RESUMO
Pyrimidodiazepine derivatives underwent an unexpected gold-catalyzed retro-Mannich-type carbon-carbon bond cleavage and intramolecular nucleophilic cyclization. The pyrimidodiazepines bearing an alkyne moiety showed novel orthogonal reactivity in the presence of a gold catalyst, as opposed to the alkynophilicity that is commonly observed with gold catalysts. The ring transformation reaction of pyrimidodiazepines probably proceeds through an acyclic iminium intermediate. The potential of this synthetic method for the skeletal diversification of pyrimidine-containing macrocycles was also demonstrated.
RESUMO
Diversity-oriented synthesis (DOS) can provide a collection of diverse and complex drug-like small molecules, which is critical in the development of new chemical probes for biological research of undruggable targets. However, the design and synthesis of small-molecule libraries with improved biological relevance as well as maximized molecular diversity represent a key challenge. Herein, we employ functional group-pairing strategy for the DOS of a chemical library containing privileged substructures, pyrimidodiazepine or pyrimidine moieties, as chemical navigators towards unexplored bioactive chemical space. To validate the utility of this DOS library, we identify a new small-molecule inhibitor of leucyl-tRNA synthetase-RagD protein-protein interaction, which regulates the amino acid-dependent activation of mechanistic target of rapamycin complex 1 signalling pathway. This work highlights that privileged substructure-based DOS strategy can be a powerful research tool for the construction of drug-like compounds to address challenging biological targets.
Assuntos
Modelos Químicos , Mapas de Interação de Proteínas/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Linhagem Celular Tumoral , Células HEK293 , Células HeLa , Humanos , Leucina-tRNA Ligase/metabolismo , Estrutura Molecular , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Ligação Proteica/efeitos dos fármacos , Pirimidinas/química , Bibliotecas de Moléculas Pequenas/químicaRESUMO
Gold-catalyzed aerobic oxygenative cleavage of triple bonds that occurs under the ambient pressure of air and at room temperature is reported; radical inhibition tests suggest that oxygenation occurs via a gold-bound metalloradical intermediate.
RESUMO
In this study, we developed an efficient and practical procedure for the synthesis of tetra-substituted Δ5-2-oxopiperazine that mimics the bioactive ß-turn structural motif of proteins. This synthetic route is robust and modular enough to accommodate four different substituents to obtain a high level of molecular diversity without any deterioration in stereochemical enrichment of the natural and unnatural amino acids. Through the in silico studies, including a distance calculation of side chains and a conformational overlapping of our model compound with a native ß-turn structure, we successfully demonstrated the conformational similarity of tetra-substituted Δ5-2-oxopiperazine to the ß-turn motif. For the library construction in a high-throughput manner, the fluorous tag technology was adopted with the use of a solution-phase parallel synthesis platform. A 140-membered pilot library of tetra-substituted Δ5-2-oxopiperazines was achieved with an average purity of 90% without further purification.
Assuntos
Técnicas de Química Combinatória , Piperazinas/química , Piperazinas/síntese química , Proteínas/química , Aminoácidos/química , Biomimética , Modelos Moleculares , Estrutura MolecularRESUMO
A gold-catalyzed intermolecular reaction of propiolic acids with alkenes led to a [4 + 2] annulation or enyne cross metathesis. The [4 + 2] annulation proceeds with net cis-addition with respect to alkenes and provides an expedient route to α,ß-unsaturated δ-lactones, for which preliminary asymmetric reactions were also demonstrated. For 1,2-disubstituted alkenes, unprecedented enyne cross metathesis occurred to give 1,3-dienes in a completely stereospecific fashion. DFT calculations and experiments indicated that the cyclobutene derivatives are not viable intermediates and that the steric interactions during concerted σ-bond rearrangements are responsible for the observed unique stereospecificity.