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1.
Eur J Med Chem ; : 112914, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-33268145

RESUMO

Previous investigation of the potent antileishmanial properties of antitubercular 7-substituted 2-nitroimidazo[2,1-b][1,3]oxazines with biaryl side chains led to our development of a new clinical candidate for visceral leishmaniasis (DNDI-0690). Within a collaborative backup program, a racemic monoaryl lead (3) possessing comparable activity in mice but a greater hERG liability formed the starting point for our pursuit of efficacious second generation analogues having good solubility and safety. Asymmetric synthesis and appraisal of its enantiomers first established that chiral preferences for in vivo efficacy were species dependent and that neither form afforded a reduced hERG risk. However, in line with our findings in a structurally related series, less lipophilic heteroaryl ethers provided significant solubility enhancements (up to 16-fold) and concomitantly attenuated hERG inhibition. One promising pyridine derivative (49) displayed 100% oral bioavailability in mice and delivered a 96% parasite burden reduction when dosed at 50 mg/kg in a Leishmania donovani mouse model of visceral leishmaniasis.

2.
Dis Markers ; 2020: 8899924, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33204367

RESUMO

CD82 acts as a tumor suppressor in a series of steps in malignant progression. Here, we identified a novel function of CD82 on posttranslational regulating E-cadherin in prostate cancer. In our study, the declined expression of CD82 was verified in prostate cancer tissues and cell lines compared with normal tissue and cell lines. Functionally, CD82 inhibited cell migration and E-cadherin cleavage from the cell membrane in prostate cancer cell. Further study proved that a disintegrin and metalloproteinase ADAM17 as an executor of E-cadherin cleavage mediated the inhibitory regulation of CD82 in E-cadherin shedding in prostate cancer. Specifically, CD82 interacted with ADAM17 and inhibited its metalloprotease activity, which led to the descent of E-cadherin shedding. These results show a nuanced but important role of CD82 in nontranscriptional regulation of E-cadherin, which may help to understand the intricate regulation of dysfunctional adhesion molecule in cancer progression.

3.
Arch Med Res ; 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33059953

RESUMO

BACKGROUND: Recent studies indicate that androgen deprivation therapy (ADT), the main therapeutic approach for metastatic prostate cancer (PCa), accelerates PCa invasion and metastasis. Annexin A1 (ANXA1) is a Ca2+-regulated phospholipid-binding protein that can promote PCa migration and invasion. AIM OF THE STUDY: The aim of this study is to determine whether ANXA1 is regulated by ADT and participates in PCa progression after ADT, and to explore the possible mechanism of ANXA1-mediated PCa migration. METHODS: Expression of ANXA1 and androgen receptor (AR) in PCa cell lines and tissues was detected, and the association between these two proteins were analyzed. Expression of ANXA1 was evaluated after AR knockdown or AR inhibition in PCa cell lines. Cell migration of PCa cell liness after ANXA1 knockdown or overexpression was determined by in vitro migration assay. Transcriptome analysis was used to explore the possible mechanism of ANXA1-mediated PCa migration. RESULTS: ANXA1 expression in PCa cell lines and tissues was reversely associated with AR. In vitro studies revealed an increase in ANXA1 expression after AR knockdown or treatment with AR antagonist. Moreover, functional assays indicated that ANXA1 knockdown in PCa cells significantly inhibited cell migration, while ANXA1 overexpression in PCa cells significantly accelerated cell migration. Transcriptome analysis showed that ANXA1 regulated multiple genes involved in cell junction organization, such as CADM1, LIMCH1 and PPM1F. CONCLUSIONS: Our results indicate that ADT might accelerate PCa metastasis via ANXA1 expression and PCa cell migration.

