CN108658915B - Hydroxamic acid compounds containing coumarin structure, application and preparation method thereof - Google Patents

Hydroxamic acid compounds containing coumarin structure, application and preparation method thereof Download PDF

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CN108658915B
CN108658915B CN201810364677.1A CN201810364677A CN108658915B CN 108658915 B CN108658915 B CN 108658915B CN 201810364677 A CN201810364677 A CN 201810364677A CN 108658915 B CN108658915 B CN 108658915B
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张华�
杨飞飞
单佩佩
赵娜
江成世
宋佳丽
葛迪
韩丽娜
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Abstract

The invention provides hydroxamic acid HDACI containing coumarin structure with novel structure, which comprises pharmaceutically acceptable salt, metabolite, isomer, prodrug and the like; also discloses a preparation method of the compound; based on coumarin key structure modules, hydroxamic acid structure skeletons are introduced on the basis, a novel hydroxamic acid micromolecule organic compound containing a coumarin structure is designed and synthesized, the compound combines the advantages of coumarin and hydroxamic acid, and the obtained compound can be applied to medicines for preventing and treating cancers or inflammations as a histone deacetylase inhibitor; can also be used in the drugs for inducing the acquired drug resistance to cause the anti-tumor therapy after chemotherapy failure.

Description

Hydroxamic acid compounds containing coumarin structure, application and preparation method thereof
Technical Field
The invention relates to the field of histone deacetylase inhibitors, in particular to a synthetic method and application of hydroxamic acid micromolecule organic compounds containing coumarin structures.
Background
Epigenetic regulatory imbalance plays an important role in the development of tumors, epigenetic refers to genetic changes of gene expression without changes in DNA sequence, mainly including DNA methylation and histone modification, in which studies are in depth that Histone Deacetylase (HDAC) highly expressed in tumors, HDAC and Histone Acetyltransferase (HAT) synergistically regulate acetylation level of histone lysine residue. Acetyl group is transferred to histone under the action of HAT, so that chromosome structure is loose, transcription factor is easy to be combined on DNA, and transcription and translation are finally promoted, while HDAC removes acetyl group on histone, and transcription and translation are inhibited. In normal tissues, HAT and HDAC act synergistically to regulate the progression of normal physiological functions, while in tumor tissues, HDAC high expression leads to transcriptional inhibition of certain tumor suppressor genes leading to the development of tumors. HDACs have been extensively studied as therapeutic targets in tumors, and five histone deacetylase inhibitors (HDACi) are now approved for the market for the treatment of various cancers, and over twenty compounds are under different clinical research stages. The inhibitor has good market application prospect. However, the HDACi currently on the market is used for the treatment of cancers in the blood system, and the treatment effect on solid tumors is not ideal, so that the development of a novel HDACi for treating solid tumors is a more popular direction.
Structurally HDACi generally comprises three parts: CAP region: binding to an enzyme surface group; linker region: extending in an elongate channel of the enzyme; a ZBG zone: combined with an enzyme catalytic center to play a role in inhibiting the activity of the enzyme. The series of engineered derivatives for the CAP region may not only increase the activity of the compound but also increase the selectivity.
Coumarin compounds are important organic heterocyclic medicinal active natural products, are widely distributed in the plant world, and also exist in metabolites of microorganisms and animals. Coumarin has wide pharmacological activity, such as antiinflammatory, antioxidant, anti-AIDS and anti-tumor etc. Meanwhile, the coumarin has the advantages of small molecular weight, high bioavailability and simple synthesis, and in the anti-tumor field in recent years, the coumarin compound shows an attractive application prospect.
Disclosure of Invention
Aiming at the problems of the histone deacetylase inhibitor in the current stage in treating solid tumors, the combined coumarin compound and hydroxamic acid compound have effective anti-tumor effect, and the coumarin structure is combined with a CAP region and a hydroxamic acid structure to synthesize novel HDACI.
A hydroxamic acid micromolecule organic compound containing a coumarin structure comprises a compound I and derivatives thereof, wherein the compound I has the following structure:
Figure 17662DEST_PATH_IMAGE001
wherein: r = H or OCH3(ii) a n = 2-6; x = NH or O.
Preferably, the derivatives of the compounds comprise acid addition salts formed by the compound I and acid; wherein the acid is hydrobromic acid, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, salicylic acid, tartaric acid, methanesulfonic acid, citric acid, lactic acid, p-toluenesulfonic acid, succinic acid, maleic acid, pyruvic acid.
Preferably, the derivatives of the compounds, including hydrates or pharmaceutically acceptable salts thereof:
N-hydroxy-3- ((chromen-2-one-4-) amino) propanamide;
N-hydroxy-6- ((chromen-2-one-4-) amino) hexanamide;
N-hydroxy-6- ((chromen-2-one-7-methoxy-4-) amino) hexanamide;
N-hydroxy-7- ((chromen-2-one-7-methoxy-4-) amino) heptanamide;
N-hydroxy-8- ((chromen-2-one-7-methoxy-4-) amino) octanoamide;
N-hydroxy-5- ((chromen-2-one-7-methoxy-4-) oxy) pentanamide;
N-hydroxy-6- ((chromen-2-one-7-methoxy-4-) oxy) hexanamide;
N-hydroxy-7- ((chromen-2-one-7-methoxy-4-) oxy) heptanamide;
N-hydroxy-8- ((chromen-2-one-7-methoxy-4-) oxy) octanamide;
