysfunction induced by ABT737 and cisplatin in ovarian cancer cells. MAIN METHODS: Apoptosis was examined by flow cytometry following Annexin V and PI staining. Sirt3 activity was assessed using Sirt3 deacetylase fluorometric assay. The mitochondrial membrane potential was examined by flow cytometry following JC-1 staining. Overexpression and knock-down of Sirt3 were confirmed by western blot analysis. Mitochondrial fission/fusion dynamics were detected by immunofluorescence staining or western blot analysis. KEY FINDINGS: Cisplatin accompanied with ABT737 promoted apoptosis and decreased mitochondrial membrane potential. ABT737 enhanced the sensitivity of ovarian cancer cells to cisplatin, which was partly achieved by activating Sirt3 to regulate the mitochondrial fission process. SIGNIFICANCE: This study identified the activation of Sirt3 played an important role in increasing sensitivity of ovarian cancer cells to cisplatin induced by ABT737. Furthermore, Sirt3 might represent a potential therapeutic target for ovarian cancer.


Assuntos
Compostos de Bifenilo/farmacologia , Nitrofenóis/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Sirtuína 3/metabolismo , Sulfonamidas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptose/efeitos dos fármacos , Carcinoma Epitelial do Ovário/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/metabolismo , Cisplatino/farmacologia , Feminino , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Neoplasias Ovarianas/fisiopatologia , Ovário/metabolismo , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Eur J Med Chem ; 176: 50-60, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096118

RESUMO

New sulfonamides 5/6 derived from 4-methoxyacetophenone 1 were synthesized by N-sulfonation reaction of ammonia (3) and aminopyrimidinone (4) with its sulfonyl chloride derivative 2. Sulfonamides 5 and 6 were used as precursors of two new series of chalcones 8a-f and 9a-f, which were obtained through Claisen-Schmidt condensation with aromatic aldehydes 7a-f. Compounds 5/6, 8a-d, 8f, 9a-d, and 9f were screened by the US National Cancer Institute (NCI) at 10 µM against sixty different human cancer cell lines (one-dose trial). Chalcones 8b and 9b satisfied the pre-determined threshold inhibition criteria and were selected for screening at five different concentrations (100, 10, 1.0, 0.1, and 0.01 µM). Compound 8b exhibited remarkable GI50 values ranging from 0.57 to 12.4 µM, with cytotoxic effects being observed in almost all cases, especially against the cell lines K-562 of Leukemia and LOX IMVI of Melanoma with GI50 = 0.57 and 1.28 µM, respectively. Moreover, all compounds were screened against Mycobacterium tuberculosis H37Rv, chalcones 8a-c and 9a-c were the most active showing MIC values between 14 and 42 µM, and interestingly they were devoid of antibacterial activity against Mycobacterium smegmatis and Staphylococcus aureus. These antituberculosis hits showed however low selectivity, being equally inhibitory to M. tuberculosis and mammalian T3T cells. The chalcone-sulfonamide hybrids 8a-f and 9a-f resulted to be appealing cytotoxic agents with significant antituberculosis activity.


Assuntos
Antineoplásicos/farmacologia , Antituberculosos/farmacologia , Chalconas/farmacologia , Sulfonamidas/farmacologia , Células 3T3 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/toxicidade , Linhagem Celular Tumoral , Chalconas/síntese química , Chalconas/química , Chalconas/toxicidade , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/toxicidade
16.
Eur J Med Chem ; 177: 198-211, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31136894

RESUMO

A series of 3-amino-substituted rutacecarpine derivatives were synthesized to identify novel multitarget-directed ligands (MTDLs) for the treatment of Alzheimer's disease (AD). Biological evaluation showed that most of the synthesized compounds inhibited butyrylcholinesterase (BuChE) and exerted antioxidant effects. Among the synthesized compounds, 6n was subjected to further biological evaluation. Lineweaver-Burk plotting and molecular modeling illustrated that 6n bound simultaneously to the peripheral anionic site (PAS) and catalytic sites (CAS) of BuChE. Furthermore, 6n modulated Aß aggregation; chelated biometals; presented good absorption, distribution, metabolism, excretion, and toxicity properties; and showed remarkable neuroprotective activity. Previous research has shown that the optimized compound 6n has considerable potential for development as an MTDL for the treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Substâncias Protetoras/farmacologia , Sulfonamidas/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Linhagem Celular Tumoral , Quelantes/síntese química , Quelantes/química , Quelantes/farmacocinética , Quelantes/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacocinética , Desenho de Drogas , Humanos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Substâncias Protetoras/síntese química , Substâncias Protetoras/química , Substâncias Protetoras/farmacocinética , Multimerização Proteica/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacocinética
17.
Gastroenterology ; 157(3): 823-837, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31078621

