RESUMO
A series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.
Assuntos
Antineoplásicos/farmacologia , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 2/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Linfoma Cutâneo de Células T/tratamento farmacológico , Quinina/análogos & derivados , Neoplasias Cutâneas/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Linfoma Cutâneo de Células T/metabolismo , Linfoma Cutâneo de Células T/patologia , Modelos Moleculares , Estrutura Molecular , Quinina/síntese química , Quinina/química , Quinina/farmacologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Solubilidade , Relação Estrutura-AtividadeRESUMO
A three component one-pot cascade reaction was developed for the synthesis of 1,4,5-trisubstituted γ-lactams. The resulting scaffold can be modified independently at three positions, two of which are conveniently accessed by changing the components of the one-pot reaction. The phases of building block generation, scaffold synthesis and subsequent appendage modification were adapted to library production, which resulted in a screening library of 500 compounds.
Assuntos
Descoberta de Drogas , Lactamas/síntese química , Bibliotecas de Moléculas Pequenas/síntese química , Catálise , Técnicas de Química Combinatória/métodos , Estrutura Molecular , EstereoisomerismoRESUMO
The design, synthesis and decoration of six small molecule libraries is described. Each library was inspired by structures embedded in the framework of specific alkaloid natural products. The development of optimised syntheses of the required molecular scaffolds is described, in which reactions including Pd-catalysed aminoarylation and diplolar cycloadditions have been exploited as key steps. The synthesis of selected exemplar screening compounds is also described. In five cases, libraries were subsequently nominated for production on the basis of the scope and limitations of the validation work, as well as predicted molecular properties. In total, the research has led to the successful synthesis of >2500 novel alkaloid-like compounds for addition to the screening collection (the Joint European Compound Library, JECL) of the European Lead Factory.
Assuntos
Alcaloides/síntese química , Desenho de Fármacos , Descoberta de Drogas , Paládio/química , Bibliotecas de Moléculas Pequenas/síntese química , Reação de Cicloadição , Estrutura MolecularRESUMO
Copper-catalyzed borylation of a variety of organic halides with bis(pinacolato)diboron allows the preparation of diverse potassium organotrifluoroborates. The reactions are mild and general, providing access to a variety of interesting, boron-containing building blocks, including those containing piperidine, pyrrole, azetidine, tetrahydropyran, and oxetane substructures. Representative Minisci reactions are reported for select examples.
Assuntos
Compostos de Boro/síntese química , Compostos Heterocíclicos/síntese química , Hidrocarbonetos Fluorados/síntese química , Compostos de Boro/química , Catálise , Cobre/química , Compostos Heterocíclicos/química , Hidrocarbonetos Fluorados/química , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
A robust and efficient protocol for the introduction of the dioxolanylethyl moiety onto various aryl and heteroaryl halides has been developed, providing cross-coupling yields up to 93%. Copper-catalyzed borylation of 2-(2-bromoethyl)-1,3-dioxolane with bis(pinacolato)diboron followed by treatment with potassium bifluoride provides the key organotrifluoroborate reagent.
Assuntos
Boratos/química , Dioxolanos/síntese química , Hidrocarbonetos Clorados/síntese química , Potássio/química , Catálise , Técnicas de Química Combinatória , Cobre/química , Dioxolanos/química , Hidrocarbonetos Clorados/química , Estrutura MolecularRESUMO
The introduction of an alkoxyethyl moiety onto aromatic substructures has remained a long-standing challenge for synthetic organic chemists. The main reasons are the inherent instability of alkoxyethylmetallic species and the lack of general procedures to access them. A new method utilizing a cross-coupling strategy based on the exceptional properties of organotrifluoroborates has been developed, and the method allows an easy and efficient installation of this unit on a broad range of aryl and heteroaryl bromides.
Assuntos
Boratos/química , Compostos Heterocíclicos/síntese química , Oxigênio/química , Catálise , Compostos Heterocíclicos/química , Estrutura Molecular , Potássio/químicaRESUMO
Ammoniomethyl trifluoroborates are very powerful reagents that can be used to access biologically relevant aryl- and heteroaryl-methylamine motifs via Suzuki-Miyaura cross-couplings. Until now, this method was limited to the production of tertiary and primary amines. The synthesis of a large array of secondary ammoniomethyltrifluoroborates has been achieved through a one step nucleophilic substitution reaction on the potassium bromomethyltrifluoroborate. Smooth cross-coupling conditions have been designed, based on the use of an aminobiphenyl palladium precatalyst, to couple these trifluoroborates efficiently with aryl bromides. This strategy offers a new way to access biologically relevant motifs and allows, with the previously developed methods, access to all three classes of aminomethylarenes.
Assuntos
Boratos/síntese química , Hidrocarbonetos Fluorados/síntese química , Metilaminas/síntese química , Boratos/química , Catálise , Hidrocarbonetos Fluorados/química , Metilaminas/química , Estrutura Molecular , Paládio/químicaRESUMO
Potassium imidomethyltrifluoroborate salts were efficiently synthesized. Potassium phthalimidomethyl-trifluoroborate was successfully used in Suzuki-Miyaura-like cross-coupling reactions with a variety of aryl chlorides.
RESUMO
Sulfonamidomethyltrifluoroborates were successfully synthesized and cross-coupled with a wide range of aryl and heteroaryl chlorides, allowing the construction of a sulfonamidomethyl aryl linkage through a new disconnection, thus offering a new way to access such structurally interesting motifs.
Assuntos
Amidas/química , Ácidos Bóricos/síntese química , Compostos de Flúor/síntese química , Compostos de Enxofre/síntese química , Metilação , Estrutura MolecularRESUMO
Planar chiral phosphines displaying a new ferrocenophane scaffold have been prepared via a stereoselective approach. The P-cyclohexyl substituted phosphine affords high levels of asymmetric induction in the organocatalytic [3 + 2] annulation reaction between allenes and electron-poor olefins.