RESUMO
Modification of the benzo rings of 3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones into heteroaromatic systems was investigated to enhance physicochemical properties and potency profile of this class of inhibitors. The synthesis and biological activity of the derived compounds is discussed.
Assuntos
Química Farmacêutica/métodos , Quinolonas/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/farmacologia , Desenho de Fármacos , Genótipo , Hepacivirus/metabolismo , Humanos , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular , Ligação Proteica , Quinolonas/farmacologia , Relação Estrutura-AtividadeRESUMO
The synthesis and optimisation of HCV NS5B polymerase inhibitors with improved potency versus the existing compound 1 is described. Substitution in the benzothiadiazine portion of the molecule, furnishing improvement in potency in the high protein Replicon assay, is highlighted, culminating in the discovery of 12h, a highly potent oxyacetamide derivative.
Assuntos
Antivirais/síntese química , Benzotiadiazinas/química , Química Farmacêutica/métodos , Hepacivirus/enzimologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Animais , Antivirais/farmacologia , Benzotiadiazinas/farmacologia , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
Recently, we disclosed a new class of HCV polymerase inhibitors discovered through high-throughput screening (HTS) of the GlaxoSmithKline proprietary compound collection. This interesting class of 3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones potently inhibits HCV polymerase enzymatic activity and inhibits the ability of the subgenomic HCV replicon to replicate in Huh-7 cells. This report will focus on the structure-activity relationships (SAR) of substituents on the quinolinone ring, culminating in the discovery of 1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-6-fluoro-4-hydroxy-2(1H)-quinolinone (130), an inhibitor with excellent potency in biochemical and cellular assays possessing attractive molecular properties for advancement as a clinical candidate. The potential for development and safety assessment profile of compound 130 will also be discussed.
Assuntos
Antivirais/síntese química , Benzotiadiazinas/síntese química , Hepacivirus/enzimologia , Quinolonas/síntese química , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Tiadiazinas/síntese química , Animais , Antivirais/química , Antivirais/farmacologia , Benzotiadiazinas/química , Benzotiadiazinas/farmacologia , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Linhagem Celular , Cristalografia por Raios X , Cães , Genótipo , Meia-Vida , Hepacivirus/genética , Macaca fascicularis , Modelos Moleculares , Estrutura Molecular , Mutação , Ligação Proteica , Quinolonas/química , Quinolonas/farmacologia , RNA Polimerase Dependente de RNA/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tiadiazinas/química , Tiadiazinas/farmacologiaRESUMO
[reaction: see text] An efficient two-pot, asymmetric synthesis of benzothiadiazine-substituted tetramic acids is reported. Starting from commercially available alpha-amino acids or esters, reductive amination followed by a novel one-pot amide bond formation/Dieckmann cyclization provided the desired products in high yield and optical purity. An analogous solid-phase approach to the same targets is also presented. These compounds were found to be potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Benzotiadiazinas/síntese química , Benzotiadiazinas/farmacologia , Hepacivirus/efeitos dos fármacos , Pirrolidinonas/síntese química , Pirrolidinonas/farmacologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Antivirais/química , Benzotiadiazinas/química , Técnicas de Química Combinatória , Ciclização , Hepacivirus/enzimologia , Estrutura Molecular , Pirrolidinonas/químicaRESUMO
We describe the synthesis of (25R)-cholest-5-en-3beta,26-diol ((25R)-26-hydroxycholesterol) from diosgenin in four steps in 58% overall, yield via a modified Clemmensen reduction followed by a Barton deoxygenation reaction.