4.
Diagn Microbiol Infect Dis ; 97(3): 115040, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32354459

RESUMO

Staphylococci are the most common causes of periprosthetic joint infection (PJI). TNP-2092 is an investigational hybrid drug composed of rifamycin and quinolizinone pharmacophores conjugated via a covalent linker. We determined minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and minimum biofilm bactericidal concentration (MBBC) values of TNP-2092 against 80 PJI-associated Staphylococcus aureus and Staphylococcus epidermidis isolates compared to ciprofloxacin and rifampin alone and in combination, alongside daptomycin and vancomycin. TNP-2092 exhibited the following activity against S. aureus: MIC50/MIC90, ≤0.0075/0.015 µg/mL; MBC50/MBC90, 0.5/4 µg/mL; and MBBC50/MBBC90, 0.5/2 µg/mL, and the following activity against S. epidermidis: MIC50/MIC90, ≤0.0075/0.015 µg/mL; MBC50/MBC90, 0.015/0.125 µg/mL; and MBBC50/MBBC90, 0.06/0.25 µg/mL. TNP-2092 MIC, MBC, and MBBC values were >8 µg/mL for 1 isolate, while MIC values were ≤0.25 µg/mL and MBC and MBBC values were ≤4 µg/mL for all other isolates. Results of this study show that TNP-2092 has promising in vitro activity against PJI-associated staphylococci.

5.
Molecules ; 25(10)2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32456032

RESUMO

The introductions of the bicyclic 4-nitroimidazole and the oxazolidinone classes of antimicrobial agents represented the most significant advancements in the infectious disease area during the past two decades. Pretomanid, a bicyclic 4-nitroimidazole, and linezolid, an oxazolidinone, are also part of a combination regimen approved recently by the US Food and Drug Administration for the treatment of pulmonary, extensively drug resistant (XDR), treatment-intolerant or nonresponsive multidrug-resistant (MDR) Mycobacterium tuberculosis (TB). To identify new antimicrobial agents with reduced propensity for the development of resistance, a series of dual-acting nitroimidazole-oxazolidinone conjugates were designed, synthesized and evaluated for their antimicrobial activity. Compounds in this conjugate series have shown synergistic activity against a panel of anaerobic bacteria, including those responsible for serious bacterial infections.

6.
Cancer Lett ; 473: 118-129, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-31843555

RESUMO

Early studies suggest that the androgen receptor (AR) may play differential roles in influencing prostate cancer (PCa) and bladder cancer (BCa) metastasis, but the underlying mechanisms remain unclear. Here, we found that the AR might function via differentially altering vasculogenic mimicry (VM) formation to either decrease PCa metastasis or increase BCa metastasis. Mechanism dissection showed that the AR could differentially alter the expression of the VM marker SLPI through miR-525-5p to regulate SLPI; moreover, it could either increase miR-525-5p transcription in PCa or decrease it in BCa via binding to different androgen-response-elements (AREs) located at different positions in the miR-525 precursor promoter. Further, results from liquid chromatography-mass spectrometry (LC-MS) showed that the co-factors of AR in PCa and BCa are NFIX and HDAC2, respectively. Together, these results provide the first detailed mechanism of how the AR can differentially alter PCa and BCa metastasis; thus, targeting the newly identified AR-miR-525-5p-SLPI axis may help suppress metastasis.


Assuntos
MicroRNAs/genética , Neovascularização Patológica/genética , Neoplasias da Próstata/genética , Receptores Androgênicos/metabolismo , Inibidor Secretado de Peptidases Leucocitárias/metabolismo , Neoplasias da Bexiga Urinária/genética , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Histona Desacetilase 2/metabolismo , Humanos , Masculino , Fatores de Transcrição NFI/metabolismo , Metástase Neoplásica/genética , Metástase Neoplásica/prevenção & controle , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Feniltioidantoína/análogos & derivados , Feniltioidantoína/farmacologia , Feniltioidantoína/uso terapêutico , Regiões Promotoras Genéticas/genética , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/patologia , RNA Interferente Pequeno/metabolismo , Receptores Androgênicos/genética , Inibidor Secretado de Peptidases Leucocitárias/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transcrição Genética/efeitos dos fármacos , Neoplasias da Bexiga Urinária/irrigação sanguínea , Neoplasias da Bexiga Urinária/patologia
7.
ACS Infect Dis ; 6(5): 820-831, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-31849218

