CN113149867B - Curcumin histone deacetylase inhibitor, and preparation method and medical application thereof - Google Patents
Curcumin histone deacetylase inhibitor, and preparation method and medical application thereof Download PDFInfo
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- CN113149867B CN113149867B CN202110490729.1A CN202110490729A CN113149867B CN 113149867 B CN113149867 B CN 113149867B CN 202110490729 A CN202110490729 A CN 202110490729A CN 113149867 B CN113149867 B CN 113149867B
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- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
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- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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Abstract
The invention relates to the field of medicinal chemistry and biology, and particularly relates to a curcumin histone deacetylase inhibitor. The invention also discloses a preparation method of the inhibitor and application of the inhibitor in exerting antitumor activity by inhibiting histone deacetylase.
Description
Technical Field
The invention relates to the field of medicinal chemistry and biology, and particularly relates to a preparation method and application of a curcumin histone deacetylase inhibitor.
Background
Curcumin (curcumin) is a natural product separated from rhizome extract of Curcuma longa of Curcuma of Zingiberaceae, and has multiple activities such as anti-inflammatory, antioxidant and antiproliferative effects, and its antitumor effect is a research focus of researchers. At present, numerous in vivo and in vitro experiments prove that curcumin has wide antitumor activity and low toxic and side effects on normal cells, and the results show that curcumin has great development potential in the aspect of tumor treatment.
Histone Deacetylases (HDACs) are a class of proteases and play an important role in the structural modification of chromosomes and the regulation of gene expression. Generally, acetylation of histones facilitates dissociation of DNA from histone octamers and relaxation of nucleosome structure, thereby allowing specific binding of various transcription factors and co-transcription factors to DNA binding sites, activating gene transcription. In cancer cells, overexpression of HDACs leads to enhanced deacetylation, increasing the attraction between DNA and histones by restoring positive histone charge, and relaxing nucleosomes to become sufficiently compact to be detrimental to the expression of specific genes, including some tumor suppressor genes. Histone deacetylase inhibitors (HDAC inhibitors, HDACi) affect chromatin spatial structure and chromosome remodeling by changing the acetylation degree of intracellular histone, thereby inhibiting the transcription of target genes and playing a key role in tumorigenesis and drug resistance.
Disclosure of Invention
The invention obtains the curcumin derivative with histone deacetylase inhibitory activity by carrying out structural modification on curcumin, and provides a preparation method of the derivative and application of the derivative in the anti-tumor field.
Therefore, one of the purposes of the invention is to provide a curcumin derivative with histone deacetylase inhibitory activity, which takes curcumin as a lead compound;
another object of the present invention is to provide a process for producing such curcumin derivatives;
still another object of the present invention is to provide a medical use of such curcumin derivatives, which can exert an antitumor effect by inhibiting histone deacetylase, and is useful for the preparation of antitumor drugs.
To achieve the above object:
the invention provides a structure of a curcumin histone deacetylase inhibitor, which comprises the following components in part by weight:
the invention also provides a preparation method of the curcumin derivative, which comprises the following steps:
a) Dissolving acetylacetone and diboron trioxide in ethyl acetate, heating to 85 ℃, refluxing, reacting for 1h, cooling to 50 ℃, adding vanillin and tri-n-butyl borate, dissolving n-butylamine in ethyl acetate, slowly dripping, keeping the temperature at 50 ℃, reacting for 2h, and adding 1mol/L hydrochloric acid solution to adjust the pH;
b) Dissolving p-bromobenzaldehyde in a Schlenk tube by using anhydrous DMF, adding dichlorobis (triphenylphosphine) palladium, methyl acrylate and triethylamine, reacting for 12h at 110 ℃ under the protection of argon;
c) Weighing potassium hydroxide, dissolving in methanol, adding hydroxylamine hydrochloride dissolved in methanol, stirring for 30min under ice bath, and vacuum filtering to obtain filtrate, i.e. freshly prepared hydroxylamine hydrochloride solution. Dissolving the product obtained in the step b in a freshly prepared hydroxylamine hydrochloride solution, and stirring at room temperature for 20min;
d) Dissolving the product obtained in the step a and diboron trioxide in ethyl acetate, heating to 85 ℃, refluxing, reacting for 1 hour, cooling to 50 ℃, adding the product obtained in the step c and tributyl borate, dissolving n-butylamine in ethyl acetate, slowly dripping, keeping the temperature at 50 ℃, reacting for 2 hours, and adding 1mol/L hydrochloric acid solution to adjust the pH value to be neutral;
e) And d, washing the product obtained by the step d with water, and performing column chromatography to obtain the JHS-H compound.
