Phenanthroindolizidine alkaloids from Tylophora atrofolliculata with hypoxia-inducible factor-1 (HIF-1) inhibitory activity

摘要

Eleven new alkaloids ( 1–11 ), together with eleven known phenanthroindolizidine alkaloids ( 12–22 ) were isolated from the whole plants of Tylophora atrofolliculata (Asclepiadaceae). Their structures were characterized by means of NMR spectroscopies including HSQC, HMBC, ~(1) H– ~(1) H COSY and NOESY experiments, assisted by high-resolution MS and CD spectral analyses. HIF-1-mediated reporter gene assay in T47D cells was used to evaluate the inhibitory effects of isolated alkaloids on HIF-1 activation. Most alkaloids exhibited extremely potent inhibitory effects with IC _(50) values in the low nanomolar range. The potency of 14 and 17 are comparable to manassantin B, one of the most potent HIF-1 inhibitors identified so far. Structure–activity relationship (SAR) analyses showed the necessities for high activity, i.e. non-planarity at indolizidine moiety, substitution types and patterns on the phenanthrene and indolizidine moieties. This is the first report on HIF-1 inhibitory activity of phenanthroindolizidine alkaloids, providing a new insight into their underlying anti-cancer mechanism.