RESUMO

TNP-2092 is a unique multitargeting drug conjugate with extremely low propensity for development of resistance. The in vitro activity of TNP-2092 against a panel of urease-producing bacteria was similar to that of rifaximin, a locally acting antibiotic approved for the treatment of hepatic encephalopathy, irritable bowel syndrome with diarrhea, and traveler's diarrhea. When given orally, TNP-2092 exhibited low absorption and the majority of compound was recovered in feces as parent. The impact of oral TNP-2092 on gut microbiota was investigated in rats. TNP-2092 was administered to rats by oral gavage for 7 days. Feces samples were collected and analyzed by 16S rRNA sequencing. Although the total amount of bacterial load appeared relatively unchanged before, during, and after treatment, significant changes in the relative abundance of certain gut bacteria at family and genus levels were observed. Some of the changes are known to be associated with improvement of symptoms associated with liver cirrhosis and hepatic encephalopathy. The observed effects of TNP-2092 on gut microbiota in rats were similar to those of rifaximin. In vivo, TNP-2092 demonstrated potent efficacy in a mouse Clostridium difficile infection model, superior to metronidazole and vancomycin, with no relapse observed after treatment. TNP-2092 is currently in clinical development for the treatment of symptoms associated with gastrointestinal and liver disorders.

8.
Cancer Lett ; 453: 193-205, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30928381

RESUMO

The prostate-specific G protein-coupled receptor (PSGR) is a class A G protein-coupled receptor (GPCR) that is specifically expressed in prostate epithelial cells, and its expression has been linked to prostate cancer (PCa) progression. Here, we show that activation of PSGR with its ligand ß-ionone, an end-ring analog of ß-carotenoid, can suppress PCa cell growth both in vitro and in vivo model. Dissection of the mechanism underlying this relationship reveals that activation of PSGR by ß-ionone suppresses AR nuclear translocation via phosphorylation of AR at residue Ser650 by p38 and JNK, which leads to the suppression of AR transactivation, further suppressing PCa cell growth. Overall, we link a cancer cell-specific GPCR with the nuclear AR and show that targeting PSGR can provide us a new target to combat PCa better.


Assuntos
Proteínas de Neoplasias/metabolismo , Norisoprenoides/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Receptores Odorantes/metabolismo , Animais , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Progressão da Doença , Humanos , MAP Quinase Quinase 4/metabolismo , Masculino , Camundongos , Camundongos Nus , Proteínas de Neoplasias/biossíntese , Células PC-3 , Fosforilação , Receptores Androgênicos/biossíntese , Receptores Odorantes/biossíntese , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
9.
Oncol Rep ; 40(6): 3543-3550, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30272315

RESUMO

Transforming growth factor (TGF)­ß1 is highly expressed in bladder transitional cell carcinoma (TCC) and is positively associated with tumor grade. TGF­ß1 signaling promotes cell metastasis by inducing epithelial­mesenchymal transition (EMT), however, the underlying mechanisms are not fully understood. Our previous study demonstrated the anti­metastatic effects of silibinin, a natural flavonoid derived from milk thistle, against TCC. The present study investigated the effects of silibinin on TGF­ß1­induced EMT in TCC, focusing on the role of prostaglandin­endoperoxide synthase 2 (COX­2). Cell migration was determined by a wound healing assay and Transwell migration assay, and cell invasion was investigated using a Transwell invasion assay. Cell morphology was observed using an inverted microscope. Cell viability was evaluated by an MTT and cell counting assays. EMT markers were detected by reverse transcription­quantitative polymerase chain reaction and western blotting. Specific small interfering RNA was used to knockdown COX­2 gene expression. TGF­ß1 promoted cell migration and invasion, induced EMT and upregulated the expression of COX­2. COX­2 knockdown attenuated TGF­ß1­induced EMT, indicating that COX­2 upregulation was essential for TGF­ß1­induced EMT. Silibinin attenuated TGF­ß1­induced migration and invasion by inhibiting EMT, and was associated with COX­2 downregulation. TGF­ß1­induced COX­2 upregulation, which was inhibited by silibinin. In addition, TGF­ß1­induced EMT was further inhibited when silibinin treatment was combined with COX­2­knockdown. The results suggested that silibinin may be a potential future treatment for metastatic TCC.