Assuntos
Hidroxicolesteróis/síntese química , Hidroxicolesteróis/química , Estrutura MolecularRESUMO
Sharks are the most dangerous predators of people in the sea, resulting in people being mauled and killed each year. A shark repellent could help to diminish this danger. The aglycone of the shark repellent pavoninin-5, (25R)-cholest-5-en-3beta,15alpha,26-triol (5a), was synthesized from diosgenin (9). Removing mercury from the Clemmensen reduction of 9 gave a higher yield of (25R)-cholest-5-en-3beta,16beta,26-triol, 10a, and was also more environmentally friendly. Attempted methods for the transposition of the C-16beta hydroxyl to the 15alpha position are described. A successful method for this transposition via the 15alpha-hydroxy-16-ketone, 8a, using the Barton deoxygenation reaction on the 16-alcohol 14b, is reported.
Assuntos
Acetilglucosamina/síntese química , Colesterol/síntese química , Tubarões , Acetilglucosamina/análogos & derivados , Acetilglucosamina/química , Animais , Colesterol/análogos & derivados , Colesterol/químicaRESUMO
BACKGROUND: Most normal cells in the presence of oxygen utilize glucose for mitochondrial oxidative phosphorylation. In contrast, many cancer cells rapidly convert glucose to lactate in the cytosol, a process termed aerobic glycolysis. This glycolytic phenotype is enabled by lactate dehydrogenase (LDH), which catalyzes the inter-conversion of pyruvate and lactate. The purpose of this study was to identify and characterize potent and selective inhibitors of LDHA. METHODS: High throughput screening and lead optimization were used to generate inhibitors of LDHA enzymatic activity. Effects of these inhibitors on metabolism were evaluated using cell-based lactate production, oxygen consumption, and 13C NMR spectroscopy assays. Changes in comprehensive metabolic profile, cell proliferation, and apoptosis were assessed upon compound treatment. RESULTS: 3-((3-carbamoyl-7-(3,5-dimethylisoxazol-4-yl)-6-methoxyquinolin-4-yl) amino) benzoic acid was identified as an NADH-competitive LDHA inhibitor. Lead optimization yielded molecules with LDHA inhibitory potencies as low as 2 nM and 10 to 80-fold selectivity over LDHB. Molecules in this family rapidly and profoundly inhibited lactate production rates in multiple cancer cell lines including hepatocellular and breast carcinomas. Consistent with selective inhibition of LDHA, the most sensitive breast cancer cell lines to lactate inhibition in hypoxic conditions were cells with low expression of LDHB. Our inhibitors increased rates of oxygen consumption in hepatocellular carcinoma cells at doses up to 3 microM, while higher concentrations directly inhibited mitochondrial function. Analysis of more than 500 metabolites upon LDHA inhibition in Snu398 cells revealed that intracellular concentrations of glycolysis and citric acid cycle intermediates were increased, consistent with enhanced Krebs cycle activity and blockage of cytosolic glycolysis. Treatment with these compounds also potentiated PKM2 activity and promoted apoptosis in Snu398 cells. CONCLUSIONS: Rapid chemical inhibition of LDHA by these quinoline 3-sulfonamids led to profound metabolic alterations and impaired cell survival in carcinoma cells making it a compelling strategy for treating solid tumors that rely on aerobic glycolysis for survival.
RESUMO
Inhibition of mitotic kinesins represents a novel approach for the discovery of a new generation of anti-mitotic cancer chemotherapeutics. We report here the discovery of the first potent and selective inhibitor of centromere-associated protein E (CENP-E) 3-chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide (GSK923295; 1), starting from a high-throughput screening hit, 3-chloro-4-isopropoxybenzoic acid 2. Compound 1 has demonstrated broad antitumor activity in vivo and is currently in human clinical trials.
RESUMO
An efficient, asymmetric solid-phase synthesis of benzothiadiazine-substituted tetramic acids is reported. Starting from commercially available chiral Fmoc-protected alpha-amino acids loaded onto Wang resin, Fmoc removal, reductive amination followed by amide bond formation, and base-catalyzed cyclization with simultaneous cleavage from the resin provided the desired products. Compounds described are potent inhibitors of the hepatitis C virus RNA-dependent RNA polymerase.