Bh. Norman et al., STUDIES ON THE MECHANISM OF PHOSPHATIDYLINOSITOL 3-KINASE INHIBITION BY WORTMANNIN AND RELATED ANALOGS, Journal of medicinal chemistry, 39(5), 1996, pp. 1106-1111
Wortmannin, a fungal metabolite, was identified as a potent inhibitor
(IC50 = 4.2 nM) of phosphatidylinositol 3-kinase (PI 3-kinase). Due to
the importance of PI 3-kinase in several intracellular signaling path
ways, structure-activity studies on wortmannin analogs were performed
in an effort to understand the structural requirements necessary for P
I 3-kinase inhibition. Since wortmannin is an irreversible inhibitor o
f PI 3-kinase, it was postulated that covalent attachment at the elect
rophilic C-21 site was a possible mode of action for PI 3-kinase inhib
ition. We have prepared various wortmannin analogs which address the p
ossibility of this mechanism. Of particular interest are compounds whi
ch affect the C-21 position of wortmannin either sterically or electro
nically. Our results support the conclusion that nucleophilic addition
by the kinase onto the 0-21 position of wortmannin is required for in
hibition of PI 3-kinase by wortmannin analogs. Additionally, we have p
repared several D-ring analogs of wortmannin, and their activities are
reported herein. We conclude that the wortmannin D ring is an importa
nt recognition site since modifications have such a dramatic effect on
inhibitor potency. Finally, the identification of 17 beta-hydroxywort
mannin represents the first reported subnanomolar inhibitor of PI 3-ki
nase. These studies, along with in vivo antitumor experiments, suggest
that the mechanism of PI 3-kinase inhibition correlates to the associ
ated toxicity observed with wortmannin-based inhibitors of PI 3-kinase
.