Assuntos
Carcinoma de Células de Transição/metabolismo , Ciclo-Oxigenase 2/metabolismo , Silibina/farmacologia , Fator de Crescimento Transformador beta1/farmacologia , Neoplasias da Bexiga Urinária/metabolismo , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Regulação para Baixo/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Invasividade Neoplásica , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética
10.
J Med Chem ; 61(6): 2329-2352, 2018 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-29461823

RESUMO

Discovery of the potent antileishmanial effects of antitubercular 6-nitro-2,3-dihydroimidazo[2,1- b][1,3]oxazoles and 7-substituted 2-nitro-5,6-dihydroimidazo[2,1- b][1,3]oxazines stimulated the examination of further scaffolds (e.g., 2-nitro-5,6,7,8-tetrahydroimidazo[2,1- b][1,3]oxazepines), but the results for these seemed less attractive. Following the screening of a 900-compound pretomanid analogue library, several hits with more suitable potency, solubility, and microsomal stability were identified, and the superior efficacy of newly synthesized 6 R enantiomers with phenylpyridine-based side chains was established through head-to-head assessments in a Leishmania donovani mouse model. Two such leads ( R-84 and R-89) displayed promising activity in the more stringent Leishmania infantum hamster model but were unexpectedly found to be potent inhibitors of hERG. An extensive structure-activity relationship investigation pinpointed two compounds ( R-6 and pyridine R-136) with better solubility and pharmacokinetic properties that also provided excellent oral efficacy in the same hamster model (>97% parasite clearance at 25 mg/kg, twice daily) and exhibited minimal hERG inhibition. Additional profiling earmarked R-6 as the favored backup development candidate.


Assuntos
Antiparasitários/síntese química , Antiparasitários/farmacologia , Leishmaniose Visceral/tratamento farmacológico , Oxazinas/síntese química , Oxazinas/farmacologia , Animais , Antiparasitários/farmacocinética , Permeabilidade da Membrana Celular , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Cricetinae , Citocromo P-450 CYP3A/efeitos dos fármacos , Inibidores do Citocromo P-450 CYP3A/síntese química , Inibidores do Citocromo P-450 CYP3A/farmacologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Canal de Potássio ERG1/antagonistas & inibidores , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/crescimento & desenvolvimento , Leishmania infantum/efeitos dos fármacos , Leishmania infantum/crescimento & desenvolvimento , Leishmaniose Visceral/parasitologia , Mesocricetus , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Oxazinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
11.
J Med Chem ; 60(10): 4212-4233, 2017 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-28459575

RESUMO

Within a backup program for the clinical investigational agent pretomanid (PA-824), scaffold hopping from delamanid inspired the discovery of a novel class of potent antitubercular agents that unexpectedly possessed notable utility against the kinetoplastid disease visceral leishmaniasis (VL). Following the identification of delamanid analogue DNDI-VL-2098 as a VL preclinical candidate, this structurally related 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazine class was further explored, seeking efficacious backup compounds with improved solubility and safety. Commencing with a biphenyl lead, bioisosteres formed by replacing one phenyl by pyridine or pyrimidine showed improved solubility and potency, whereas more hydrophilic side chains reduced VL activity. In a Leishmania donovani mouse model, two racemic phenylpyridines (71 and 93) were superior, with the former providing >99% inhibition at 12.5 mg/kg (b.i.d., orally) in the Leishmania infantum hamster model. Overall, the 7R enantiomer of 71 (79) displayed more optimal efficacy, pharmacokinetics, and safety, leading to its selection as the preferred development candidate.


Assuntos
Antiprotozoários/química , Antiprotozoários/uso terapêutico , Leishmania donovani/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Nitroimidazóis/química , Nitroimidazóis/uso terapêutico , Animais , Antiprotozoários/farmacocinética , Antiprotozoários/farmacologia , Antituberculosos/química , Antituberculosos/farmacocinética , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Cricetinae , Descoberta de Drogas , Feminino , Humanos , Masculino , Mesocricetus , Camundongos , Camundongos Endogâmicos BALB C , Nitroimidazóis/farmacocinética , Nitroimidazóis/farmacologia , Oxazinas/química , Oxazinas/farmacologia , Oxazinas/uso terapêutico , Ratos Sprague-Dawley
12.
Bioorg Med Chem Lett ; 27(11): 2583-2589, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28462832

