RESUMEN
Herein, we disclose a facile synthetic strategy to access an important class of drug molecules that contain chiral 1,2-amino alcohol functionality utilizing highly effective ruthenium-catalyzed asymmetric transfer hydrogenation of unprotected α-ketoamines. Recently, the COVID-19 pandemic has caused a crisis of shortage of many important drugs, especially norepinephrine and epinephrine, for the treatment of anaphylaxis and hypotension because of the increased demand. Unfortunately, the existing technologies are not fulfilling the worldwide requirement due to the existing lengthy synthetic protocols that require additional protection and deprotection steps. We identified a facile synthetic protocol via a highly enantioselective one-step process for epinephrine and a two-step process for norepinephrine starting from unprotected α-ketoamines 1b and 1a, respectively. This newly developed enantioselective ruthenium-catalyzed asymmetric transfer hydrogenation was extended to the synthesis of many 1,2-amino alcohol-containing drug molecules such as phenylephrine, denopamine, norbudrine, and levisoprenaline, with enantioselectivities of >99% ee and high isolated yields.
Asunto(s)
Amino Alcoholes , Rutenio , Hidrogenación , Catálisis , Amino Alcoholes/química , Amino Alcoholes/síntesis química , Rutenio/química , Estereoisomerismo , Estructura Molecular , Aminas/químicaRESUMEN
Friedreich ataxia (FRDA) is a progressive neuro- and cardio-degenerative disorder characterized by ataxia, sensory loss, and hypertrophic cardiomyopathy. In most cases, the disorder is caused by GAA repeat expansions in the first introns of both alleles of the FXN gene, resulting in decreased expression of the encoded protein, frataxin. Frataxin localizes to the mitochondrial matrix and is required for iron-sulfur-cluster biosynthesis. Decreased expression of frataxin is associated with mitochondrial dysfunction, mitochondrial iron accumulation, and increased oxidative stress. Ferropotosis is a recently identified pathway of regulated, iron-dependent cell death, which is biochemically distinct from apoptosis. We evaluated whether there is evidence for ferroptotic pathway activation in cellular models of FRDA. We found that primary patient-derived fibroblasts, murine fibroblasts with FRDA-associated mutations, and murine fibroblasts in which a repeat expansion had been introduced (knockin/knockout) were more sensitive than normal control cells to erastin, a known ferroptosis inducer. We also found that the ferroptosis inhibitors ethyl 3-(benzylamino)-4-(cyclohexylamino)benzoate (SRS11-92) and ethyl 3-amino-4-(cyclohexylamino)benzoate, used at 500 nM, were efficacious in protecting human and mouse cellular models of FRDA treated with ferric ammonium citrate (FAC) and an inhibitor of glutathione synthesis [L-buthionine (S,R)-sulfoximine (BSO)], whereas caspase-3 inhibitors failed to show significant biologic activity. Cells treated with FAC and BSO consistently showed decreased glutathione-dependent peroxidase activity and increased lipid peroxidation, both hallmarks of ferroptosis. Finally, the ferroptosis inhibitor SRS11-92 decreased the cell death associated with frataxin knockdown in healthy human fibroblasts. Taken together, these data suggest that ferroptosis inhibitors may have therapeutic potential in FRDA.
Asunto(s)
Ferroptosis/efectos de los fármacos , Ataxia de Friedreich/tratamiento farmacológico , Ataxia de Friedreich/patología , Terapia Molecular Dirigida/métodos , Animales , Línea Celular , Ataxia de Friedreich/metabolismo , Técnicas de Silenciamiento del Gen , Glutatión/biosíntesis , Humanos , Hierro/metabolismo , Proteínas de Unión a Hierro/genética , Proteínas de Unión a Hierro/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Piperazinas/farmacología , FrataxinaRESUMEN
We report a new class of highly effective, benzooxaphosphole-based, water-soluble ligands in the application of Suzuki-Miyaura cross-coupling reactions for sterically hindered substrates in aqueous media. The catalytic activities of the coupling reactions were greatly enhanced by the addition of catalytic amounts of organic phase transfer reagents, such as tetraglyme and tetrabutylammonium bromide. The optimized general protocol can be conducted with a low catalyst load, thereby providing a practical solution for these reactions. The viability of this new Suzuki-Miyaura protocol was demonstrated with various substrates to generate important building blocks, including heterocycles, for the synthesis of biologically active compounds.
RESUMEN
The unfolded protein response (UPR) is a cellular stress response mechanism that is critical for cell survival. Pharmacological modulation of the ATPase activity of the chaperone Hsp70 can trigger UPR-mediated cell death, thus removing pathogenic cells in human malignancies, or, alternatively, stimulate survival, thereby preventing apoptosis in neuronal cells and slowing the progress of inflammation, neurodegeneration, and aging. This Viewpoint highlights the complexity of the protein homeostasis network and discusses different approaches for modulating Hsp70 activity, including the use of a chemical reaction development-inspired library of Hsp70 agonists and antagonists.
RESUMEN
The scope of the acid-mediated 3-component synthesis of thiadiazines was investigated. A selective functionalization of the six-membered heterocyclic core structure was accomplished by sequential alkylations, saponifications, and coupling reactions. Several new analogs of a dihydropyrimidinone Hsp70 chaperone agonist, MAL1-271, showed promising activity in a cell based model of Huntington's disease.