Separation and SAR Study of HIF-1α Inhibitory Tubulosines from Alangium cf. longiflorum

Abstract

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 ¹H and ¹³C 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.

Key words

Alangium cf. longiflorum - Alangiaceae - tubulosine - U251 human cancer cells - HIF-1α - chiral chromatography

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