Compounds for proteasome enzyme inhibition

Abstract

Peptide-based compounds including heteroatom-containing, three-membered rings efficiently and selectively inhibit specific activities of N-terminal nucleophile (Ntn) hydrolases. The activities of those Ntn having multiple activities can be differentially inhibited by the compounds described. For example, the chymotrypsin-like activity of the 20S proteasome may be selectively inhibited with the inventive compounds. The peptide-based compounds include at least three peptide units, an epoxide or aziridine, and functionalization at the N-terminus. Among other therapeutic utilities, the peptide-based compounds are expected to display anti-inflammatory properties and inhibition of cell proliferation.

Description

technical field

[0001] The present invention relates to compounds and methods for inhibiting enzymes. In particular, the invention relates to therapeutic methods based on enzyme inhibition. Background of the invention

[0002] In eukaryotes, protein degradation is mainly mediated through the ubiquitin pathway, in which the target protein for degradation is linked to the 76 amino acid polypeptide ubiquitin. Once targeted, ubiquitinated proteins become substrates for the 26S proteasome, a multicatalytic protease that cleaves proteins into short peptides through its three main proteolytic activities. Proteasome-mediated degradation, while having a general function in intracellular protein turnover, is critical in processes as diverse as class I major histocompatibility complex (MHC) presentation, apoptosis, cell differentiation, and NF-κB activation. also play an important role.

[0003] The 20S proteasome is a 700kDa cylindrical multi-catalytic protease complex that contain...

Examples

Embodiment

[0222] Scenario 1: Example 1 Synthesis

[0223]

[0224] (B) Synthesis

[0225]HOBT (10.81 g, 80.0 mmol) and DIEA (200.0 mmol, 25.85 g , 35mL). The mixture was cooled to 0°C in an ice bath, and BOP (80.0 mmol, 35.38 g) was added in portions over 5 minutes. The reaction solution was placed under an argon atmosphere and stirred overnight. The reaction was diluted with brine (1000 mL), and extracted with ethyl acetate (5 x 200 mL). The combined organic layers were washed with water (10 x 100 mL) and brine (2 x 150 mL), dried over magnesium sulfate. Magnesium sulfate was removed by filtration and volatiles were removed under reduced pressure to afford (A) (18.17g). BocNHLeuPheOMe (45.86 mmol, 18.0 g) was added to 50 mL of 80% TFA / DCM solution cooled at 0°C. The solution was stirred and allowed to warm to room temperature over 2 hours. The volatiles were removed under reduced pressure to give an oil. To this oil was added BocNHhPhe (45.86 mmol, 12.81 g), DMF (500 mL), H...

technical field

[0001] The present invention relates to compounds and methods for inhibiting enzymes. In particular, the invention relates to therapeutic methods based on enzyme inhibition. Background of the invention

[0002] In eukaryotes, protein degradation is mainly mediated through the ubiquitin pathway, in which the target protein for degradation is linked to the 76 amino acid polypeptide ubiquitin. Once targeted, ubiquitinated proteins become substrates for the 26S proteasome, a multicatalytic protease that cleaves proteins into short peptides through its three main proteolytic activities. Proteasome-mediated degradation, while having a general function in intracellular protein turnover, is critical in processes as diverse as class I major histocompatibility complex (MHC) presentation, apoptosis, cell differentiation, and NF-κB activation. also play an important role.

[0003] The 20S proteasome is a 700kDa cylindrical multi-catalytic protease complex that contain...

Examples

Embodiment

[0222] Scenario 1: Example 1 Synthesis

[0223]

[0224] (B) Synthesis

[0225]HOBT (10.81 g, 80.0 mmol) and DIEA (200.0 mmol, 25.85 g , 35mL). The mixture was cooled to 0°C in an ice bath, and BOP (80.0 mmol, 35.38 g) was added in portions over 5 minutes. The reaction solution was placed under an argon atmosphere and stirred overnight. The reaction was diluted with brine (1000 mL), and extracted with ethyl acetate (5 x 200 mL). The combined organic layers were washed with water (10 x 100 mL) and brine (2 x 150 mL), dried over magnesium sulfate. Magnesium sulfate was removed by filtration and volatiles were removed under reduced pressure to afford (A) (18.17g). BocNHLeuPheOMe (45.86 mmol, 18.0 g) was added to 50 mL of 80% TFA / DCM solution cooled at 0°C. The solution was stirred and allowed to warm to room temperature over 2 hours. The volatiles were removed under reduced pressure to give an oil. To this oil was added BocNHhPhe (45.86 mmol, 12.81 g), DMF (500 mL), H...

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