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Trichostatin A derivatives, preparation method and use thereof

A technology of trichostatin and its derivatives, which is applied in the field of trichostatin A derivatives and its preparation, and can solve the problems of decreased activity of derivatives, difficulty in synthesis, loss of clinical application, etc.

Inactive Publication Date: 2008-08-13
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although trichostatin A has high in vitro histone deacetylase inhibitory activity (IC 50 several nanomole), but its in vivo metabolic instability caused it to lose the possibility of clinical application. There have been some reports in the literature on the synthesis and biological activity of TSA analogues. Because TSA contains a chiral center adjacent to the carbonyl group , and its synthesis is quite difficult. Most of the TSA derivatives reported so far are structural simplifications of some TSA. Compared with the parent compound TSA, the activity of the simplified derivatives has a greater degree of decline.

Method used

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  • Trichostatin A derivatives, preparation method and use thereof
  • Trichostatin A derivatives, preparation method and use thereof
  • Trichostatin A derivatives, preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Example 1: (R, 2E, 4E)-7-(4-aminophenyl)-N-hydroxyl-4,6-dimethyl-7-oxo-2,4-dieneheptamide (TA- 1) Preparation

[0060] A: Preparation of intermediate (2E, 4E 6R, 7R)-7-(4-aminophenyl)-7-hydroxyl-4,6-dimethyl-2,4-dieneheptanoic acid ethyl ester (its preparation Refer to the patent application: application number 200510030149.5)

[0061] (1) Dissolve 1.51g of p-nitrobenzaldehyde in 35ml of DMF, add 230mg of L-proline, then add 1.44ml of propionaldehyde, and stir at room temperature for 7 hours. Add 100ml of water, extract three times with ethyl acetate, combine the organic layers, dry over magnesium sulfate, filter, and concentrate the filtrate to obtain the crude product, which is directly put into the next step.

[0062] (2) Dissolve the crude product obtained in the previous step in 30ml methylene chloride, add 9.6g wittig reagent Ph 3 P=C(CH 3 )CO 2 Me, heated to reflux for 12 hours, evaporated to dryness, silica gel column chromatography (ethyl acetate / petroleum...

Embodiment 2

[0074] Example 2: (R, 2E, 4E)-7-(4-(diethylamino)phenyl)-N-hydroxyl-4,6-dimethyl-7-oxo-2,4-dienehepta Preparation of Amide (TA-2)

[0075] A: 150 mg of the intermediate (2E, 4E 6R, 7R)-7-(4-aminophenyl)-7-hydroxyl-4,6-dimethyl-2,4- Dissolve ethyl diene heptanoate in 5ml tetrahydrofuran, add 685mg of 40% acetaldehyde aqueous solution (3eq.), stir at room temperature for 10 minutes, add 530mg sodium triacetoxyborohydride, continue stirring at room temperature for 10 hours, add saturated NaHCO 3solution, was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether=1 / 5 (V / V)) to obtain 148 mg of (2E, 4E, 6R, 7R)-(4-(diethylamino)phenyl)- Ethyl 7-hydroxy-4,6-dimethyl-2,4-dieneheptanoate (yield: 83%).

[0076] B: The product obtained in the pre...

Embodiment 3

[0079] Example 3: (R, 2E, 4E)-7-(4-(dipropylamino)phenyl)-N-hydroxy-4,6-dimethyl-7-oxo-2,4-dienehepta Preparation of Amide (TA-3)

[0080] The operation was the same as in Example 2, substituting propionaldehyde for acetaldehyde to obtain the title compound with the following structure.

[0081] 1 H-NMR (CD 3 OD: CDCl 3 =5:1, 300Hz, δppm): d=7.68(2H, d, J=9.3Hz), 7.07(1H, d, J=15.6Hz), 6.49(2H, d, J=9.3Hz), 5.82( 1H, d, J = 10.2Hz), 5.66 (1H, d, J = 15.6Hz), 4.26 (1H, m), 3.22 (4H, t, J = 7.2Hz), 1.77 (3H, s), 1.50 ( 4H, m), 1.17 (3H, d, J=6.6Hz), 0.82 (6H, t, J=7.2Hz)

[0082]

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Abstract

The invention provides a trichostatin A derivative with a structure formula as follow, and a preparing method thereof; the derivative has histone deacetylase inhibitory activity and is useful as antineoplastics.

Description

technical field [0001] The invention relates to a trichostatin A derivative and a preparation method thereof, and also relates to the use of the trichostatin A derivative as an antitumor drug because the trichostatin A derivative has histone deacetylase inhibitory activity. Background technique [0002] The acetylation and deacetylation of core histones are closely related to gene regulation, and responsible for histone acetylation and deacetylation is a pair of functionally antagonistic enzymes, namely histone acetyltransferase (HAT) and histone deacetylase (HDAC). HAT can acetylate the basic amino acid at the end of histones, that is, the amino group of lysine, stretch the nucleosome structure, and activate gene transcription. In contrast to the function of HATs, HDACs repress gene transcription. The dynamic balance of HATs and HDACs controls the structure of chromosomes and the expression of genes. HDAC is a key protease that regulates genes, and its abnormal function ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C239/16C07C239/14A61K31/16A61P35/00
CPCY02P20/55
Inventor 段文虎赵曦张士磊丁健桂敏
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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