Diversity-oriented synthesis of pochonins and biological evaluation against a panel of kinases.
Pochonins A-F were recently characterized as six new members of the naturally occurring family of 14-membered resorcylic acid lactones. As there are a high number of ATPase and kinase inhibitors among natural resorcylic lactones, a library based on the pochonin scaffold, with five points of diversity, was prepared which includes diversity beyond that of the natural analogues. The library was synthesized by using solid-supported reagents amenable to automation. Testing the library for its inhibition against a panel of 24 kinases at 10 microM afforded a >14 % hit rate. These results demonstrate the potential of the resorcylides towards the inhibition of therapeutically relevant kinases.
Moulin
Emilie
E
Organic and Bioorganic Chemistry Laboratory, Institut de Science et Ingénierie Supramoléculaires, Université Louis Pasteur-CNRS, 8 allée Gaspard Monge, 67000 Strasbourg, France.
Barluenga
Sofia
S
Totzke
Frank
F
Winssinger
Nicolas
N
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007783:Lactones / Q000138:chemical synthesis / Q000494:pharmacology*; D018942:Macrolides / Q000138:chemical synthesis / Q000494:pharmacology*; D010770:Phosphotransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012118:Resorcinols / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007783:Lactones; D018942:Macrolides; D012118:Resorcinols; D010770:Phosphotransferases; D000251:Adenosine Triphosphatases