RESUMO

BACKGROUND & AIMS: Most pancreatic ductal adenocarcinomas (PDACs) express an activated form of KRAS, become hypoxic and dysplastic, and are refractory to chemo and radiation therapies. To survive in the hypoxic environment, PDAC cells upregulate enzymes and transporters involved in pH regulation, including the extracellular facing carbonic anhydrase 9 (CA9). We evaluated the effect of blocking CA9, in combination with administration of gemcitabine, in mouse models of pancreatic cancer. METHODS: We knocked down expression of KRAS in human (PK-8 and PK-1) PDAC cells with small hairpin RNAs. Human and mouse (KrasG12D/Pdx1-Cre/Tp53/RosaYFP) PDAC cells were incubated with inhibitors of MEK (trametinib) or extracellular signal-regulated kinase (ERK), and some cells were cultured under hypoxic conditions. We measured levels and stability of the hypoxia-inducible factor 1 subunit alpha (HIF1A), endothelial PAS domain 1 protein (EPAS1, also called HIF2A), CA9, solute carrier family 16 member 4 (SLC16A4, also called MCT4), and SLC2A1 (also called GLUT1) by immunoblot analyses. We analyzed intracellular pH (pHi) and extracellular metabolic flux. We knocked down expression of CA9 in PDAC cells, or inhibited CA9 with SLC-0111, incubated them with gemcitabine, and assessed pHi, metabolic flux, and cytotoxicity under normoxic and hypoxic conditions. Cells were also injected into either immune-compromised or immune-competent mice and growth of xenograft tumors was assessed. Tumor fragments derived from patients with PDAC were surgically ligated to the pancreas of mice and the growth of tumors was assessed. We performed tissue microarray analyses of 205 human PDAC samples to measure levels of CA9 and associated expression of genes that regulate hypoxia with outcomes of patients using the Cancer Genome Atlas database. RESULTS: Under hypoxic conditions, PDAC cells had increased levels of HIF1A and HIF2A, upregulated expression of CA9, and activated glycolysis. Knockdown of KRAS in PDAC cells, or incubation with trametinib, reduced the posttranscriptional stabilization of HIF1A and HIF2A, upregulation of CA9, pHi, and glycolysis in response to hypoxia. CA9 was expressed by 66% of PDAC samples analyzed; high expression of genes associated with metabolic adaptation to hypoxia, including CA9, correlated with significantly reduced survival times of patients. Knockdown or pharmacologic inhibition of CA9 in PDAC cells significantly reduced pHi in cells under hypoxic conditions, decreased gemcitabine-induced glycolysis, and increased their sensitivity to gemcitabine. PDAC cells with knockdown of CA9 formed smaller xenograft tumors in mice, and injection of gemcitabine inhibited tumor growth and significantly increased survival times of mice. In mice with xenograft tumors grown from human PDAC cells, oral administration of SLC-0111 and injection of gemcitabine increased intratumor acidosis and increased cell death. These tumors, and tumors grown from PDAC patient-derived tumor fragments, grew more slowly than xenograft tumors in mice given control agents, resulting in longer survival times. In KrasG12D/Pdx1-Cre/Tp53/RosaYFP genetically modified mice, oral administration of SLC-0111 and injection of gemcitabine reduced numbers of B cells in tumors. CONCLUSIONS: In response to hypoxia, PDAC cells that express activated KRAS increase expression of CA9, via stabilization of HIF1A and HIF2A, to regulate pH and glycolysis. Disruption of this pathway slows growth of PDAC xenograft tumors in mice and might be developed for treatment of pancreatic cancer.


