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Stereoselective synthesis of (3-aminodecahydro-1,4-methanonaphthalen-2-yl)methanols targeted to the C1 domain of protein kinase C |
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| Authors: | Alexandros Kiriazis,Gustav Boije af Gennä s,Virpi TalmanElina Ekokoski,Timo Ruotsalainen,Irene Kylä nlahtiTobias Rü ffer,Gloria Wissel,Henri XhaardHeinrich Lang,Raimo K. TuominenJari Yli-Kauhaluoma |
| Affiliation: | a Division of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland b Division of Pharmacology and Toxicology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland c Technische Universität Chemnitz, Fakultät für Naturwissenschaften, Institut für Chemie, Strasse der Nationen 62, D-09111 Chemnitz, Germany d Centre for Drug Research, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland |
| Abstract: | Protein kinase C (PKC) is a widely studied molecular target for the treatment of cancer and other diseases. We have approached the issue of modifying PKC function by targeting the C1 domain in the regulatory region of the enzyme. By using the X-ray crystal structure of the PKCδ C1b domain combined with molecular modeling, we discovered (3-aminodecahydro-1,4-methanonaphthalen-2-yl)methanol as a novel C1 domain ligand. The stereoselective synthesis of this tricyclic γ-amino alcohol was based on two successive Diels-Alder reactions to construct the six continuous stereocenters of the key intermediate. |
| Keywords: | Diels-Alder reaction Protein kinase C Molecular modeling Curtius-Schmidt rearrangement |
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