RESUMO

As part of a quest for backups to the antitubercular drug pretomanid (PA-824), we investigated the unexplored 6-nitro-2,3-dihydroimidazo[2,1-b][1,3]-thiazoles and related -oxazoles. The nitroimidazothiazoles were prepared in high yield from 2-bromo-4-nitroimidazole via heating with substituted thiiranes and diisopropylethylamine. Equivalent examples of these two structural classes provided broadly comparable MICs, with 2-methyl substitution and extended aryloxymethyl side chains preferred; albeit, S-oxidised thiazoles were ineffective for tuberculosis. Favourable microsomal stability data for a biaryl thiazole (45) led to its assessment in an acute Mycobacterium tuberculosis mouse model, alongside the corresponding oxazole (48), but the latter proved to be more efficacious. In vitro screening against kinetoplastid diseases revealed that nitroimidazothiazoles were inactive versus leishmaniasis but showed interesting activity, superior to that of the nitroimidazooxazoles, against Chagas disease. Overall, "thio-delamanid" (49) is regarded as the best lead.


Assuntos
Antituberculosos/síntese química , Nitroimidazóis/química , Tiazóis/química , Animais , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Doença de Chagas/tratamento farmacológico , Modelos Animais de Doenças , Camundongos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Nitroimidazóis/farmacologia , Nitroimidazóis/uso terapêutico , Oxazóis/química , Oxazóis/farmacologia , Oxazóis/uso terapêutico , Relação Estrutura-Atividade , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Tuberculose/tratamento farmacológico
13.
Oncotarget ; 8(5): 8162-8172, 2017 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-28030804

RESUMO

MicroRNAs, a kind of small non-coding RNAs, can regulate gene expression by targeting mRNAs for translational repression or degradation. Much evidence has suggested that miR-218 was a tumor suppressor in many human cancers including prostate cancer. However, the underlying role of miR-218 in tumor angiogenesis and the mechanisms in PCa and other cancers remains to be unclear. Here in this present study, we demonstrated that miR-218 inhibited the tumor angiogenesis of PCa cells in vitro and in vivo. RICTOR, the mTOR component 2, was a direct target of miR-218 and miR218-RICTOR-VEGFA axis was the mechanism inhibiting the tumor angiogenesis of PCa cells. RICTOR knockdown phenocopied miR-218 overexpression in inhibiting prostate cancer angiogenesis. Altogether, our findings indicate that down-regulation of miR-218 contributes to tumor angiogenesis through RICTOR/VEGFA axis in PCa, providing new insights into the potential mechanisms of PCa oncogenesis and revealing the potential of miR-218 as a useful serum biomarker and a new therapeutic target for human PCa.


Assuntos
Biomarcadores Tumorais/metabolismo , MicroRNAs/metabolismo , Neovascularização Patológica , Neoplasias da Próstata/metabolismo , Proteína Companheira de mTOR Insensível à Rapamicina/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Regiões 3' não Traduzidas , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Sítios de Ligação , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos Nus , MicroRNAs/genética , Fosforilação , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Interferência de RNA , Coelhos , Proteína Companheira de mTOR Insensível à Rapamicina/genética , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Antimicrob Agents Chemother ; 60(10): 6271-80, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27503647

RESUMO

The recent development and spread of extensively drug-resistant and totally drug-resistant resistant (TDR) strains of Mycobacterium tuberculosis highlight the need for new antitubercular drugs. Protein synthesis inhibitors have played an important role in the treatment of tuberculosis (TB) starting with the inclusion of streptomycin in the first combination therapies. Although parenteral aminoglycosides are a key component of therapy for multidrug-resistant TB, the oxazolidinone linezolid is the only orally available protein synthesis inhibitor that is effective against TB. Here, we show that small-molecule inhibitors of aminoacyl-tRNA synthetases (AARSs), which are known to be excellent antibacterial protein synthesis targets, are orally bioavailable and effective against M. tuberculosis in TB mouse infection models. We applied the oxaborole tRNA-trapping (OBORT) mechanism, which was first developed to target fungal cytoplasmic leucyl-tRNA synthetase (LeuRS), to M. tuberculosis LeuRS. X-ray crystallography was used to guide the design of LeuRS inhibitors that have good biochemical potency and excellent whole-cell activity against M. tuberculosis Importantly, their good oral bioavailability translates into in vivo efficacy in both the acute and chronic mouse models of TB with potency comparable to that of the frontline drug isoniazid.


