RESUMO
Four corners: The syntheses of four key building blocks for the total synthesis of norhalichondrin B (see structure) are described. The assembly of these subunits into the natural product is also reported. Key features of the synthesis are the use of the Achmatowicz oxidation/ionic hydrogenation for the synthesis of pyrans and pyranopyrans, and the application of tandem metathesis for the synthesis of pyranopyrans.
Assuntos
Furanos/síntese química , Piranos/síntese química , Furanos/química , Hidrogenação , Piranos/químicaRESUMO
A concise route to the C1-C15 domain of the halichondrins is described. The key reaction is the conversion of a furfuryl alcohol to a pyranone. The stereocenter of this pyranone serves as the starting point for the other 8 stereocenters.
RESUMO
The removal of intervening sequences from transcripts is catalyzed by the spliceosome, a multicomponent complex that assembles on the newly synthesized pre-mRNA. Pre-mRNA translation in the cytoplasm leads to the generation of aberrant proteins that are potentially harmful. Therefore, tight control to prevent undesired pre-mRNA export from the nucleus and its subsequent translation is an essential requirement for reliable gene expression. Here, we show that the natural product FR901464 (1) and its methylated derivative, spliceostatin A (2), inhibit in vitro splicing and promote pre-mRNA accumulation by binding to SF3b, a subcomplex of the U2 small nuclear ribonucleoprotein in the spliceosome. Importantly, treatment of cells with these compounds resulted in leakage of pre-mRNA to the cytoplasm, where it was translated. Knockdown of SF3b by small interfering RNA induced phenotypes similar to those seen with spliceostatin A treatment. Thus, the inhibition of pre-mRNA splicing during early steps involving SF3b allows unspliced mRNA leakage and translation.
Assuntos
Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Antineoplásicos/farmacologia , Fosfoproteínas/antagonistas & inibidores , Precursores de RNA/efeitos dos fármacos , Splicing de RNA/efeitos dos fármacos , Ribonucleoproteína Nuclear Pequena U2/antagonistas & inibidores , Linhagem Celular Tumoral , Humanos , Fosfoproteínas/genética , Piranos/farmacologia , Precursores de RNA/metabolismo , Fatores de Processamento de RNA , RNA Interferente Pequeno/farmacologia , Proteínas de Ligação a RNA , Ribonucleoproteína Nuclear Pequena U2/genética , Compostos de Espiro/farmacologiaRESUMO
The structure-activity relationship for FR901464, a potent cell-cycle inhibitor, was examined by synthesizing its analogs. A versatile method for converting FR901464 was devised. This method made it possible to synthesize biologically active FR901464-biotin conjugates which could be used to isolate the binding proteins.