a spiroligomer α-helix mimic that binds hdm2, penetrates human cells and stabilizes hdm2 in cell culture一个spiroligomerα-helix模拟,结合hdm2穿透人体细胞在细胞培养和稳定hdm2.pdfVIP

A Spiroligomer a-Helix Mimic That Binds HDM2, Penetrates Human Cells and Stabilizes HDM2 in Cell Culture 1 2 3 1 2 Zachary Z. Brown , Kavitha Akula , Alla Arzumanyan , Jennifer Alleva , Marcus Jackson , 3 3 3 2 Eugeney Bichenkov , Joel B. Sheffield , Mark A. Feitelson , Christian E. Schafmeister * 1 Department of Chemistry, Princeton University, Princeton, New Jersey, United States of America, 2 Chemistry Department, Temple University, Philadelphia, Pennsylvania, United States of America, 3 Department of Biology, Temple University, Philadelphia, Pennsylvania, United States of America Abstract We demonstrate functionalized spiroligomers that mimic the HDM2-bound conformation of the p53 activation domain. Spiroligomers are stereochemically defined, functionalized, spirocyclic monomers coupled through pairs of amide bonds to create spiro-ladder oligomers [1]. Two series of spiroligomers were synthesized, one of structural analogs and one of stereochemical analogs, from which we identified compound 1, that binds HDM2 with a Kd value of 400 nM. The spiroligomer 1 penetrates human liver cancer cells through passive diffusion and in a dose-dependent and time-dependent manner increases the levels of HDM2 more than 30-fold in Huh7 cells in which the p53/HDM2 negative feed-back loop is inoperative. This is a biological effect that is not seen with the HDM2 ligand nutlin-3a. We propose that compound 1 modulates the levels of HDM2 by stabilizing it to proteolysis, allowing it to accumulate in the absence of a p53/HDM2 feedback loop. Citation