Assuntos
Antituberculosos/farmacologia , Leucina-tRNA Ligase/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Inibidores da Síntese de Proteínas/farmacologia , Administração Oral , Animais , Antituberculosos/administração & dosagem , Antituberculosos/química , Antituberculosos/farmacocinética , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Leucina-tRNA Ligase/química , Leucina-tRNA Ligase/genética , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Testes de Sensibilidade Microbiana , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium smegmatis/genética , Mycobacterium tuberculosis/genética , Inibidores da Síntese de Proteínas/administração & dosagem , Inibidores da Síntese de Proteínas/química , Inibidores da Síntese de Proteínas/farmacocinética , Relação Estrutura-Atividade , Tuberculose/tratamento farmacológico , Células Vero
15.
J Med Chem ; 59(14): 6645-57, 2016 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-27336583

RESUMO

The clinical management of prosthetic joint infections and other persistent bacterial infections represents a major unmet medical need. The rifamycins are one of the most potent antibiotic classes against persistent bacterial infections, but bacteria can develop resistance to rifamycins rapidly and the clinical utility of the rifamycin class is typically limited to antibiotic combinations to minimize the development of resistance. To develop a better therapy against persistent bacterial infections, a series of rifamycin based bifunctional molecules were designed, synthesized, and evaluated with the goal to identify a dual-acting drug that maintains the potent activity of rifamycins against persistent pathogens and at the same time minimize the development of rifamycin resistance. TNP-2092 was identified as a drug candidate and is currently in an early stage of clinical development for the treatment of prosthetic joint infections.


Assuntos
Antibacterianos/farmacologia , Infecções Bacterianas/tratamento farmacológico , Rifamicinas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Rifamicinas/síntese química , Rifamicinas/química , Relação Estrutura-Atividade
16.
J Med Chem ; 59(6): 2530-50, 2016 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-26901446

RESUMO

6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole derivatives were initially studied for tuberculosis within a backup program for the clinical trial agent pretomanid (PA-824). Phenotypic screening of representative examples against kinetoplastid diseases unexpectedly led to the identification of DNDI-VL-2098 as a potential first-in-class drug candidate for visceral leishmaniasis (VL). Additional work was then conducted to delineate its essential structural features, aiming to improve solubility and safety without compromising activity against VL. While the 4-nitroimidazole portion was specifically required, several modifications to the aryloxy side chain were well-tolerated e.g., exchange of the linking oxygen for nitrogen (or piperazine), biaryl extension, and replacement of phenyl rings by pyridine. Several less lipophilic analogues displayed improved aqueous solubility, particularly at low pH, although stability toward liver microsomes was highly variable. Upon evaluation in a mouse model of acute Leishmania donovani infection, one phenylpyridine derivative (37) stood out, providing efficacy surpassing that of the original preclinical lead.


Assuntos
Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Antituberculosos/síntese química , Antituberculosos/farmacologia , Leishmaniose Visceral/tratamento farmacológico , Animais , Antiprotozoários/farmacocinética , Antituberculosos/farmacocinética , Cricetinae , Reposicionamento de Medicamentos , Feminino , Ensaios de Triagem em Larga Escala , Concentração de Íons de Hidrogênio , Leishmania infantum/efeitos dos fármacos , Mesocricetus , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Solubilidade , Relação Estrutura-Atividade
18.
Mol Med Rep ; 13(1): 881-7, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26648574

RESUMO

The recurrence of bladder cancer after surgery with or without chemotherapy remains a major challenge in bladder cancer treatment. Previous studies have shown that transient receptor potential vanilloid 1 (TRPV1) acts as a tumor suppressor through inducing apoptosis in bladder cancer cells. However, whether activation of TRPV1 has any synergistic effects with pirarubicin (THP), one of main drugs used in urinary bladder instillation chemotherapy to improve chemotherapeutic efficacy has remained elusive. The present study verified that TRPV1 was differentially expressed in bladder cancer cell lines. Furthermore, activation of TRPV1 by capsaicin was shown to induce growth inhibition of 5637 cells in which TRPV1 was highly expressed, while the growth of T24 cells, which express TRPV1 at low levels, was not affected. In addition, the present study demonstrated that activation of TRPV1 enhanced the anti­proliferative effects of pirarubicin using an MTT assay and cell cycle analysis. Finally, immunofluorescent microscopy revealed that activation of TRPV1 prevented the translocation of proliferating cell nuclear antigen to the nucleus. This phenomenon was reversed by pre­treatment with capsazepine, a specific TRPV1 antagonist. In conclusion, the present study confirmed the anti­tumor activity of TRPV1 against bladder cancer. Activation of TRPV1 may be applied as a novel strategy to treat bladder cancer or enhance the therapeutic efficacy of traditional chemotherapeutic drugs.


