Synthesis and in vitro evaluation of new wortmannin esters: potent inhibitors of phosphatidylinositol 3-kinase.
New C-11 esters of the fermentation product wortmannin have been synthesized, with some of them further derivatized at C-17. The new esters show greater inhibition of isolated phosphatidylinositol 3-kinase and increased cell cytotoxicity in a rapidly proliferating leukemia cell line, when compared to wortmannin. Reduction of the C-17 ketone caused a slight increase in activity, while acylation of this new alcohol caused severe loss of activity. With their increased activity, the new C-11 esters may be good candidates to explore the in vivo antitumor effects of phosphatidylinositol 3-kinase inhibitors.
Creemer
L C
LC
Lilly Research Laboratories, Greenfield, Indiana 46140, USA.
Kirst
H A
HA
Vlahos
C J
CJ
Schultz
R M
RM
D000730:Androstadienes / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004952:Esters; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D004952:Esters; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D000077191:Wortmannin