Ubiquitin E1 inhibitor and preparation method thereof
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A technology of inhibitors and ubiquitin, applied in the field of compounds of ubiquitin E1 inhibitors
Inactive Publication Date: 2011-02-02
西安杰诺瓦生物科技有限公司
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Moreover, according to the Lipinski regulation, the substance contains groups that are not ideal as drugs
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Embodiment 1
[0086] Example 1: Preparation of ubiquitin E1 inhibitor compounds and derivatives thereof
[0087] figure 2 Show the preparation method and technological process of present embodiment:
[0088] (a) prepare alkali-free hydrazine group, take phenylhydrazine as example (see scheme II):
[0089] Anhydrous sodium carbonate (0.015M) was added to 50ml of an aqueous solution containing 0.01M phenylhydrazine hydrochloride, and extracted three times with dichloromethane, 30ml each time, to obtain a solution. It was dried over anhydrous sodium carbonate and concentrated to release phenylhydrazine, which was used in subsequent synthesis without purification.
[0090] (b) Preparation of compound (iii), methyl-3-oxo-3-(N'-phenylhydrazino) propionic acid
[0091] Dissolve phenylhydrazine (5.94 g, 55 mM) in 100 ml dry THF and Et 3 H (8.11 ml, 58.3 mM). The mixed reaction was cooled to -10°C, and 50 ml of anhydrous THF containing methyl-3-chloro-3-oxo-propionic acid (7.12 ml, 56.6 mM) wa...
Embodiment 2
[0096] Example 2: Detection of ubiquitin E1 inhibitory effect of ubiquitin E1 inhibitor compounds and derivatives thereof
[0097]Experimental method: use DMEM / F-12 medium (Hyclone, logan, UT) (wherein containing 10% FCS, 0.3% sodium bicarbonate, 100U / ml penicillin, 100 μ g / ml streptomycin) to cultivate RPE cells for detection Ubiquitin E1 inhibitors penetrate into cells and bind intracellularly to the level of E1 ubiquitin complexes. The cells were seeded in a 12-well tissue culture plate and cultured overnight, and the cell confluency reached 85%. Incubate with DMSO, PYR-41 (50 μM) and compound (50 μM) for 30 minutes. Wash gently twice with PBS, add lysis buffer to scrape off the cells (lysis buffer: 5mM Tris-HCl, pH6.8, 8.7M urea, 1% NP-40, 20mM N-hexylmaleimide , 3mM EDTA, 10mM iodoacetamide and mixed protease inhibitors), simple sonication, 12000 rpm, centrifugation at 4°C for 20 minutes, and the supernatant was collected. Divide the sample into 2 equal parts, add to 4...
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Abstract
The invention relates to an ubiquitin E1 inhibitor and a preparation method thereof. Series compound Y-1-benzene pyrazole silane-3,5-diketone and relevant derivative (such as 4-(4-ethyoxyl-3-methoxybenzylidene)-1-benzene pyrazole silane-3,5-diketone, and the like) with different alternative groups are prepared by a liquid-phase organic synthesis method according to the structure of PRY-41(4(4-(5-nitro-furan group-methylene]-3,5-dioxo-pyrazolidine-1-radical)-ethyl benzoate). The ubiquitin E1 inhibitor can be used for inhibiting protein degradation mediated by ubiquitination and nondegradation of ubiquitination, and can kill transformed cells containing p53 in the process of blocking up the NFkB activity by the inhibitor, that is to say, the inhibitor possibly has the potential property of treating tumor and can be used as an important tool for researching ubiquitin proteinase system mechanism.
Description
technical field [0001] The invention relates to a ubiquitin E1 inhibitor compound, its derivatives and a preparation method. Background technique [0002] The ubiquitin-proteasome system (UPS), mainly includes binding enzymes (E1, E2 and E3) and a degradation complex (proteasome). E1 forms a high-energy thioester bond with the C-terminus of ubiquitin through its active cysteine, thereby activating ubiquitin. In turn, this bond is transferred to the cysteine active site of E2. E3 interacts with E2, recognizes the ubiquitin that is catalyzed by the target protein, and converts the lysine residue on the target protein into an ε amino group through an isopeptide bond. The activated ubiquitin can also combine with the ubiquitin already bound to the target protein, and finally form a polyubiquitin chain. These ubiquitins can be linked via one of their seven lysines (notably K48 and K63). It has been demonstrated that ubiquitination by K48-linked polyubiquitin chains usually ...
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