Modulators of hypoxia inducible factor-1 and related uses

A technology of R12 and R16, applied in the field of cardiac lactone and bufadienolide compounds, can solve the problem of not yet clear hypoxia overall regulator and the like

Inactive Publication Date: 2009-04-01
BRITISH TECH GRP LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] While HIF-1 is now known to be a master regulator of local or cellular responses to hypoxia, the overall regulator of hypoxia has not been identified

Method used

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  • Modulators of hypoxia inducible factor-1 and related uses
  • Modulators of hypoxia inducible factor-1 and related uses
  • Modulators of hypoxia inducible factor-1 and related uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0216] Example 1: Cardiac glycoside compounds inhibit the expression of HIF-1α

[0217] The ability of BNC1 and BNC4 to suppress hypoxia-mediated induction of HIF1α in human tumor cells was investigated. figure 2 Shown are the results of immunoblotting of HIF-1α, HIF-1β and β-actin (control) expression in Caki-1 or Panc-1 cells treated with BNC1 or BNC4 under hypoxia. The results showed that BNC4 was about 10-fold more active in suppressing HIF-1α expression than BNC1.

Embodiment 2

[0218] Example 2: BNC4 inhibits PHD inhibitor-induced HIF-1α under normoxia

[0219] In order to study the mechanism of BNC4 inhibiting HIF-1α, the ability of BNC1 or BNC4 to inhibit the expression of HIF-1α induced by PHD inhibitor L-mimosone (mimosone) was studied under normoxic conditions.

[0220] exist image 3 In a representative experiment, Hep3B cells were grown under normoxic conditions, but also treated with 200 [mu]M L-mimosolone for 18 hours in the presence or absence of BNC1 or BNC4 as indicated. The abundance of HIF1α and β-actin was determined by western blotting.

[0221] The results showed that under normoxic conditions, L-mimosoone induced the accumulation of HIF-1α, and the addition of BNC4 could abolish the L-mimosoone-induced HIF-1α accumulation. In this experiment, BNC1 at low concentrations tested appeared to have no effect on HIF-la accumulation. While not wishing to be bound by any particular theory, the fact that BNC4 inhibits PHD inhibitor-induced...

Embodiment 3

[0222] Example 3: Preparation of 3-oxime ethers and 3-amino derivatives of calcitonin

[0223] Synthesis of calicoin

[0224]

[0225] EtOH (1.25mL) solution (partial suspension)-0.02M acetate buffer (pH 4.0, 3.75mL) of insantrinin (66.3mg, 0.125mmol) and naringinase (23.2mg) was incubated at 40°C Incubate for 6.5h. After adding EtOH (30 mL), the whole mixture was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (SiO 2 , 10 g, n-Hexane-EtOAc (1:1)) was purified to obtain indivalin (48 mg).

[0226] Synthesis of Scillarenon

[0227]

[0228] Dissolve 700mg (1.82mmol) calicoin in 30mL of anhydrous dichloromethane, add 1.4g molecular sieve powder and 1.57g (7.28mmol) pyridinium chlorochromate. The mixture was stirred overnight at room temperature under nitrogen atmosphere. The dark mixture was filtered through a pad of celite and concentrated. The crude mixture was purified by flash chromatography to afford 604 mg (86%)...

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Abstract

The invention features compounds of formulas I or II: and pharmaceutically acceptable salts and prodrugs thereof, as well methods for modulating the effects of local and systemic hypoxic events using the compounds.

Description

Background of the invention [0001] The present invention relates to cardiolide and bufadienolide compounds and their use for modulating the effects of local and systemic hypoxic events. [0002] Hypoxia induces a variety of physiological and cellular responses in humans and other mammals. The effects of hypoxia vary substantially depending on how long hypoxic conditions are maintained. Acute hypoxia is characterized by increased respiratory ventilation, but after 3-5 minutes, ventilation decreases. Individuals exposed to chronic hypoxic conditions experience a range of effects, including decreased heart rate and increased blood pressure. Metabolically, hypoxia leads to decreased oxidation of glucose, from oxidative phosphorylation to glycolysis. Glycolysis yields less energy from carbohydrates and significantly less fatty acid oxidation. Possibly for these reasons, hypoxia also triggers increased consumption of carbohydrates. Hypoxia stimulates the production of erythropo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J19/00C07J41/00C07J43/00A61P35/00A61K31/585
CPCC07J41/0005C07J41/0038C07J19/005C07J19/00C07J43/003A61P9/00A61P27/02A61P27/06A61P29/00A61P35/00A61P35/02A61P43/00A61K31/585C07J41/00C07J41/0011C07J41/0016C07J41/0027C07J41/0033C07J41/0088C07J43/00
Inventor M·霍达杜斯特H·赫斯S·哈森R·C·布吕宁G·E·加迪纳
Owner BRITISH TECH GRP LTD
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