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, 19 (14), 3783-6

Analysis of HIF-1 Inhibition by Manassantin A and Analogues With Modified Tetrahydrofuran Configurations

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Analysis of HIF-1 Inhibition by Manassantin A and Analogues With Modified Tetrahydrofuran Configurations

Amanda C Kasper et al. Bioorg Med Chem Lett.

Abstract

We have shown that manassantin A downregulated the HIF-1alpha expression and inhibited the secretion of VEGF. We have also demonstrated that the 2,3-cis-3,4-trans-4,5-cis-configuration of the tetrahydrofuran is critical to the HIF-1 inhibition of manassantin A.

Figures

Figure 1
Figure 1
Structure of dineolignans from Saururus cernuus.
Figure 2
Figure 2
Inhibition of HIF-1α expression by 1. (a) After treating 4T1 cells under hypoxia (0.5% O2, 24 h) with and without 1, HIF-1α expression was evaluated using Western blots. By comparison with loading control (histone H1), nuclear expression of HIF-1α was significantly inhibited by 1 at concentrations higher than 10 nM. (b) In 4T1 and MDA-MB-231 cells, HIF-1α expression induced by CoCl2 (240μM, 24 h) was also inhibited by 1.
Figure 3
Figure 3
Inhibition of VEGF secretion by 1. Inhibition of VEGF was determined in 4T1 cells after hypoxia treatment (0.5% O2, 24 h). After treatment with and without 1, cell culture supernates were collected, and VEGF secretion was measured using ELISA. Compound 1 significantly inhibited VEGF at concentrations higher than 10 nM (p<0.001).
Figure 4
Figure 4
Inhibition of HIF-1 by 11 and 13.
Figure 5
Figure 5
Optimized conformations of truncated structures of 1, 11, and 13 (a) Truncated structures (1416) (b) Overlay I (c) Overlay II: front view (d) Overlay II: side view (14 in black, 15 in red, 16 in blue, and tetrahydrofurans in green).
Scheme 1
Scheme 1
(a) Ar2 Li, THF, −78 °C, 40 min, 70%; (b) BF3·OEt2, NaBH3CN, CH2Cl2, −78 °C, 30 min, 99%; (c) BF3·OEt2, CH2Cl2, −78 to −20 °C, 2 h; then, NaBH3CN, −78 °C, 30 min, 96%: (d) H2, Pd/C, EtOAc/EtOH (3:1), 25 °C, 2 h; (e) TBAF, THF, 25 °C, 1 h, 88% for 2 steps; (f) 10, BEMP, CH2Cl2, 25 °C, 18 h, 66%; (g) (polystyrylmethyl)trimethylammonium borohydride, MeOH, 25 °C 48 h, 75%; (h) 10, BEMP, CH2Cl2, 25 °C, 20 h, 92%; (i) (polystyrylmethyl)trimethylammonium borohydride, MeOH, 25 °C, 30 h, 86%.

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