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Inhibitors of Sir2: Evaluation of Splitomicin Analogues

2004; American Chemical Society; Volume: 47; Issue: 10 Linguagem: Inglês

10.1021/jm030473r

1520-4804

Jeff Posakony, Maki Hirao, S.D. Stevens, Julian A. Simon, Antonio Bedalov,

Adenosine and Purinergic Signaling

Splitomicin (1) and 41 analogues were prepared and evaluated in cell-based Sir2 inhibition and toxicity assays and an in vitro Sir2 inhibition assay. Lactone ring or naphthalene (positions 7−9) substituents decrease activity, but other naphthalene substitutions (positions 5 and 6) are well-tolerated. The hydrolytically unstable aromatic lactone is important for activity. Lactone hydrolysis rates were used as a measure of reactivity; hydrolysis rates correlate with inhibitory activity. The most potent Sir2 inhibitors were structurally similar to and had hydrolysis rates similar to 1.