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

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, H-1-H-1 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 IC50 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.