ABSTRACT
The carbocatalyzed synthesis of 2,3-disubstituted quinolines is disclosed. This process involved a three-component Povarov reaction of anilines, aldehydes and electron-enriched enol ethers, which gave the substrate for the subsequent oxidation. Graphene oxide (GO) was exploited as a heterogeneous, metal-free and sustainable catalyst for both transformations. The multicomponent reaction proceeded under simple and mild reaction conditions, exhibited good functional group tolerance, and could be easily scaled up to the gram level. A selection of tetrahydroquinolines obtained was subsequently aromatized to quinolines. The multistep synthesis could also be performed as a one-pot procedure. Investigation of the real active sites of GO was carried out by performing control experiments and a by full characterization of the carbon material by X-ray photoelectron spectroscopy (XPS) and solid-state nuclear magnetic resonance (ssNMR).
ABSTRACT
Acid ceramidase (AC) is a cysteine hydrolase that plays a crucial role in the metabolism of lysosomal ceramides, important members of the sphingolipid family, a diversified class of bioactive molecules that mediate many biological processes ranging from cell structural integrity, signaling, and cell proliferation to cell death. In the effort to expand the structural diversity of the existing collection of AC inhibitors, a novel class of substituted oxazol-2-one-3-carboxamides were designed and synthesized. Herein, we present the chemical optimization of our initial hits, 2-oxo-4-phenyl-N-(4-phenylbutyl)oxazole-3-carboxamide 8a and 2-oxo-5-phenyl-N-(4-phenylbutyl)oxazole-3-carboxamide 12a, which resulted in the identification of 5-[4-fluoro-2-(1-methyl-4-piperidyl)phenyl]-2-oxo-N-pentyl-oxazole-3-carboxamide 32b as a potent AC inhibitor with optimal physicochemical and metabolic properties, showing target engagement in human neuroblastoma SH-SY5Y cells and a desirable pharmacokinetic profile in mice, following intravenous and oral administration. 32b enriches the arsenal of promising lead compounds that may therefore act as useful pharmacological tools for investigating the potential therapeutic effects of AC inhibition in relevant sphingolipid-mediated disorders.
Subject(s)
Acid Ceramidase/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/chemical synthesis , Oxazolone/chemistry , Acid Ceramidase/metabolism , Administration, Oral , Animals , Binding Sites , Cell Line, Tumor , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacokinetics , Half-Life , Humans , Inhibitory Concentration 50 , Kinetics , Male , Mice , Mice, Inbred C57BL , Microsomes/metabolism , Molecular Docking Simulation , Oxazolone/metabolism , Oxazolone/pharmacokinetics , Solubility , Structure-Activity RelationshipABSTRACT
Sphingolipids (SphLs) are a diverse class of molecules that are regulated by a complex network of enzymatic pathways. A disturbance in these pathways leads to lipid accumulation and initiation of several SphL-related disorders. Acid ceramidase is one of the key enzymes that regulate the metabolism of ceramides and glycosphingolipids, which are important members of the SphL family. Herein, we describe the lead optimization studies of benzoxazolone carboxamides resulting in piperidine 22m, where we demonstrated target engagement in two animal models of neuropathic lysosomal storage diseases (LSDs), Gaucher's and Krabbe's diseases. After daily intraperitoneal administration at 90 mg kg-1, 22m significantly reduced the brain levels of the toxic lipids glucosylsphingosine (GluSph) in 4L;C* mice and galactosylsphingosine (GalSph) in Twitcher mice. We believe that 22m is a lead molecule that can be further developed for the correction of severe neurological LSDs where GluSph or GalSph play a significant role in disease pathogenesis.
Subject(s)
Acid Ceramidase/antagonists & inhibitors , Benzoxazoles/pharmacology , Enzyme Inhibitors/pharmacology , Administration, Oral , Animals , Benzoxazoles/administration & dosage , Benzoxazoles/chemical synthesis , Benzoxazoles/pharmacokinetics , Brain/metabolism , Cell Line, Tumor , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Female , Gaucher Disease/enzymology , Gaucher Disease/metabolism , Humans , Leukodystrophy, Globoid Cell/enzymology , Leukodystrophy, Globoid Cell/metabolism , Male , Mice , Molecular Structure , Psychosine/analogs & derivatives , Psychosine/metabolism , Structure-Activity RelationshipABSTRACT
Multiple multicomponent reactions rapidly assemble complex structures. Despite being very productive, the lack of selectivity and the reduced number of viable transformations restrict their general application in synthesis. Hereby, we describe a rationale for a selective version of these processes based in the preferential generation of intermediates which are less reactive than the initial substrates. In this way, applying the Groebke-Blackburn-Bienaymé reaction on a range of α-polyamino-polyazines, we prepared a family compact heterocyclic scaffolds with relevant applications in medicinal and biological chemistry (live cell imaging probes, selective binders for DNA quadruplexes, and antiviral agents against human adenoviruses). The approach has general character and yields complex molecular targets in a selective, tunable and direct manner.
Subject(s)
Macrocyclic Compounds/chemical synthesis , A549 Cells , Adenoviridae/drug effects , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cell Survival/drug effects , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/chemistry , G-Quadruplexes , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacology , Models, Molecular , Molecular Probes/chemical synthesis , Molecular Probes/chemistry , Molecular Structure , Oligonucleotides/chemistry , Optical ImagingABSTRACT
Enantiomerically pure ß-aminoalcohols, produced through an organocatalytic Mannich reaction, were subjected to an Ugi multicomponent reaction under classical or Lewis acid-promoted conditions with diastereoselectivities ranging from moderate to good. This approach represents a step-economical path to enantiomerically pure, polyfunctionalized peptidomimetics endowed with three stereogenic centers, allowing the introduction of five diversity inputs.