Synthesis and biological evaluation of synthetic viridins derived from C(20)-heteroalkylation of the steroidal PI-3-kinase inhibitor wortmannin.
A series of viridin analogs was prepared from wortmannin by nucleophilic ring opening at C(20) and evaluated against the signaling kinases PI-3-kinase and mTOR. Several subnanomolar enzyme inhibitors with orders of magnitude selectivity for PI-3-kinase and strong cytotoxic activity against four cancer cell lines were identified. Among the ten most promising derivatives, six demonstrated lower liver toxicity and greater promise for inhibition of tumor cell growth than the lead structure wortmannin.
Wipf
Peter
P
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Minion
Daniel J
DJ
Halter
Robert J
RJ
Berggren
Margareta I
MI
Ho
Caroline B
CB
Chiang
Gary G
GG
Kirkpatrick
Lynn
L
Abraham
Robert
R
Powis
Garth
G
D000478:Alkylation; D000730:Androstadienes / Q000737:chemistry* / Q000494:pharmacology; D000736:Androstenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001430:Bacteriocins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010716:Phosphatidylinositols / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013379:Substrate Specificity; D000077191:Wortmannin
D000730:Androstadienes; D000736:Androstenes; D001430:Bacteriocins; D010716:Phosphatidylinositols; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C012097:viridin; D000077191:Wortmannin