Abstract
Dual action compounds (DACs) based on 4-substituted aza-bicyclo[5.3.0]decane Smac mimetic scaffolds (ABDs) linked to a Zn2+-chelating moiety (DPA, o-hydroxy, m-allyl, N-acyl (E)-phenylhydrazone) through their 10 position are reported and characterized. Their synthesis, their target affinity (XIAP BIR3, Zn2+) in cell-free assays, their pro-apoptotic effects and cytotoxicity in tumor cells with varying sensitivity to Smac mimetics are described. The results are interpreted to evaluate the influence of Zn2+ chelators on cell-free potency and on cellular permeability of DACs, and to propose novel avenues towards more potent antitumoral DACs based on Smac mimetics and Zn2+ chelation.
Original language | English |
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Pages (from-to) | 4613-4619 |
Number of pages | 7 |
Journal | Bioorganic and Medicinal Chemistry Letters |
Volume | 26 |
Issue number | 19 |
DOIs | |
Publication status | Published - Oct 1 2016 |
Keywords
- Apoptosis
- Dual action compounds
- Peptidomimetics
- Smac mimetics
- Zinc chelation
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry