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      Dimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part II: Structural and biological characterization

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          Abstract

          Novel pro-apoptotic, homodimeric and heterodimeric Smac mimetics/IAPs inhibitors connected through head-head (8), tail-tail (9) or head-tail linkers (10), were biologically and structurally characterized. In vitro characterization (binding to BIR3 and linker-BIR2-BIR3 domains from XIAP and cIAP1, cytotoxicity assays) identified early leads from each dimer family. Computational models and structural studies (crystallography, NMR, gel filtration) partially rationalized the observed properties for each dimer class. Tail-tail dimer 9a was shown to be active in a breast and in an ovary tumor model, highlighting the potential of dimeric Smac mimetics/IAP inhibitors based on the N-AVPI-like 4-substituted 1-aza-2-oxobicyclo[5.3.0]decane scaffold as potential antineoplastic agents. Copyright © 2012 Elsevier Ltd. All rights reserved.

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          Author and article information

          Journal
          Bioorganic & Medicinal Chemistry
          Bioorganic & Medicinal Chemistry
          Elsevier BV
          09680896
          November 2012
          November 2012
          : 20
          : 22
          : 6709-6723
          Article
          10.1016/j.bmc.2012.09.041
          23062821
          © 2012

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