RESUMO
Lactate dehydrogenase (LDH) is a critical enzyme in the glycolytic metabolism pathway that is used by many tumor cells. Inhibitors of LDH may be expected to inhibit the metabolic processes in cancer cells and thus selectively delay or inhibit growth in transformed versus normal cells. We have previously disclosed a pyrazole-based series of potent LDH inhibitors with long residence times on the enzyme. Here, we report the elaboration of a new subseries of LDH inhibitors based on those leads. These new compounds potently inhibit both LDHA and LDHB enzymes, and inhibit lactate production in cancer cell lines.
Assuntos
Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Éteres/farmacologia , L-Lactato Desidrogenase/antagonistas & inibidores , L-Lactato Desidrogenase/metabolismo , Compostos de Anilina/química , Antineoplásicos/química , Linhagem Celular Tumoral , Éteres/química , Humanos , L-Lactato Desidrogenase/químicaRESUMO
This Letter describes the continued optimization of an MLPCN probe molecule (ML012) through an iterative parallel synthesis approach. After exploring extensive modifications throughout the parent structure, we arrived at a more highly M(1)-selective antagonist, compound 13l (VU0415248). Muscarinic subtype selectivity across all five human and rat receptors for 13l, along with rat selectivity for the lead compound (ML012), is presented.
Assuntos
Sondas Moleculares/farmacologia , Quinolinas/farmacologia , Receptor Muscarínico M1/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Relação Dose-Resposta a Droga , Humanos , Sondas Moleculares/síntese química , Sondas Moleculares/química , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Ratos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/químicaRESUMO
Chemical synthesis has been described as a central science. Its practice provides access to the chemical structures of known and/or designed function. In particular, human health is greatly impacted by synthesis that enables advancements in both basic science discoveries in chemical biology as well as translational research that can lead to new therapeutics. To support the chemical synthesis needs of investigators across campus, the Vanderbilt Institute of Chemical Biology established a chemical synthesis core as part of its foundation in 2008. Provided in this Review are examples of synthetic products, known and designed, produced in the core over the past 10 years.
Assuntos
Técnicas de Química Sintética/métodos , Indicadores e Reagentes/síntese química , Preparações Farmacêuticas/síntese química , Animais , Produtos Biológicos/síntese química , Fenômenos Biofísicos , Meios de Contraste/síntese química , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Pesquisa , Estudos Retrospectivos , EstereoisomerismoRESUMO
Bacillithiol (BSH) has been prepared on the gram scale from the inexpensive starting material, D-glucosamine hydrochloride, in 11 steps and 8-9% overall yield. The BSH was used to survey the substrate and metal-ion selectivity of FosB enzymes from four Gram-positive microorganisms associated with the deactivation of the antibiotic fosfomycin. The in vitro results indicate that the preferred thiol substrate and metal ion for the FosB from Staphylococcus aureus are BSH and Ni(II), respectively. However, the metal-ion selectivity is less distinct with FosB from Bacillus subtilis, Bacillus anthracis, or Bacillus cereus.