RESUMO
Fluorinated alcohols and phenols are potentially useful as bioisosteres of the carboxylic acid functional group. To enable a direct comparison of the properties of fluorinated carboxylic acid surrogates with those of other commonly used, non-fluorinated bioisosteres, we conducted a structure-property relationship (SPR) study based on matched molecular pair (MMP) analyses. A series of representative examples have been characterized by experimentally determining physicochemical properties, such as acidity (pKa), lipophilicity (logD7.4), and permeability (PAMPA). The results presented can help estimate the relative changes in physicochemical properties that may be attainable by replacing the carboxylic acid functional group with fluorine containing surrogate structures.
Assuntos
Álcoois , Ácidos Carboxílicos , Ácidos Carboxílicos/química , Flúor/químicaRESUMO
A substituted donor-acceptor cyclobutenecarboxamide is synthesized with modest enantiocontrol through a chiral copper(I) complex catalyzed [3 + 1]-cycloaddition reaction of α-acyl diphenylsulfur ylides with 3-siloxy-2-diazo-3-butenamides. With a methyl substituent on the 4-position of the 3-butenamide, the cis-vicinal-3,4-disubstituted cyclobutenecarboxamide is formed with >20:1 diastereocontrol. Donor-acceptor 3-methyl-2-siloxycyclopropenecarboxamide is rapidly formed from the reactant enoldiazoamide and undergoes catalytic ring opening to give only the Z-γ-substituted metallo-enolcarbene. Elimination from 3-siloxy-2-diazo-3-pentenamide to form the conjugated 3-siloxy-2,4-pentadienamide is competitive but minimized at low temperature.
RESUMO
Acute kidney injury (AKI), a sudden loss of kidney function, is a common and serious condition for which there are no approved specific therapies. While there are multiple approaches to treat the underlying causes of AKI, no targets have been clinically validated. Here, we assessed a series of potent, selective competitive inhibitors of histone deacetylase 8 (HDAC8), a promising therapeutic target in an AKI setting. Using biochemical assays, zebrafish AKI phenotypic assays, and human kidney organoid assays, we show that selective HDAC8 inhibitors can lead to efficacy in increasingly stringent models. One of these, PCI-34051, was efficacious in a rodent model of AKI, further supporting the potential for HDAC8 inhibitors and, in particular, this scaffold as a therapeutic approach to AKI.
RESUMO
Friedreich ataxia (FRDA) is an inherited neurodegenerative disorder for which there is no cure or approved treatment. It is characterized by the loss or impaired activity of frataxin protein, which is involved in the biogenesis of iron-sulfur clusters. Our previous studies suggested that cell death in FRDA may involve ferroptosis, an iron-dependent form of cell death requiring lipid peroxidation. Based on reports that oleic acid acts as a ferroptosis inhibitor, we evaluated whether it, other fatty acids, and fatty acid derivatives could rescue viability in cellular models of FRDA. We identified a trifluoromethyl alcohol analog of oleic acid that was significantly more potent than oleic acid itself. Further evaluation indicated that the effects were stereoselective, although a specific molecular target has not yet been identified. This work provides a potential starting point for therapeutics to treat FRDA, as well as a valuable probe molecule to interrogate FRDA pathophysiology.
Assuntos
Ferroptose , Ataxia de Friedreich , Ataxia de Friedreich/tratamento farmacológico , Ataxia de Friedreich/metabolismo , Humanos , Proteínas de Ligação ao Ferro/metabolismo , Peroxidação de Lipídeos , Mitocôndrias/metabolismo , Ácido Oleico/metabolismo , Ácido Oleico/farmacologiaRESUMO
Enoyl-ACP reductase (ENR), the product of the FabI gene, from Bacillus anthracis (BaENR) is responsible for catalyzing the final step of bacterial fatty acid biosynthesis. A number of novel 2-pyridone derivatives were synthesized and shown to be potent inhibitors of BaENR.
Assuntos
Antibacterianos/síntese química , Bacillus anthracis/enzimologia , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/antagonistas & inibidores , Piridonas/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Bacillus anthracis/efeitos dos fármacos , Cristalografia por Raios X , Desenho de Fármacos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Peso Molecular , Piridonas/química , Piridonas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The synthesis of a C1-C19 precursor to pectenotoxin 4 is presented. The strategy employed the functionalized allene shown. Key features include: olefin metathesis of two simple fragments to prepare the left portion of the allene-precursor, diastereoselective propargylation of an epoxy aldehyde to form the right portion, use of the DMDO-stable m-fluorobenzyl ether, and an allene spirodiepoxidation/C-ring formation cascade.
Assuntos
Compostos de Epóxi/química , Macrolídeos/química , Macrolídeos/síntese química , Alcadienos/química , Catálise , Cobre/química , Estereoisomerismo , Especificidade por SubstratoRESUMO
The first synthesis and biological evaluation of antibiotic 31 (A-33853) and its analogues are reported. Initial screening for inhibition of L. donovani, T. b. rhodesiense, T. cruzi, and P. falciparum cultures followed by determination of IC(50) in L. donovani and cytotoxicity on L6 cells revealed 31 to be 3-fold more active than miltefosine, a known antileishmanial drug. Compounds 14, 15, and 25 selectively inhibited L. donovani at nanomolar concentrations and showed much lower cytotoxicity.