Saururus cernuus lignans—Potent small molecule inhibitors of hypoxia-inducible factor-1

Abstract

Hypoxia-inducible factor-1 (HIF-1) represents an important tumor-selective therapeutic target for solid tumors. In search of novel small molecule HIF-1 inhibitors, 5400 natural product-rich extracts from plants, marine organisms, and microbes were examined for HIF-1 inhibitory activities using a cell-based reporter assay. Bioassay-guided fractionation and isolation, followed by structure elucidation, yielded three potent natural product-derived HIF-1 inhibitors and two structurally related inactive compounds. In a T47D cell-based reporter assay, manassantin B 1 , manassantin A, and 4-O-methylsaucerneol inhibited hypoxia-induced HIF-1 activation with IC 50 values of 3, 3, and 20 nM, respectively. All three compounds are relatively hypoxia-specific inhibitors of HIF-1 activation, in comparison to other stimuli. The hypoxic induction of HIF-1 target genes CDKN1A, VEGF and GLUT-1 were also inhibited. These compounds inhibit HIF-1 by blocking hypoxia-induced nuclear HIF-1α protein accumulation without affecting HIF-1α mRNA levels. In addition, preliminary structure-activity studies suggest specific structural requirements for this class of HIF-1 inhibitors.

Sodwanone and Yardenone Triterpenes from a South African Species of the Marine Sponge Axinella Inhibit Hypoxia-Inducible Factor-1 (HIF-1) Activation in Both Breast and Prostate Tumor Cells

“…The 13 C NMR spectrum (Table 2) contained 30 carbon resonances, and the 13 C DEPT spectrum indicated the presence of seven methyl groups, eleven methylenes, five methines and seven quaternary carbon atoms. 15 Comparison of the 13 C NMR spectroscopic data of 1 with those of sodwanone K, showed nearly complete analogy of the chemical shifts, except for C-2 and C-3. Clear NOESY correlations between H-24 and H-7; and between H-25 and H-26 suggested that the relative configuration of this portion of 1 was similar to that of sodwanone K, except that a NOE between H-3 and H-24 indicated that 1 was the C-3 epimer of sodwanone K. The absolute configuration of C-3 was determined using the modified Mosher ester method.…”

“…Comparison of the 1 H and 13 C NMR spectra of 7 (Tables 1 and 2) with those of 4 indicated that the bicyclic C-2-C-11 portion of the structures were analogous in both compounds. Long-range 1 H- 13 Thus 7 possess a new carbon skeleton where the two separate bicyclic portions of the structure are connected at the bridgehead carbon C-19 by the C-12 -C-13 linker. This new sodwanone analog was assigned the trivial name sodwanone U (7).…”

“…The IR spectrum was obtained using a Genesis Series FTIR. The NMR spectra were recorded in CDCl 3 on Bruker AMX-NMR spectrometers operating at either 400 or 500 MHz for 1 H and either 100 or 125 MHz for 13 C, respectively. The NMR spectra were recorded running gradients and using residual solvent peaks (δ 7.27 for 1 H) and (δ 77.0 for 13 C) as internal references.…”

“…12 Potent HIF-1 inhibitors such as manassantin B were subsequently identified from these studies. 12,13 Iron chelators like desferrioxamine and 1,10-phenanthroline activate HIF-1 by inhibiting the hydroxylases that promote the degradation and inactivation of the oxygen-regulated HIF-1α subunit. 12,14 Manassantin B and related compounds selectively inhibited HIF-1 activation by hypoxia, in contrast to their relatively weak ability to inhibit 1,10-phenanthroline-induced HIF-1 activation.…”

“…12,14 Manassantin B and related compounds selectively inhibited HIF-1 activation by hypoxia, in contrast to their relatively weak ability to inhibit 1,10-phenanthroline-induced HIF-1 activation. 12,13 Herein, we report the isolation and molecular characterization of eleven sodwanone/yardenone triterpenoids from an active marine sponge Axinella sp. extract, that inhibited HIF-1 activation.…”