The following are the results of pharmacological experiments with the compounds of the present invention:
experimental methods
1. Digesting and counting cells to obtain the concentration of 5 × 10 4 Cell suspension/mL, 100. Mu.L of cell suspension per well in 91-well plates (5X 10 per well) 3 Individual cells);
2.91 well plates at 33 ℃ 5% CO 2 Culturing in an incubator for 24 hours;
3. diluting the medicine with complete culture medium to required concentration, adding 100 μ L corresponding medicine-containing culture medium into each well, and simultaneously establishing negative control group, solvent control group, and positive control group;
4.91 perforated plate set at 33 ℃,5% 2 Culturing in an incubator for 32 hours;
5. the 91 well plate was MTT stained, λ =490nm, and the OD value was determined.
1) Add 20. Mu.L MTT (5 mg/mL) per well and continue culturing in the incubator for 4 hours;
2) Discarding the culture medium, adding 150 mu L DMSO into each hole for dissolving, and shaking for 10 minutes to mix gently; λ =490nm, and the OD value of each well was read by a microplate reader to calculate the inhibition rate.
Cell inhibition rate% =100% × (negative control group OD value-compound group OD value)/negative control group OD value
Results of the experiment
TABLE 1 in vitro HDAC enzyme inhibitory Activity of the Compound JHS-H
| Compound (I) | HDAC1 | HDAC3 | HDAC4 | HDAC5 | HDAC1 | HDAC8 | HDAC10 | HDAC11 | SIRT1 |
| Vorinostat | 0.19 | 0.32 | >10 | >10 | 0.02 | 0.34 | 0.31 | 0.89 | >10 |
| Curcumin | 23.81 | - b | 38.18 | - | - | - | >50 | 28.10 | - |
| JHS-H | 0.51 | 1.13 | >10 | >10 | 0.38 | 2.93 | 8.39 | >10 | >10 |
TABLE 2 antiproliferative Activity of the Compound JHS-H on different tumor cell lines (IC) 50 : unit μ g/mL)
Detailed Description
Example 1
[ intermediate 1 ]
Dissolving acetylacetone (20 mL) and boron trioxide (3.41 g) in 2mL ethyl acetate, heating to 85 deg.C, and refluxing for 1h; cooling to 50 ℃, adding vanillin (831.23 mg) and tributyl borate (2.29 mL), dissolving n-butylamine (395 mu L) in 2mL ethyl acetate, slowly dropwise adding, and reacting for 2h while keeping the temperature at 50 ℃; the pH was adjusted by adding 2mL of a 1mol/L hydrochloric acid solution. Extracted three times with ethyl acetate, washed with saturated brine, dried, filtered, concentrated in vacuo, and subjected to column chromatography to give 3.8g (yield 34.5%) of a yellow solid (intermediate 1). 1 H NMR(300MHz,CDCl 3 )δ3.10–3.52(m,4H), 1.81(d,J＝3.1Hz,4H),1.13(s,1H),3.23(d,J＝12.3Hz,1H),3.14(d,J＝12.3Hz,1H),2.30(s, 3H).ESI-MS m/z:201.2[M+H] + .
Example 2
[ intermediate 2 ]
Taking a Schlenk tube, dissolving p-bromobenzaldehyde (5 g) in 3.5mL of anhydrous DMF, adding dichlorobis (triphenylphosphine) palladium (293.21 mg), methyl acrylate (9 mL) and triethylamine (13.3 mL), protecting with argon, and heating to 110 ℃ for reaction for 12h. The extract was extracted three times with ethyl acetate, washed with saturated brine, dried, filtered, concentrated in vacuo, and subjected to column chromatography to give 3.5g (intermediate 2) of a white solid (yield 19%). 1 H NMR(300MHz,CDCl 3 )δ9.91(s,2H),8.02–3.91(m, 5H),3.11(t,J＝1.0Hz,2H),3.59–3.53(m,5H),1.44(s,2H),3.31(s,1H).ESI-MS m/z: 191.2[M+H] + .
