Structure-based design and synthesis of tricyclic IAP (Inhibitors of Apoptosis Proteins) inhibitors.

Alexander W Hird, Brian M Aquila, Michael H Block, Edward J Hennessy, Victor M Kamhi, Charles A Omer, Naomi M Laing, Jamal C Saeh, Li Sha, Bin Yang

Bioorganic & medicinal chemistry letters 2014 Apr 1

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The design and synthesis of a series of novel tricyclic IAP inhibitors is reported. Rapid assembly of the core tricycle involved two key steps: Rh-catalyzed hydrogenation of an unsaturated bicyclic ring system and a Ru-catalyzed ring closing alkene metathesis reaction. The final Smac mimetics bind to cIAP1 and XIAP BIR3 domains and elicit the desired phenotype in cellular proliferation assays. Dimeric IAP inhibitors were found to possess nanomolar potency in a cellular proliferation assay and favourable in vitro drug-like properties. Copyright © 2014 Elsevier Ltd. All rights reserved.

Citation

Alexander W Hird, Brian M Aquila, Michael H Block, Edward J Hennessy, Victor M Kamhi, Charles A Omer, Naomi M Laing, Jamal C Saeh, Li Sha, Bin Yang. Structure-based design and synthesis of tricyclic IAP (Inhibitors of Apoptosis Proteins) inhibitors. Bioorganic & medicinal chemistry letters. 2014 Apr 1;24(7):1820-4