Assuntos
Antígenos de Neoplasias/metabolismo , Anidrase Carbônica IX/metabolismo , Carcinoma Ductal Pancreático/enzimologia , Neoplasias Pancreáticas/enzimologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Microambiente Tumoral , Animais , Antígenos de Neoplasias/genética , Antimetabólitos Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica IX/genética , Inibidores da Anidrase Carbônica/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Hipóxia Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Glicólise/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fenótipo , Compostos de Fenilureia/farmacologia , Transdução de Sinais , Sulfonamidas/farmacologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J Enzyme Inhib Med Chem ; 34(1): 1030-1040, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31074303

RESUMO

A series of sulphonamide benzoquinazolinones 5-18 was synthesized and evaluated for cytotoxic activity against MDA-MB-231 cell line. The compounds showed IC50 ranging from 0.26 to 161.49 µM. The promising compounds were evaluated for their inhibitory profile against epidermal growth factor (EGFR) and HER2 enzymes. Compound 10 showed more potent activity on both EGFR and HER2 than erlotinib (IC50 3.90 and 5.40 µM versus 6.21 and 9.42 µM). The pro-apoptotic activity of 10 was evaluated against caspase-3, Bax, B-cell lymphoma protein 2 (Bcl-2) expression levels, and cell cycle analysis. Compound 10 increased the level of caspase-3 by 10 folds, Bax level by 9 folds, decreased the level of the Bcl-2 by 0.14 and arrested the cell cycle in the G2/M phase. The radio-sensitizing activity of 10 was measured using a single dose of 8 Gy gamma radiation (IC50 decreased from 0.31 to 0.22 µM). Molecular docking was performed on EGFR and HER2 receptors.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinonas/farmacologia , Radiossensibilizantes/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinonas/síntese química , Quinazolinonas/química , Radiossensibilizantes/síntese química , Radiossensibilizantes/química , Receptor ErbB-2/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
19.
J Enzyme Inhib Med Chem ; 34(1): 1051-1061, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31074307

RESUMO

A large library of fibrate-based N-acylsulphonamides was designed, synthesised, and fully characterised in order to propose them as zinc binders for the inhibition of human carbonic anhydrase (hCA) enzymatic activity. Synthesised compounds were tested against four hCAs (I, II, IX, and XII) revealing a promising submicromolar inhibitory activity characterised by an isozyme selectivity pattern. Structural modifications explored within this scaffold are: presence of an aryl ring on the sulphonamide, p-substitution of this aryl ring, benzothiazole or benzophenone as core nuclei, and an n-propyl chain or a geminal dimethyl at Cα carbon. Biological results fitted well with molecular modelling analyses, revealing a putative direct interaction with the zinc ion in the active site of hCA I, II and IX. These findings supported the exploration of less investigated secondary sulphonamides as potential hCA inhibitors.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Simulação de Acoplamento Molecular , Sulfonamidas/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Domínio Catalítico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
20.
Chem Commun (Camb) ; 55(40): 5720-5723, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31038135

RESUMO

Epacadostat (EPA), a selective indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor, has been investigated in vitro as a human (h) Carbonic Anhydrase Inhibitor (CAI). The kinetic data clearly show, for the first time, EPA to be a highly effective and selective inhibitor for the tumor-associated isoforms hCA IX/XII. We report the high resolution X-ray crystal structure of the EPA-hCA II adduct, and assessed its binding mode to CA IX/XII by means of computational techniques. EPA may exert antitumor effects also due to the potent inhibition of the tumor-associated CAs.


Assuntos
Anidrase Carbônica IX/efeitos dos fármacos , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/efeitos dos fármacos , Neoplasias/enzimologia , Oximas/farmacologia , Polifarmacologia , Sulfonamidas/farmacologia , Anidrase Carbônica IX/química , Anidrases Carbônicas/química , Domínio Catalítico , Cristalografia por Raios X , Humanos , Ligações de Hidrogênio , Simulação de Acoplamento Molecular , Estrutura Molecular , Oximas/química , Sulfonamidas/química
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