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1.
Front Microbiol ; 13: 1099330, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36741900

RESUMO

Despite the availability of several vaccines against multiple disease-causing strains of Streptococcus pneumoniae, the rise of antimicrobial resistance and pneumococcal disease caused by strains not covered by the vaccine creates a need for developing novel antimicrobial strategies. N,N-dimethyldithiocarbamate (DMDC) was found to be a potent copper-dependent antimicrobial against several pathogens, including S. pneumoniae. Here, DMDCs efficacy against Streptococcal pathogens Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus anginosus was tested using bactericidal and inductively coupled plasma - optical emission spectrometry. After confirming DMDC as broad-spectrum streptococcal antimicrobial, DMDC was derivatized into five compounds. The derivatives' effectiveness as copper chelators using DsRed2 and as copper-dependent antimicrobials against S. pneumoniae TIGR4 and tested in bactericidal and animal models. Two compounds, sodium N-benzyl-N-methyldithiocarbamate and sodium N-allyl-N-methyldithiocarbamate (herein "Compound 3" and "Compound 4"), were effective against TIGR4 and further, D39 and ATCC® 6303™ _(a type 3 capsular strain). Both Compound 3 and 4 increased the pneumococcal internal concentrations of copper to the same previously reported levels as with DMDC and copper treatment. However, in an in vivo murine pneumonia model, Compound 3, but not Compound 4, was effective in significantly decreasing the bacterial burden in the blood and lungs of S. pneumoniae-infected mice. These derivatives also had detrimental effects on the other streptococcal species. Collectively, derivatizing DMDC holds promise as potent bactericidal antibiotics against relevant streptococcal pathogens.

2.
J Chem Neuroanat ; 111: 101879, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33197553

RESUMO

BACKGROUND: The spinal cord is one of the central nervous system. Spinal cord injury (SCI) will cause loss of physical function and dysfunction below the injury site, causing them to lose sensation and mobility, thereby reducing the quality of life of patients. Although regular rehabilitation management can reduce its severity, the current effective treatment methods are limited to the treatment of secondary injuries to SCI. The purpose of treatment should not only include the restoration of the histology of the lesion, but also should focus on the restoration of sensory and mobility and. The key to effective treatment is to reduce secondary injuries. RhoA inhibitor can improve the pathophysiological changes related to secondary injury and promote the recovery of activity ability, so it may become a clinical drug for the treatment of SCI. This article systematically analyzed the effects of RhoA inhibitors on the promotion of axon regeneration and the recovery of mobility and compared the therapeutic effects of different inhibitors on SCI and their effects on physical function recovery. METHODS: We used a meta-analysis to systematically evaluate the effects of Rho inhibitors on SCI treatment and the recovery of body function. RESULTS: 21 articles (738 animals) were identified in the literatures search. Studies were selected if they reported the therapeutic effects of RhoA/ROCK inhibitors (BA-210, EGCG, ß-elemene, C3-exoenzmye, LINGO-1-Fc, Ibuprofen, SiRhoA, iRhoA + FK506, Fasudil, p21Cip1/WAF1, HA-1007, Y-27,632 and C3bot154-182). We measure the functional recovery by BBB and BMS scores. The random effect model of weighted mean difference (WMD, 95 % confidence interval) was used to analyze the effects. The WMD of the forest graph was 2.277; 95 % CI: 1.705∼2.849, P < 0.001, suggesting that RhoA inhibitors can effectively treat SCI. In addition to EGCG, all the other agents also showed the effects on the activity recovery post-SCI (P < 0.05). CONCLUSION: ß-elemene, LINGO-1-Fc, Ibuprofen, SiRhoA, RhoA + FK506, Fasudil, p21Cip1/WAF1 and Y-27,632 have similar effects to BA-210, they can promote axon germination and nerve fiber regeneration after thoracic spinal cord injury and reduce the formation of syringomyelia and protect white matter, thereby improving locomotor recovery. RhoA inhibitors have great potential to restore motor function and provide a new trend for the treatment of SCI.


Assuntos
Inibidores Enzimáticos/farmacologia , Regeneração Nervosa/efeitos dos fármacos , Condicionamento Físico Animal/fisiologia , Traumatismos da Medula Espinal/tratamento farmacológico , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , Animais , Inibidores Enzimáticos/uso terapêutico , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Regeneração Nervosa/fisiologia , Traumatismos da Medula Espinal/fisiopatologia
3.
Eur J Med Chem ; 191: 112142, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32088497

RESUMO

The upregulation of the protein myeloid cell leukemia-1 (Mcl-1) is closely associated with various human cancers, which can result in the evasion of apoptosis and a low survival rate. Therefore, developing Mcl-1 inhibitors has become a promising paradigm for cancer therapy. Herein, we designed and synthesized a novel series of tyrosine derivatives, among which compounds 5g, 6l and 6c exhibited very high binding affinity to Mcl-1 with Ki values of 0.18, 0.27 and 0.23 µM, respectively. Interestingly, compound 6l showed not only potent activity against Mcl-1 but also considerable selectivity over Bcl-2 and Bcl-xL, which was rationalized by molecular docking and fragment-centric topographical mapping (FCTM). It is worth noting that compounds 5g, 6l and 6c displayed potent antiproliferative activity against several cancer cell lines and could induce apoptosis of KM3 and HepG2 cells in a dose-dependent manner.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Tirosina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Modelos Moleculares , Estrutura Molecular , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Relação Estrutura-Atividade , Tirosina/síntese química , Tirosina/química
4.
Bioorg Chem ; 88: 102938, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31028992

RESUMO

Bcl-2 family proteins play a vital role for cancer cell in escaping apoptosis, and small-molecule anti-apoptotic Bcl-2 protein inhibitors have been developed as new anticancer therapies. In current study, a series of substituted 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were developed based on the lead compound 1 (Ki = 5.2 µM against Bcl-2 protein). The fluorescence polarization assays suggested that active compounds possessed potent binding affinities to both Bcl-2 and Mcl-1 protein, but had minor or no binding affinities to Bcl-XL protein. MTT assays showed that these compounds had certain anti-proliferative activities against cancer cells. Furthermore, it was found that active compound 11t could induce cell apoptosis and caspase-3 activation in a dose-dependent manner in Jurkat cells.


