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MTOR protein degradation targeting chimera as well as preparation method and application thereof

A technology of protein degradation and chimera, applied in the field of medicine

Inactive Publication Date: 2022-05-17
SHANDONG UNIV OF TRADITIONAL CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this technology has rarely been reported on targeting mTOR degradation

Method used

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  • MTOR protein degradation targeting chimera as well as preparation method and application thereof
  • MTOR protein degradation targeting chimera as well as preparation method and application thereof
  • MTOR protein degradation targeting chimera as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Preparation of tert-butyl 4-amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidine-1-carboxylate (2)

[0042]

[0043] Compound 1 (5g, 23.3mmol), DMAP (0.28g, 0.01mmol) was dissolved in anhydrous DCM (100mL), and Boc2O (5.58g, 25.63mmol) was added at room temperature at one time, and stirring was continued for 12 hours, followed by TLC detection (EA; PE=1:1, Rf=0.5) Compound 1 disappeared completely, the reaction solution was spin-dried in vacuum, and the residue was washed with 60 mL of a mixture of methyl tert-butyl ether and ethyl acetate (MTBE / EA=5:1) , to obtain white solid compound 2 (4.1 g, 13.06 mmol yield: 56.1%).

Embodiment 2

[0045] Preparation of 5-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine (4)

[0046]

[0047] Compound 2 (1g, 3.18mmol), 2-aminobenzoxazole-5-boronate (1.25g, 4.78mmol), sodium carbonate (0.67g, 6.36mmol), Pd (pph 3 ) 4 (0.3g, 0.26mmol) was dissolved in the mixed solution of dioxane and water (50ml, 10:1), and the N 2 Three times, heated to 90°C, N 2 Reaction under protective conditions for 12 hours, TLC tracking detection (EA, Rf = 0.3) compound 2 disappeared completely, cooled to room temperature, added 20mL water, EA extracted 3 times, 10ml each time, the organic phase was washed once with saturated saline, anhydrous sodium sulfate Dry, filter, and spin dry to obtain the crude product. The crude product was washed with EA (10 mL) to give gray compound 4 (0.48 g, 1.80 mmol, yield: 56.6%). 1 H NMR(400MHz,DMSO)δ8.18(s,1H),7.57(s,2H),7.46(d,J=8.1Hz,1H),7.41(s,1H),7.23(d,J=8.1Hz ,1H).

Embodiment 3

[0049] 5-(4-amino-1-(prop-2-yn-1-yl)-1H-pyrazol[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine ( 5) Preparation

[0050] Compound 4 (0.45g, 1.68mmol), sodium carbonate (0.35g, 3.37mmol) was dissolved in anhydrous DMF (10mL), and compound 3-bromoprop-1-yne (0.80g, 6.74mmol) was added in one go, Reacted at room temperature for 12 hours, LCMS detected that compound 4 was completely reacted, added 20ml of water, extracted 3 times with EA, backwashed the organic phase once with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain crude compound 5 (0.1g, purity about 73 %). 1 H NMR (400MHz, DMSO) δ8.28(s,1H),7.57(s,2H),7.48(d,J=8.0Hz,1H),7.41(s,1H),7.25(d,J=8.1Hz ,1H),5.19(s,2H),3.39(s,1H).

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to an mTOR protein degradation targeting chimera as well as a preparation method and application thereof. The mTOR protein degradation targeting chimera compound disclosed by the invention shows a strong mTOR inhibition capability and inhibits the proliferation of MCF-7. The compound P1 can reduce the expression of mTOR downstream protein p-S6 (Ser240 / 244) and p-AKT (Ser473), and further research shows that the compound inhibits the growth of cancer cells by inducing autophagy, and has no influence on cell apoptosis or cell cycle.

Description

technical field [0001] The application belongs to the technical field of medicine, and in particular relates to an mTOR protein degradation targeting chimera and its preparation method and application. Background technique [0002] Mechanistic target of rapamycin (mTOR) is a serine / threonine kinase that belongs to the phosphoinositide 3-kinase-related kinase (PIKK) family. The mTOR complexes mTORC1 and mTORC2 serve as nutrient, energy and redox sensors, both of which participate in the regulation of the PI3K / AKT / mTOR pathway. The activation of mTORC1 downstream of PI3K / AKT promotes the production of proteins, lipids and nucleotides, which is beneficial to cell survival, growth and proliferation; mTORC2 promotes cell proliferation and survival by regulating protein kinases, including AKT. Studies have found that mTOR is abnormally active in various types of cancer, increasing cell proliferation and metabolism, thereby promoting tumor initiation and development. [0003] The...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61P35/00
CPCC07D487/04A61P35/00
Inventor 毛蓓蓓赵盼颜培正赵东升
Owner SHANDONG UNIV OF TRADITIONAL CHINESE MEDICINE
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