RESUMO
Saframycin A (SafA) is a member of a class of natural products with potent antiproliferative effects in leukemia- and tumor-derived cells. This activity is frequently conjectured to derive from the ability of saframycins to covalently modify duplex DNA. We used a DNA-linked affinity purification technique to identify GAPDH as a protein target of DNA-small molecule adducts of several members of the saframycin class. Nuclear translocation of GAPDH occurs upon treatment of cancer cells with saframycins, and depletion of cellular GAPDH levels by small interfering RNA transfection confers drug resistance. Roeder and coworkers have recently suggested that GAPDH is a key transcriptional coactivator necessary for entry into S phase. Our data suggest that GAPDH is also capable of forming a ternary complex with saframycin-related compounds and DNA that induces a toxic response in cells. These studies implicate a previously unknown molecular mechanism of antiproliferative activity and, given that one member of the saframycin class has shown efficacy in cancer treatment, suggest that GAPDH may be a potential target for chemotherapeutic intervention.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Gliceraldeído-3-Fosfato Desidrogenases/efeitos dos fármacos , Isoquinolinas/farmacologia , Sequência de Bases , Southwestern Blotting , Linhagem Celular , Cromatografia de Afinidade , Adutos de DNA , Primers do DNA , Gliceraldeído-3-Fosfato Desidrogenases/genética , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Glicólise , Humanos , Transporte Proteico , RNA Interferente Pequeno/genéticaRESUMO
A short, enantioselective, and diastereoselective synthesis of cytoxazone, a Th2-selective immunomodulator from Streptomyces, is described. The route was readily adapted to the synthesis of the three other stereoisomers of natural cytoxazone. Evaluation of these compounds revealed that the stereochemical configuration of the oxazolidinone ring did not influence their biological activity.
