Synthesis and structure-activity relationships of ring-opened 17-hydroxywortmannins: potent phosphoinositide 3-kinase inhibitors with improved properties and anticancer efficacy.
The phosphoinositide 3-kinase (PI3K) signaling pathway is frequently up-regulated in human cancer and is a promising target for the treatment of cancer. Wortmannin and its analogues are potent inhibitors of PI3K but suffer from inherent defects such as instability, insolubility, and toxicity. Opening of the reactive furan ring of 17-hydroxywortmannin with amines gives compounds with improved properties such as greater stability and aqueous solubility and a larger therapeutic index. Ring-opened analogues such as compound 13 containing basic amine groups have significantly increased PI3K inhibitory potency and greater efficacy in nude mouse xenograft assays.
Zask
Arie
A
Wyeth Research, Pearl River, New York 10965, USA. zaska@wyeth.com
Kaplan
Joshua
J
Toral-Barza
Lourdes
L
Hollander
Irwin
I
Young
Mairead
M
Tischler
Mark
M
Gaydos
Christine
C
Cinque
Michael
M
Lucas
Judy
J
Yu
Ker
K
D000730:Androstadienes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000730:Androstadienes; D000970:Antineoplastic Agents; D001578:Benzopyrans; D007192:Indenes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C529293:1-(((3-(dimethylamino)propyl)(methyl)amino)methylene)-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-dodecahydroindeno(4,5-h)isochromene-5-yl acetate; C053480:17-hydroxywortmannin