RESUMO
Synthetic modification of cyclosporin A at P3-P4 positions led to the discovery of NIM258, a next generation cyclophilin inhibitor with excellent anti-hepatitis C virus potency, with decreased transporter inhibition, and pharmacokinetics suitable for coadministration with other drugs. Herein is disclosed the evolution of the synthetic strategy to from the original medicinal chemistry route, designed for late diversification, to a convergent and robust development synthesis. The chiral centers in the P4 fragment were constructed by an asymmetric chelated Claisen rearrangement in the presence of quinidine as the chiral ligand. Identification of advanced crystalline intermediates enabled practical supply of key intermediates. Finally, macrocyclization was carried out at 10% weight concentration by a general and unconventional "slow release" concept.
Assuntos
Antivirais/química , Ciclosporina/química , Hepacivirus/fisiologia , Antivirais/síntese química , Antivirais/farmacologia , Ciclização , Ciclosporina/síntese química , Ciclosporina/farmacologia , Dipeptídeos/síntese química , Dipeptídeos/química , Desenho de Fármacos , Quinidina/química , Estereoisomerismo , Replicação Viral/efeitos dos fármacosRESUMO
Careful regulation of mRNA half-lives is a fundamental mechanism allowing cells to quickly respond to changing environmental conditions. The mRNA-binding Hu proteins are important for stabilization of short-lived mRNAs. Here we describe the identification and mechanistic characterization of the first low-molecular-weight inhibitors for Hu protein R (HuR) from microbial broths (Actinomyces sp.): dehydromutactin (1), MS-444 (2) and okicenone (3). These compounds interfere with HuR RNA binding, HuR trafficking, cytokine expression and T-cell activation. A mathematical and experimental analysis of the compounds' mode of action suggests that HuR homodimerizes before RNA binding and that the compounds interfere with the formation of HuR dimers. Our results demonstrate the chemical drugability of HuR; to our knowledge HuR is the first example of a drugable protein within the Hu family. MS-444, dehydromutactin and okicenone may become valuable tools for studying HuR function. An assessment of HuR inhibition as a central node in malignant processes might open up new conceptual routes toward combatting cancer.
Assuntos
Antígenos de Superfície/química , Avaliação Pré-Clínica de Medicamentos/métodos , Proteínas de Ligação a RNA/química , Actinomyces/metabolismo , Antracenos/química , Anti-Infecciosos/química , Ligação Competitiva , Relação Dose-Resposta a Droga , Desenho de Fármacos , Proteínas ELAV , Proteína Semelhante a ELAV 1 , Polarização de Fluorescência , Furanos/química , Humanos , Cinética , Modelos Teóricos , Dados de Sequência Molecular , Naftóis/química , Pironas/químicaRESUMO
The high mass accuracy and resolution of Fourier transform (FT)-ion cyclotron resonance (ICR) mass spectrometry are making it an increasingly useful tool in drug discovery and development. The basics of FT-ICR are described here, including modern ion sources and fragmentation methods. Although FT-ICR is not a high-throughput method in the traditional sense, previously difficult and complex problems are being efficiently approached using steadily improving instruments and magnets. Applications are surveyed in fields such as proteomics, metabonomics, natural product analysis and non-covalent complexes.