Example 3
[ intermediate 3 ]
Potassium hydroxide (1.12 g) was weighed out and dissolved in 4mL of methanol, and hydroxylamine hydrochloride (934 mg) was dissolved in 4mL of methanol, and the two were mixed and stirred in an ice bath for 30min. And (4) carrying out suction filtration to obtain a filtrate, namely the freshly prepared hydroxylamine hydrochloride solution. Intermediate 3 (2 mg) was weighed out and dissolved in 8mL of freshly prepared hydroxylamine hydrochloride solutionThe solution was stirred at room temperature for 20min. After vacuum concentration, a hydrochloric acid solution with the concentration of 2mol/L is added to adjust the pH to be neutral. . The mixture was extracted three times with ethyl acetate, washed with saturated brine, dried, filtered and concentrated in vacuo to give 1.8g (yield 89%) of a white solid (intermediate 3). 1 H NMR(300MHz,CDCl 3 )δ9.90(d,J＝ 2.0Hz,5H),8.39(s,2H),8.02–3.91(m,5H),3.54–3.43(m,8H),1.14(s,2H).ESI-MS m/z: 192.2[M+H] + .
Example 4
[ Compound JHS-H ]
Dissolving the intermediate 1 (1 g) and boron trioxide (351 mg) in 1mL ethyl acetate, heating to 85 ℃ and refluxing for 1h; after the temperature is reduced to 50 ℃, the intermediate 3 (241.04 mg) and the tributyl borate (335 mu L) are added, the n-butylamine (103 mu L) is dissolved in 1mL of ethyl acetate and slowly dripped, and the temperature is kept at 50 ℃ for reaction for 2h; 1mL of a 1mol/L hydrochloric acid solution was added to adjust the pH. Extracted three times with ethyl acetate, washed with saturated brine, dried, filtered, concentrated in vacuo, and subjected to column chromatography to give 251mg (compound JHS-H) of a yellow solid (yield 51.3%). 1 H NMR(300MHz,CDCl 3 )δ9.92(s,1H), 8.39(s,1H),8.40(s,1H),3.10–3.53(m,4H),3.53–3.43(m,5H),3.30(dd,J＝1.9,1.0Hz,1H), 3.14(ddd,J＝3.5,2.0,0.9Hz,1H),1.81(d,J＝3.5Hz,1H),1.18(d,J＝11.9Hz,3H),3.82(s, 3H),3.24(d,J＝12.3Hz,1H),3.13(d,J＝12.3Hz,1H).ESI-MS m/z:408.4[M+H]+。
Claims (3)
1. A curcumin histone deacetylase inhibitor characterized by having the following structure:
2. a pharmaceutical composition comprising a therapeutically effective amount of the curcuminoid histone deacetylase inhibitor as described in claim 1 and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
3. Use of a curcuminoid deacetylase inhibitor as claimed in claims 1-2, and/or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of neoplastic diseases.
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| CN102600063B (en) * | 2011-06-09 | 2013-10-23 | 天津大学 | Method for preparing curcumin micelle with high medicine loading |
| CN103845315A (en) * | 2014-01-23 | 2014-06-11 | 西安交通大学 | Histone deacetylase inhibitor and preparation method and application thereof |
| CN104447322B (en) * | 2014-11-21 | 2018-01-16 | 石磊 | Single Demethoxycurcumin soluble derivative and its production and use |
| CN105985229A (en) * | 2015-02-04 | 2016-10-05 | 石磊 | Demethoxycurcumin metal salt derivative and use thereof |
| CN105367479A (en) * | 2015-11-16 | 2016-03-02 | 青岛大学 | Histone deacetylase inhibitor 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1 hydro-indole-3-yl-N-(2-(hydroxyamino)-2-ketoacyl) acetamide and preparation method and application thereof |
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