Separation and SAR study of HIF-1alpha inhibitory tubulosines from Alangium cf. longiflorum.
A crude organic solvent extract of Alangium cf. longiflorum exhibited potent inhibition of hypoxia-induced HIF-1 transcriptional activity in human U251 glioma cells. Dereplication and bioactivity-guided fractionation, including Sephadex LH-20 and chiral HPLC chromatographies, led to the isolation of tubulosine ( 1), 9-desmethyltubulosine ( 2), and isotubulosine ( 3). Structures were verified by complete (1)H and (13)C assignments using 1D- and 2D-NMR techniques. Tubulosine strongly inhibited HIF-1 transcriptional activity, isotubulosine was devoid of activity, and 9-desmethyltubulosine possessed 6-fold less potency than tubulosine.
Klausmeyer
Paul
P
Natural Products Support Group, SAIC-Frederick Inc., NCI Frederick, Frederick, MD 21702, USA.
McCloud
Thomas G
TG
Uranchimeg
Badarch
B
Melillo
Giovanni
G
Scudiero
Dominic A
DA
Cardellina
John H
JH
Shoemaker
Robert H
RH
D032604:Alangiaceae / Q000737:chemistry*; D045744:Cell Line, Tumor; D004640:Emetine / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D018517:Plant Roots / Q000737:chemistry; D013329:Structure-Activity Relationship
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C009805:tubulosine; D004640:Emetine