Natural Fragments in the Design of Modulators of Multiple Targets (Abstract/Comunicazione in atti di convegno)

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Label
  • Natural Fragments in the Design of Modulators of Multiple Targets (Abstract/Comunicazione in atti di convegno) (literal)
Anno
  • 2012-01-01T00:00:00+01:00 (literal)
Alternative label
  • Sofie Edvinsson, Lina-Maria Nordvall, Morakot Sakulsombat, Sara Boström, Paola Carta, Paola Burredu, Nabil Souihi, Luciana Auzzas, and Andreas Larsson (2012)
    Natural Fragments in the Design of Modulators of Multiple Targets
    in Organikedagarna 2012, Götheburg, Sweden, June 12-15, 2012
    (literal)
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  • Sofie Edvinsson, Lina-Maria Nordvall, Morakot Sakulsombat, Sara Boström, Paola Carta, Paola Burredu, Nabil Souihi, Luciana Auzzas, and Andreas Larsson (literal)
Pagina inizio
  • 117 (literal)
Pagina fine
  • 117 (literal)
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  • Oral communication, contribution by PhD student S. Edvinsson (literal)
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  • Organikedagarna XXIII - Book of abstract (literal)
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  • 1 (literal)
Note
  • Comunicazione (literal)
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  • Sofie Edvinsson, Lina-Maria Nordvall, Morakot Sakulsombat, Sara Boström, and Andreas Larsson: Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden. Paola Carta: Porto Conte Ricerche, 07041 Alghero (SS), Italy. Paola Burreddu, Luciana Auzzas: Institute of Biomolecular Chemistry, National Research Council of Italy, Traversa La Crucca 3, 07100 Sassari, Italy (literal)
Titolo
  • Natural Fragments in the Design of Modulators of Multiple Targets (literal)
Abstract
  • A multitude of Natural Products that display diverse biological activities are based on a benzoquinone core.1 Aiming at identifying potential mimetics of the dihydroxymethyl derivative DHMBQ (Figure 1A), we have applied physicochemical descriptors and Principal Component Analysis (PCA) to a database containing nearly 14000 fragments. Upon selection, DHMBQ-like fragments were evaluated for binding to two different targets, namely the BIR3 domain of X-chromosome linked Inhibitor of Apoptosis Protein (XIAP) and the kinase domain of Insulin-like Growth Factor Receptor 1 (IGF-1R). IAPs and IGF-1R are known proteins involved in cell signaling pathways which regulate vital functions in cells, and benzoquinone-containing compounds have been reported as inhibitors of either XIAP or IGF-1R (e.g. 1 and 2, Figure 1A).2,3 A Surface Plasmon Resonance protocol has been used, from which binders of XIAP and IGF-1R were identified (Figure 1B). Guided by a ligand-based rationale, simplified mimetics of 1 and 2 were prepared (Figure 1C), which will be discussed in this communication. Figure 1. A: Embelin (1) and a nakijiquinone-analogue (2), known inhibitors of XIAP and IGF-1R, respectively. B: Examples of potential DHMBQ mimetics identified by PCA. C: Examples of simplified mimetics of 1 and 2. References [1] Drugs of Natural Origin - A Treatise of Pharmacognosy, 6th ed., Samuelsson G., Bohlin, L., Apotekarsocieteten-Swedish Pharmaceutical Society, Swedish Pharmaceutical Press, 2009, Stockholm, Sweden; Owton, W. M., J. Chem. Soc., Perkin Trans. 1, 1999, 17, 2409-2420. [2] Mace, P. D. et al., Cell Death Differ., 2010, 17, 46-53; Wu, J. et al., EMBO J., 2008, 27, 1985-1994. [3] Nikolovska-Coleska, Z. et al., J. Med. Chem., 2004, 47, 2430-2440; Stahl, P. et al., Angew. Chem. Int. Ed., 2002, 41, 1174-1178. (literal)
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