title: Kinase inhibition by deoxy analogues of the resorcylic lactone L-783277.
abstract: The natural product L-783277 is a resorcylic lactone type covalent kinase inhibitor. We have prepared the 5'-deoxy analogue of L-783277 (1) in a stereoselective fashion. Remarkably, this analogue retains almost the full kinase inhibitory potential of natural L-783277, with low nanomolar IC50 values against the most sensitive kinases, and it exhibits essentially the same selectivity profile (within the panel of 39 kinases investigated). In contrast, removal of both the 4'- and the 5'-hydroxyl groups leads to a more significant reduction in kinase inhibitory activity and so does a change in the geometry of the C7'-C8' double bond in 1 from Z to E. These findings offer new perspectives for the design of second generation resorcylic lactone-based kinase inhibitors.
authors.affiliation: Swiss Federal Institute of Technology (ETH) Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, 8093 Zurich, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Liniger
authors.affiliation: Swiss Federal Institute of Technology (ETH) Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, 8093 Zurich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Neuhaus
authors.affiliation: Swiss Federal Institute of Technology (ETH) Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, 8093 Zurich, Switzerland.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Hofmann
authors.affiliation: Swiss Federal Institute of Technology (ETH) Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, 8093 Zurich, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Fransioli-Ignazio
authors.affiliation: Swiss Federal Institute of Technology (ETH) Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, 8093 Zurich, Switzerland.
authors.forename: Michel
authors.initials: M
authors.lastname: Jordi
authors.affiliation: Novartis Institute for Biomedical Research, Center for Proteomic Chemistry, Expertise Platform Kinases, 4002 Basel, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Drueckes
authors.affiliation: Novartis Institute for Biomedical Research, Center for Proteomic Chemistry, Expertise Platform Kinases, 4002 Basel, Switzerland.
authors.forename: Jörg
authors.initials: J
authors.lastname: Trappe
authors.affiliation: Novartis Institute for Biomedical Research, Center for Proteomic Chemistry, Expertise Platform Kinases, 4002 Basel, Switzerland.
authors.forename: Doriano
authors.initials: D
authors.lastname: Fabbro
authors.affiliation: Swiss Federal Institute of Technology (ETH) Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, 8093 Zurich, Switzerland.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Altmann
keywords: Cancer; SAR; irreversible inhibitor; kinase inhibitor; natural product; resorcylic lactone (RL); stereoselective synthesis