34 results about "Proteasome Inhibition" patented technology

The invention provides a tripeptide epoxy ketone compound constructed by heterocycles. Carfilzomib is taken a pilot compound, a Boc protecting group is removed under condensation and acid conditions, reaction is carried out under alkaline condition to obtain amino acid methyl ester isocyanate, and hydrolysis is carried out under the action of a condensation agent, so that the tripeptide epoxy ketone compound is obtained. The tripeptide epoxy ketone compound is a micromolecule short-peptide proteasome inhibitor; the tripeptide epoxy ketone compound has extremely strong proteasome inhibitory activity and cell prolifation inhibitory activity and has a prospect, and a new way is provided for study of a cancer treatment medicine; raw materials for synthesizing the tripeptide epoxy ketone compound are available, route design is reasonable, reaction conditions are mild, yield of each step is high, operation is easy, and the tripeptide epoxy ketone compound is applicable to industrial production; and the tripeptide epoxy ketone compound has a general structural formula shown in a formula I (described in the specification).

Disclosed is a total synthesis of a biologically active β-Lactam—Compound 3, which is related to Salinosporamide A and Omuralide, both structurally and by its activity as a proteasome inhibitor.Also disclosed are proteasome inhibiting compounds having the formula:wherein:R1 is a cyclolower alkyl group; or R1 is a lower alkyl group; and R2 is either hydrogen or a lower alkyl group; R3 is either hydrogen or a lower alkyl group; R4 a halo-lower alkyl group; and R5 is either hydrogen or a lower alkyl group.

Disclosed herein is the use of HLM-008182, as well as its analogues formed via in-house synthesis, as a potent proteasome inhibitors. A new method was developed for HLM-008182 through a four-step protocol and the method was further optimized to a two step protocol. The synthesis in both protocols was regioselective with TiCl4. The reaction was highly efficient with microwave assisted heating and THF as solvent. The modification around the molecule HLM-008182 established primary SAR, indicating that the proteasome inhibition activity was a function of the 2-side chain.

The invention disclosed herein generally relates to methods and compositions for inhibiting proteasome activity comprising a syrbactin compound have the structure of Formula (I) or (II).

The invention provides a novel macrocyclic ketone peptide derivative, an optical isomer or pharmaceutically acceptable salt or solvolyte thereof. Carboxyl protection compounds are used as starting rawmaterials to be subjected to condensation with amino protection amino acid, deamination protection, olefin ring closing double decomposition and decarboxylizing protection, and condensation with epoxy ketone fragment. The macrocyclic ketone peptide compound with a fire-new framework has high protease body inhibition activity; the high in vitro proliferation inhibition effect is achieved on multiple myeloma such as RPMI 8226, MM.1S and NCI-H929 and various other solid tumor cell strains; meanwhile, the compound has good oral administration effects, and can also be applied to preparation of anti-tumor and immune disease medicine. The compound has the advantages that raw materials required for synthesis can be easily obtained; the route design is reasonable; the reaction conditions are mild;the yield in each step is high; the operation is simple and convenient; the compound is suitable for industrial production. The compound has a structure shown by a formula (I) shown in the description.

The invention discloses a bortezomib pharmaceutical composition and applications thereof, wherein the bortezomib pharmaceutical composition comprises, by weight, 0.1-200 parts of bortezomib, 0.1-500 parts of an auxiliary material for adjusting release rate, 0-10 parts of a small molecule adjusting agent, and 0-2000 parts of a pharmaceutically acceptable injectable solvent. According to the presentinvention, the bortezomib pharmaceutical composition has the controlled drug release behavior, and can maintain the effective blood concentration and the proteasome inhibition level in the body; through the long-acting injection of the bortezomib pharmaceutical composition, the in vivo blood concentration and the efficacy providing of bortezomib can be controlled, the treatment effect of the drugcan e improved, the acting time can be prolonged, and the toxic-side effect of the drug can be reduced; the in vivo proteasome inhibition pharmaceutical composition with characteristics of high efficiency, long acting and low toxic-side effect is provided; and the invention further discloses uses of the bortezomib pharmaceutical composition in treatment of refractory / recurrent multiple myeloma.

The invention relates to the field of 26S proteasome inhibition, activation and modulation and to identify compounds which activate 26S proteasome in live cells and a method of treating autoimmune diseases, cancer, inflammation and neurogenerative disorders by inhibition, activation and modulation of the 26S proteasome.

The present invention designs and synthesizes a series of novel non-covalent small molecule short peptide proteasome inhibitors, which are dipeptide compounds constructed from six-membered heterocycles with the structure of general formula (I): Ⅰ The six-membered heterocycle of the present invention The short peptide non-covalent compound constructed by the ring has good proteasome inhibitory activity, and has a strong in vitro proliferation inhibitory effect on multiple myeloma cell lines such as RPMI8226, H929, and MM‑1S. The raw materials required for the synthesis of the compound of the invention are easily available, the route design is reasonable, the reaction conditions are mild, the yield of each step is high, the operation is simple and convenient, and the method is suitable for industrial production.

The invention provides a tripeptide epoxy ketone compound constructed by a heterocyclic ring. Carfilzomib is used as a lead compound. After condensation and removal of the Boc protecting group under acidic conditions, amino acid methyl ester isocyanate is obtained by reaction under alkaline conditions, hydrolyzed, and condensed. Obtained under the effect of mixture. The invention is a small molecular short peptide proteasome inhibitor. The compound of the invention has extremely strong proteasome inhibitory activity and cell proliferation inhibitory activity, is a promising proteasome inhibitor, and provides a new idea for the research of cancer treatment drugs. The raw materials required for the synthesis of the compound of the invention are easily available, the route design is reasonable, the reaction conditions are mild, the yield of each step is high, the operation is simple and convenient, and the method is suitable for industrial production. It has the general structural formula of the following formula I:.

Protein ubiquitylation, an essential post-translational modification, regulates almost every cellular process including protein degradation, protein trafficking, signal transduction, and DNA damage response in eukaryotic cells. The diverse functions of ubiquitylation are thought to be mediated by distinct chain topologies resulting from eight different ubiquitin linkages, chain lengths, and complexities. Currently, ubiquitin linkages are generally thought to be a critical determinant of ubiquitin signaling. However, ubiquitin chain lengths, another key element of ubiquitin signaling, have not been well documented especially in vivo situation during past three decades from the discovery of ubiquitin. The reason of this was simply because no method has been available for determination of ubiquitin chain length in endogenous ubiquitylated substrates. In the present invention, a practical technique for determining the actual length of substrate-attached polyubiquitin chains from biological samples is established. Using the method, the mean length of substrate-attached polyubiquitin chains was determined and the robustness of ubiquitin chain length regulation in cells is investigated. The following is a summary of findings in this invention: 1. A method for determining ubiquitin chain length was developed and this method was named ‘ubiquitin protection from trypsinization’ (Ub-ProT). 2. Using Ub-ProT, it was determined that the mean length of substrate-attached ubiquitin chains is in the dimer to decamer range. 3. By quantitative proteomics, it was found that the mean lengths of five major types of ubiquitin chains can be divided into two groups. 4. Proteasome-inhibition did not alter the mean length of substrate-attached polyubiquitin chains, indicating that cells have a robust system for regulating ubiquitin chain length.

Assays that can measure the effect of proteasome inhibitors on target cells in a biological sample are provided. The assays include evaluation of the effects of proteasome inhibitors on proteasome activity in cells in a biological sample.