Assuntos
Descoberta de Drogas , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Tetra-Hidroisoquinolinas/farmacologia , Relação Dose-Resposta a Droga , Humanos , Células Jurkat , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/química
5.
Bioorg Med Chem ; 26(17): 4907-4915, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30170927

RESUMO

Anti-apoptotic Bcl-2 family proteins are vital for cancer cells to escape apoptosis, which make them attractive targets for cancer therapy. Recently, a lead compound 1 was found to modestly inhibit the binding of BH3 peptide to Bcl-2 protein with a Ki value of 5.2 µM. Based on this, a series of substituted tyrosine derivatives were developed and tested for their binding affinities to Bcl-2 protein. Results indicated that these compounds exhibited potent binding affinities to Bcl-2 and Mcl-1 protein but not to Bcl-XL protein. Promisingly, compound 6i inhibited the binding of BH3 peptide to Bcl-2 and Mcl-1 protein with a Ki value of 450 and 190 nM respectively, and showed obvious anti-proliferative activities against tested cancer cells.


Assuntos
Descoberta de Drogas , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Tirosina/química , Tirosina/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Proliferação de Células/efeitos dos fármacos , Humanos , Células Jurkat , Espectrometria de Massas , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Tirosina/metabolismo
6.
Bioorg Med Chem ; 25(6): 1939-1948, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28233676

RESUMO

The B-cell lymphoma-2 (Bcl-2) family proteins are attractive targets for cancer therapy. In our previous work, the structure-activity relationship of WL-276 was studied. According to the results, rhodanine derivatives show potent binding affinity for Bcl-2 and Mcl-1 protein and show weaker activity against Bcl-XL protein. Based on the previous results, a new class of indole-3-carboxylic acid-based derivatives were designed and synthesized as Bcl-2/Mcl-1 dual inhibitors. Among them, compound 17 has a Ki value of 0.26µM for Bcl-2 protein and is better than WL-276. Furthermore, it inhibits the myeloid cell leukemia sequence 1 (Mcl-1) protein with a Ki value of 72nM. Especially, compound 31 can selectively acting on Bcl-2 and Mcl-1 protein but not Bcl-XL protein, which has great significance for developing dual inhibitors targeting Bcl-2 and Mcl-1 protein, as well as specific antitumor abilities in cells.


Assuntos
Desenho de Fármacos , Indóis/farmacologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Avaliação Pré-Clínica de Medicamentos , Polarização de Fluorescência , Humanos , Indóis/química , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray
7.
Bioorg Med Chem ; 24(7): 1446-54, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26907204

RESUMO

Histone deacetylase inhibitors have been proved to be great potential for the treatment of cancer. Recently, we designed and modified a series of substituted purine hydroxamate analogs as potent HDAC inhibitors based on our previous studies. The target compounds were investigated for their in vitro HDAC inhibitory activities and anti-proliferative activities. Results indicated that these compounds could effectively inhibit HDAC and possess obvious anti-proliferative activity against tumor cells. Promisingly, target compounds 4m and 4n outperformed SAHA in both enzymatic inhibitory activity and cellular anti-proliferative activity assay.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/farmacologia , Purinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Inibidores de Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Estrutura Molecular , Purinas/síntese química , Purinas/química , Relação Estrutura-Atividade
8.
Yao Xue Xue Bao ; 50(1): 7-14, 2015 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-25924468

RESUMO

Histone deacetylase 6 (HDAC6) is an unique subtype of histone deacetylases with two tandem deacetylase domains and substrate specificity for non-histone proteins. It is involved in many important physiological and pathological processes and has become a promising therapeutic target in recent decades. Different kinds of potent HDAC6-selective inhibitors have been reported around the world. This paper reviews the progress in the study of structure and functions of HDAC6 as well as the development of HDAC6-selective inhibitors.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/química , Humanos , Especificidade por Substrato
9.
J Chem Inf Model ; 55(4): 861-71, 2015 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-25757142

RESUMO

As key regulators of epigenetic regulation, human histone deacetylases (HDACs) have been identified as drug targets for the treatment of several cancers. The proper recognition of zinc-binding groups (ZBGs) will help improve the accuracy of virtual screening for novel HDAC inhibitors. Here, we developed a high-specificity ZBG-based pharmacophore model for HDAC8 inhibitors by incorporating customized ZBG features. Subsequently, pharmacophore-based virtual screening led to the discovery of three novel HDAC8 inhibitors with low micromole IC50 values (1.8-1.9 µM). Further studies demonstrated that compound H8-A5 was selective for HDAC8 over HDAC 1/4 and showed antiproliferation activity in MDA-MB-231 cancer cells. Molecular docking and molecular dynamic studies suggested a possible binding mode for H8-A5, which provides a good starting point for the development of HDAC8 inhibitors in cancer treatment.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Zinco/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Histona Desacetilases/química , Humanos , Conformação Proteica , Proteínas Repressoras/química , Interface Usuário-Computador
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