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Mitochondria-targeted anti-tumor pentacyclic triterpene derivatives, preparation method and application thereof

A technology of pentacyclic triterpenes and derivatives, which is applied in the field of medicine, can solve problems such as in-depth research, synthesis methods of tumor cell apoptosis, and complexity, and achieve the effects of stable process, strong operability, and simple preparation methods

Active Publication Date: 2017-05-10
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the synthesis method of directly targeting pentacyclic triterpenoids to mitochondria to trigger tumor cell apoptosis is complicated, and no in-depth mechanism research has been done (Russian Chemical Bulletin, International Edition, 2013, 62, 188-198.)

Method used

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  • Mitochondria-targeted anti-tumor pentacyclic triterpene derivatives, preparation method and application thereof
  • Mitochondria-targeted anti-tumor pentacyclic triterpene derivatives, preparation method and application thereof
  • Mitochondria-targeted anti-tumor pentacyclic triterpene derivatives, preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Embodiment 1: Compound Ⅰ-a preparation

[0061] Betulin (1.0g, 2.26mmol) was mixed with EDC (1.09g, 9.04mmol), DMAP (112mg, 0.90mmol), 5-bromovaleric acid (1.68g, 9.04mmol) and placed in a 100ml round bottom flask, and added 40ml of dichloromethane, reacted at room temperature for about 11h, TLC detected that the reaction reached equilibrium, added triple distilled water and washed three times, and the organic phase was dried with anhydrous sodium sulfate for 7h, then filtered to remove sodium sulfate, concentrated under reduced pressure, silica gel column chromatography to obtain compound 1 250mg of white powder, dissolve this white powder in 10ml of acetonitrile, add 325mg (1.24mmol) of TPP, heat up the oil bath to 75-80°C, stir magnetically for 24 hours, and TLC detects that the reaction is basically complete. After the solvent is evaporated to dryness under reduced pressure, the silica gel column Chromatography yielded 30 mg of the product as white crystals I-a. Da...

Embodiment 2

[0064] Embodiment 2: Compound I-b preparation

[0065] The operation was the same as that of compound Ⅰ-a to obtain a white solid. Data forⅠ-b: Mp: 145-154℃[α] D 20 =+23.2°(c0.1, CH 3 OH), 1 H NMR (CD 3 OD 400MHz,)7.94-7.88(m,6H)7.87-7.76(m,24H)4.73(s,1H),4.61(s,2H),4.44(d,J=5.1Hz,1H),4.39(d, J=10.4Hz, 1H), 3.83(d, J=11.0Hz, 1H), 3.55–3.44(m,5H), 2.49–2.38(m,5H), 1.97–1.84(m,5H).1.72 1.071. 03 0.89 0.83 0.81(s,3H)(6-CH3). 13 C NMR (CD 3 OD,100MHz):173.59,173.10,149.98,134.95,133.45,130.20,118.90,118.04,109.26,81.04,63.89,62.20,55.31,50.22,48.54,48.18,47.86,47.60,47.22,47.20,47.10,47.00,46.36 , 42.45, 41.85, 40.71, 38.09, 37.54, 36.84(s), 34.18, 33.91, 33.17, 32.77, 29.90, 29.34, 28.90, 27.19, 26.80, 25.54, 25.08, 23.35, 23.06, 23.79, 20.79, 21.06 20.54, 17.94, 15.71, 15.28, 13.87, 13.10, 10.08; HR-ESI-MS (m / z): [(M-2Br) / 2] + .

[0066] The synthetic route is as follows:

[0067]

Embodiment 3

[0068] Embodiment 3: Compound I-c preparation

[0069] Betulin (5.0g, 11.3mmol) was mixed with EDC (5.45g, 45.2mmol), DMAP (560mg, 4.5mmol), 5-bromovaleric acid (8.4g, 45.2mmol) and placed in a 500ml round bottom flask, and added 200ml of dichloromethane, reacted at room temperature for about 11h, TLC detected that the reaction reached equilibrium, added triple steamed water and washed three times, and the organic phase was dried with anhydrous sodium sulfate for 7h, then filtered to remove sodium sulfate, concentrated under reduced pressure, silica gel column chromatography to obtain compound 1 Take 1.19 g of the above-mentioned compound 1 and dissolve it in 20 mL of formic acid, raise the temperature of the oil bath to 85 ° C and stir for 2 h, and then TLC detects that the reaction is basically complete. After drying with sodium sulfate in water for 7 hours, remove the sodium sulfate by suction filtration, concentrate under reduced pressure, and obtain 700 mg of compound 3 b...

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Abstract

The invention discloses mitochondrion-targeted antitumor pentacyclic triterpene derivatives of which the structural formula are disclosed as Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V), wherein R1 is hydrogen, formacyl, acetyl or a group (n=1-19) disclosed in the specification; R2 is disclosed in the specification (n=1-19); R3 is hydroxy, methoxy or ethoxy; and R4 is disclosed in the specification (n=1-19). The compounds have favorable antitumor activity; and the natural compounds are targeted to the mitochondrion, so that the antitumor pentacyclic triterpene derivatives can be better applied to the development of antitumor drugs. The compounds are salts, thereby greatly enhancing the water solubility of drugs and improving the pharmacokinetic parameters.

Description

technical field [0001] The invention relates to a class of anti-tumor pentacyclic triterpene derivatives targeting mitochondria and its preparation method and application, in particular to TPP derivatives of betulin, betulinic acid, oleanolic acid, ursolic acid and boswellic acid and their preparation The method and application belong to the technical field of medicine. Background technique [0002] As a very important type of organelle in cells, mitochondria not only undertake the work of supplying energy for cells, but also are important organelles for controlling programmed cell death (also known as apoptosis). Studies have shown that the mechanism of action of most antineoplastic drugs is related to the induction of tumor cell apoptosis. Compared with normal cells, mitochondria have some morphological and physiological changes, such as glycolysis becoming the main energy supply mode, mtDNA mutation, ROS increase and mitochondrial membrane potential increase (European Jo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J63/00A61K31/56A61P35/00
CPCC07J63/008
Inventor 范培红叶雅晴娄红祥
Owner SHANDONG UNIV
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