Assuntos
Capsaicina/farmacologia , Núcleo Celular/metabolismo , Doxorrubicina/análogos & derivados , Antígeno Nuclear de Célula em Proliferação/metabolismo , Canais de Cátion TRPV/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/farmacologia , Fase G2/efeitos dos fármacos , Humanos , Mitose/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Fase S/efeitos dos fármacos , Canais de Cátion TRPV/agonistas
19.
Oncol Rep ; 34(5): 2461-8, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26323996

RESUMO

The downstream transcriptional factor of the hedgehog (Hh) pathway, GLI family zinc finger 1 (GLI1), plays a crucial role in regulating tumor progression. In the present study, we demonstrated that silibinin, a natural flavonoid antioxidant isolated from extracts of the milk thistle herb, exerts its anticancer capabilities by restraining GLI1 function in renal cell carcinoma (RCC) cells in vitro and in vivo. In the present study, we confirmed that silibinin induced growth inhibition of RCC through caspase-dependent apoptosis and downregulation of GLI1 and BCL2, which could be partially reversed by GLI1 overexpression. Moreover, we determined that the decreased GLI1 expression by silibinin was mediated by the mammalian target of rapamycin (mTOR) pathway. The in vivo mouse xenograft study also showed that silibinin significantly reduced RCC tumor growth and specifically targeted the mTOR-GLI1-BCL2 signaling pathway. In conclusion, our findings demonstrated for the first time that silibinin induces apoptosis of RCC cells through inhibition of the mTOR-GLI1­BCL2 pathway. These findings also indicate that GLI1 is a novel regulator for the potential therapeutic application of silibinin against RCC.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Silimarina/farmacologia , Animais , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/patologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Renais/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais , Silibina , Silimarina/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína GLI1 em Dedos de Zinco
20.
PLoS One ; 10(9): e0138390, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26397365

RESUMO

G9a has been reported to highly express in bladder transitional cell carcinoma (TCC) and G9a inhibition significantly attenuates cell proliferation, but the underlying mechanism is not fully understood. The present study aimed at examining the potential role of autophagy in the anti-proliferation effect of G9a inhibition on TCC T24 and UMUC-3 cell lines in vitro. We found that both pharmaceutical and genetical G9a inhibition significantly attenuated cell proliferation by MTT assay, Brdu incorporation assay and colony formation assay. G9a inhibition induced autophagy like morphology as determined by transmission electron microscope and LC-3 fluorescence assay. In addition, autophagy flux was induced by G9a inhibition in TCC cells, as determined by p62 turnover assay and LC-3 turnover assay. The autophagy induced positively contributed to the inhibition of cell proliferation because the growth attenuation capacity of G9a inhibition was reversed by autophagy inhibitors 3-MA. Mechanically, AMPK/mTOR pathway was identified to be involved in the regulation of G9a inhibition induced autophagy. Intensively activating mTOR by Rheb overexpression attenuated autophagy and autophagic cell death induced by G9a inhibition. In addition, pre-inhibiting AMPK by Compound C attenuated autophagy together with the anti-proliferation effect induced by G9a inhibition while pre-activating AMPK by AICAR enhanced them. In conclusion, our results indicate that G9a inhibition induces autophagy through activating AMPK/mTOR pathway and the autophagy induced positively contributes to the inhibition of cell proliferation in TCC cells. These findings shed some light on the functional role of G9a in cell metabolism and suggest that G9a might be a therapeutic target in bladder TCC in the future.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia , Carcinoma de Células de Transição/enzimologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Neoplasias da Bexiga Urinária/enzimologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinoma de Células de Transição/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Bexiga Urinária/patologia , Vacúolos/efeitos dos fármacos , Vacúolos/metabolismo
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