ml1001807_si_001.pdf (267.39 kB)
Kinase Inhibition by Deoxy Analogues of the Resorcylic Lactone L-783277
journal contributionposted on 2011-01-13, 00:00 authored by Marc Liniger, Christian Neuhaus, Tatjana Hofmann, Luca Fransioli-Ignazio, Michel Jordi, Peter Drueckes, Jörg Trappe, Doriano Fabbro, Karl-Heinz Altmann
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.