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Tripeptide macrocyclic derivatives, preparation method and application thereof
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A technology of macrocyclic derivatives and drugs, applied in the field of drugs, can solve problems such as cell cycle arrest, apoptosis, and protein level imbalance
Active Publication Date: 2021-05-04
ZHEJIANG UNIV +1
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Thus, inhibition of proteasome function can lead to dysregulation of protein levels associated with multiple signaling pathways, leading to cell cycle arrest and apoptosis
Method used
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preparation Embodiment 1
[0072] Preparation Example 1, 2-(allyloxy) methyl benzoate (1a)
[0073] Methyl salicylate (4.2ml, 33mmol), potassiumcarbonate (13.8g, 99mmol) and 3-bromopropene (4.0ml, 46mmol) were placed in a 100mL three-necked flask, 50mL of acetone was added, and the reaction solution was refluxed The reaction was carried out for 18 hours. After the reaction was monitored by TLC, the reaction solution was cooled to room temperature, the solvent was removed under reduced pressure, 100ml of ethyl acetate was added, washed with water (2×100ml) and saturated brine (2×100ml) successively, dried over anhydroussodiumsulfate and then decompressed The solvent was removed and separated by column chromatography to obtain 5.9 g of a colorless oily liquid with a yield of 93%. 1 H NMR (500MHz, CDCl 3 )δ7.80(dd, J=8.0,2.0Hz,1H),7.44(ddd,J=8.0,7.5,2.0Hz,1H),7.01–6.94(m,2H),6.11–6.02(m,1H) ,5.54–5.48(m,1H),5.32–5.27(m,1H),4.63(dt,J=5.0,1.5Hz,2H),3.90(s,3H)ppm; ESI-MS: m / z=193 [M+H] + .
preparation Embodiment 2
[0074] Preparation Example 2, 2-(3-buten-1-yloxy)methyl benzoate (1b)
[0075] Using 4-bromo-1-butene as raw material, the synthesis and post-treatment were the same as in Preparation Example 1 to obtain 4.0 g of a colorless oily liquid with a yield of 88%. 1 H NMR (500MHz, CDCl 3)δ7.77(dd,J=7.5,1.5Hz,1H),7.47–7.38(m,1H),7.00–6.91(m,2H),6.00–5.88(m,1H),5.22–5.07(m, 2H), 4.08(t, J=6.5Hz, 2H), 3.88(s, 3H), 2.62–2.54(m, 2H)ppm; ESI-MS: m / z=207[M+H] + .
preparation Embodiment 3
[0076] Preparation Example 3, 2-(4-penten-1-yloxy)methyl benzoate (1c)
[0077] Using 5-bromo-1-pentene as raw material, the synthesis and post-treatment were the same as in Preparation Example 1 to obtain 5.8 g of a colorless oily liquid with a yield of 80%. 1 H NMR (500MHz, CDCl 3 )δ7.78(dd, J=7.5,1.5Hz,1H),7.44(ddd,J=8.0,7.5,1.5Hz,1H),6.99–6.94(m,2H),5.92–5.80(m,1H) ,5.09–5.04(m,1H),5.02–4.98(m,1H),4.05(t,J=6.5Hz,2H),3.89(s,3H),2.34–2.25(m,2H),1.98–1.88 (m,2H)ppm; ESI-MS: m / z=221[M+H] + .
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Abstract
The invention provides a tripeptide macrocycle derivative and its optical isomer or a pharmaceutically acceptable salt or solvate thereof. By using the carboxyl-protected compound as the starting material, it is condensed with an acid, followed by olefin ring-closing metathesis and carboxyl removal, and at the same time, the Boc-protected amino acid is condensed with the epoxyketone segment, and then the amino protecting group is removed. Condensation of the carboxyl intermediate gives the desired product. Experiments have proved that the novel skeleton of the present invention has better proteasome inhibitory activity, and has better proliferation inhibitory effect on multiple myeloma such as RPMI 8226 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 operation is simple and convenient, and the method is suitable for industrial production. It has formula (I) structure:
Description
technical field [0001] The present invention relates to the field of medicine, relates to a tripeptide macrocycle derivative and its preparation method and application, and relates to a tripeptide macrocycle derivative as a proteasome inhibitor, a salt containing it, and the compound or its salt as an active ingredient The application of the prepared medicine in anti-tumor. Background technique [0002] With the increasing population and the aging trend of the population, coupled with the widespread existence of various unhealthy lifestyles including smoking and environmental pollution, malignant tumors are seriously threatening human life, and malignant tumors have become the first in my country. A fatal disease, its prevention and treatment has become an important research topic in the medical circles of our country and even the world. Traditional cancer treatment methods mainly include surgery, radiation therapy and drugchemotherapy, among which drugchemotherapy is the ...
Claims
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