Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros

Base de dados
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
Org Biomol Chem ; 12(6): 881-6, 2014 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-24389824

RESUMO

Nearly all clinically used antibiotics have been (1) discovered from microorganisms (2) using phenotype screens to identify inhibitors of bacterial growth. The effectiveness of these antibiotics is attributed to their endogenous roles as bacterial warfare agents against competing microorganisms. Unfortunately, every class of clinically used antibiotic has been met with drug resistant bacteria. In fact, the emergence of resistant bacterial infections coupled to the dismal pipeline of new antibacterial agents has resulted in a global health care crisis. There is an urgent need for innovative antibacterial strategies and treatment options to effectively combat drug resistant bacterial pathogens. Here, we describe the implementation of a Pseudomonas competition strategy, using redox-active phenazines, to identify novel antibacterial leads against Staphylococcus aureus and Staphylococcus epidermidis. In this report, we describe the chemical synthesis and evaluation of a diverse 27-membered phenazine library. Using this microbial warfare inspired approach, we have identified several bromophenazines with potent antibacterial activities against S. aureus and S. epidermidis. The most potent bromophenazine analogue from this focused library demonstrated a minimum inhibitory concentration (MIC) of 0.78-1.56 µM, or 0.31-0.62 µg mL(-1), against S. aureus and S. epidermidis and proved to be 32- to 64-fold more potent than the phenazine antibiotic pyocyanin in head-to-head MIC experiments. In addition to the discovery of potent antibacterial agents against S. aureus and S. epidermidis, we also report a detailed structure-activity relationship for this class of bromophenazine small molecules.


Assuntos
Antibacterianos/farmacologia , Descoberta de Drogas , Fenazinas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus epidermidis/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Fenazinas/síntese química , Fenazinas/química , Staphylococcus aureus/crescimento & desenvolvimento , Staphylococcus epidermidis/crescimento & desenvolvimento , Relação Estrutura-Atividade
2.
JCI Insight ; 8(10)2023 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-37097751

RESUMO

Although thymidylate synthase (TYMS) inhibitors have served as components of chemotherapy regimens, the currently available inhibitors induce TYMS overexpression or alter folate transport/metabolism feedback pathways that tumor cells exploit for drug resistance, limiting overall benefit. Here we report a small molecule TYMS inhibitor that i) exhibited enhanced antitumor activity as compared with current fluoropyrimidines and antifolates without inducing TYMS overexpression, ii) is structurally distinct from classical antifolates, iii) extended survival in both pancreatic xenograft tumor models and an hTS/Ink4a/Arf null genetically engineered mouse tumor model, and iv) is well tolerated with equal efficacy using either intraperitoneal or oral administration. Mechanistically, we verify the compound is a multifunctional nonclassical antifolate, and using a series of analogs, we identify structural features allowing direct TYMS inhibition while maintaining the ability to inhibit dihydrofolate reductase. Collectively, this work identifies nonclassical antifolate inhibitors that optimize inhibition of thymidylate biosynthesis with a favorable safety profile, highlighting the potential for enhanced cancer therapy.


Assuntos
Antagonistas do Ácido Fólico , Camundongos , Animais , Humanos , Antagonistas do Ácido Fólico/farmacologia , Antagonistas do Ácido Fólico/uso terapêutico , Antagonistas do Ácido Fólico/química , Inibidores Enzimáticos/farmacologia , Resistência a Medicamentos , Timidilato Sintase
3.
J Org Chem ; 77(19): 8410-6, 2012 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-22998591

RESUMO

The total synthesis of acortatarin A relying on a Pd(II)-catalyzed spiroketalization is reported. This strategy allows a single stereocenter in the spiroketalization substrate to produce the target efficiently under mild conditions, installing the necessary oxygenation in the backbone through an allylic transposition. The synthesis also verifies that pollenopyrroside B and acortatarin A are the same compound, and electrochemical studies suggest that the reported bioactivity is not due to simple antioxidant properties.


Assuntos
Morfolinas/química , Morfolinas/síntese química , Paládio/química , Compostos de Espiro/química , Catálise , Estrutura Molecular , Compostos de Espiro/síntese química
4.
Org Lett ; 17(7): 1754-7, 2015 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-25797466

RESUMO

A gold-catalyzed synthesis of cyclic 2-oxodienes from readily prepared propargyl alcohols and the subsequent Diels-Alder reaction are reported. The dehydrative cyclization reactions proceeded smoothly, and the dienes formed in situ were demonstrated to undergo cycloaddition with a variety of dienophiles. This method offers a new strategy for the synthesis of indolocarbazole alkaloids, whereby the convergent synthetic design allows for differentiation between the indole nitrogens.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA