A Spiroligomer α-Helix Mimic That Binds HDM2, Penetrates Human Cells and Stabilizes HDM2 in Cell Culture 英文参考文献.docVIP

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A Spiroligomer α-Helix Mimic That Binds HDM2, Penetrates Human Cells and Stabilizes HDM2 in Cell Culture 英文参考文献.doc

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A Spiroligomer α-Helix Mimic That Binds HDM2, Penetrates Human Cells and Stabilizes HDM2 in Cell Culture 英文参考文献

ASpiroligomera-HelixMimicThatBindsHDM2, PenetratesHumanCellsandStabilizesHDM2inCell Culture ZacharyZ.Brown1,KavithaAkula2,AllaArzumanyan3,JenniferAlleva1,MarcusJackson2, EugeneyBichenkov3,JoelB.Sheffield3,MarkA.Feitelson3,ChristianE.Schafmeister2* 1DepartmentofChemistry,PrincetonUniversity,Princeton,NewJersey,UnitedStatesofAmerica,2ChemistryDepartment,TempleUniversity,Philadelphia,Pennsylvania, UnitedStatesofAmerica,3DepartmentofBiology,TempleUniversity,Philadelphia,Pennsylvania,UnitedStatesofAmerica Abstract We demonstrate functionalized spiroligomers that mimic the HDM2-bound conformation of the p53 activation domain. Spiroligomersarestereochemicallydefined,functionalized,spirocyclicmonomerscoupledthroughpairsofamidebondsto 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 400nM. The spiroligomer1penetrateshumanlivercancercellsthroughpassivediffusionandinadose-dependentandtime-dependent mannerincreasesthelevelsofHDM2morethan30-foldinHuh7cellsinwhichthep53/HDM2negativefeed-backloopis 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 feedbackloop. Citation: Brown ZZ, Akula K, Arzumanyan A, Alleva J, Jackson M, et al. (2012) A Spiroligomer a-Helix Mimic That Binds HDM2, Penetrates Human Cells and StabilizesHDM2inCellCulture.PLoSONE7(10):e45948.doi:10.1371/journal.pone.0045948 Editor:GiorgioColombo,ConsiglioNazionaledelleRicerche,Italy ReceivedJune18,2012;AcceptedAugust23,2012;PublishedOctober18,2012 Copyright: ? 2012 Brown et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalau