Synthesis and kinase inhibitory activity of 3'-(S)-epi-K-252a.
The 3'-epi diastereomer of K-252a was synthesized with the goal of evaluating the stereochemical requirements of the 3'-sugar alcohol on kinase inhibitory activity. Inverting the 3'-alcohol resulted in a 20 nM inhibitor of VEGFR2 and a 1 nM inhibitor of TrkA tyrosine kinase.
Gingrich
Diane E
DE
Department of Medicinal Chemistry, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. dgingric@cephalon.com
Hudkins
Robert L
RL
D000438:Alcohols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002227:Carbazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D026121:Indole Alkaloids; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D020917:Receptor, trkA / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
D000438:Alcohols; D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; C049985:staurosporine aglycone; D010770:Phosphotransferases; D020917:Receptor, trkA; D040301:Vascular Endothelial Growth Factor Receptor-2