N-hydroxy-9- ((chromen-2-one-7-methoxy-4-) oxy) anthranilamide;
N-hydroxy-8- ((chromen-2-one-4-) oxy) octanamide.
The application of the compound I and the derivatives thereof as histone deacetylase inhibitors in medicaments for preventing and treating diseases caused by imbalance of histone acetylation regulation, wherein the diseases comprise cancers or inflammations; can also be used in the drugs for inducing the acquired drug resistance to cause the anti-tumor therapy after chemotherapy failure.
A method for preparing hydroxamic acid small-molecule organic compounds containing coumarin structures, wherein R = H and X = NH, comprises the following steps:
Figure 328557DEST_PATH_IMAGE002
compound 1 and diethyl carbonate are buckled to generate compound 2, compound 2 is chloridized in solvent A to obtain compound 3, compound 3 reacts with amino acid ester with different chain lengths to generate compound 4, the compound 4 reacts with hydroxylamine hydrochloride in solvent B to generate target compound 5, ice water is generally used for quenching after the reaction is finished, extraction is carried out, water and saturated saline water are sequentially used for washing, drying, the solvent is removed by low temperature and reduced pressure, and the final product is obtained by column chromatography.
Coumarin knot-containing agentPreparation method of structured hydroxamic acid small-molecule organic compound, R = OCH3X = O, comprising the steps of:
Figure 254925DEST_PATH_IMAGE003
the compound 6 and diethyl carbonate are subjected to ring closure to generate a compound 7, the compound 7 reacts in a solvent A to obtain a compound 8, the compound 8 reacts with hydroxylamine hydrochloride in a solvent B to generate a target compound 9, the target compound is generally quenched by ice water after the reaction is finished, extracted, washed by water and saturated saline solution in sequence, dried, subjected to low-temperature reduced pressure to remove the solvent, and subjected to column chromatography to obtain a final product.
Preferably, in the above preparation method, the solvent a is dimethylformamide, dioxane, toluene, benzene or tetrahydrofuran; the solvent B is dichloromethane, methanol, ethanol, dimethyl sulfoxide or toluene; the extraction liquid is ethyl acetate, dichloromethane or diethyl ether.
The application of the compound is a pharmaceutical composition for inhibiting proliferation, growth, infiltration and migration of tumor cells, and the pharmaceutical composition contains the small molecular organic compound, the hydrate or the pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
The pharmaceutical composition in the above application may be formulated as a cream, an aerosol, an injectable fluid, a gel, a pill, a syrup, a capsule, a transdermal patch or an excipient.
The compounds are labeled, including but not limited to, with radioactivity, fluorophores, or Biotin (Biotin).
Drawings
FIG. 1 is a graph showing the results of the inhibition of proliferation of various cancer cells by the compounds of the present invention;
FIG. 2 is a graph showing the results of the compounds of the present invention increasing the acetylation level of histone H3 in lung cancer cells.
The invention has the advantages of
1. The invention provides hydroxamic acid HDACI containing coumarin structures, which comprises pharmaceutically acceptable salts, metabolites, isomers, prodrugs and the like, and has good inhibition activity on HDAC1, wherein the inhibition activity of compounds JD03, JD08 and JD09 is superior to that of SAHA, and particularly the inhibition activity of JD09 is improved by about 30 times compared with that of SAHA.
2. The inhibition activity of the compound JD05 on the cervical cancer Hela cells is equivalent to that of SAHA, and the inhibition activity of the compounds JD05 and JD09 on the lung cancer A549 cells is obviously superior to that of SAHA.
3. The compounds JD05 and JD09 were used to significantly increase acetylation of histone H3 at concentrations of 0.2. mu.M, 0.5. mu.M and 1. mu.M, and were dose-dependent, with a more significant improvement effect than the positive control SAHA.
4. The invention is based on coumarin key structure module, introduces hydroxamic acid structure skeleton on the basis, designs and synthesizes a novel hydroxamic acid micromolecule organic compound containing coumarin structure, the compound combines the advantages of coumarin and hydroxamic acid, and the obtained compound can be used as histone deacetylase inhibitor to be applied to drugs for preventing and treating cancer or inflammation; can also be used in the drugs for inducing the acquired drug resistance to cause the anti-tumor therapy after chemotherapy failure.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples and drawings, and the present invention is not limited to the following examples. Variations that may occur to those skilled in the art are intended to be included within the invention without departing from the spirit and scope of the inventive concept and are intended to be protected by the following claims.
1H-NMR was measured with a Bruker AVANCE III HD 600 Mm NMR spectrometer; MS is measured by an Agilent 6440 Triple Quad LC/MS type instrument and is in an ESI mode except for the indication, all solvents are redistilled before use, and the used anhydrous solvents are obtained by drying according to a standard method; all reactions were carried out under argon protection and followed by TLC except for the indication, and the post-treatment was carried out by washing with saturated saline and drying with anhydrous magnesium sulfate; purification of the product Using silicon, except for the indicationColumn chromatography of gum (200-30 mesh); the silica gel used, including 200-300 mesh and GF254, was produced by Qingdao Seawa silica gel desiccant, Inc.
EXAMPLE 1 preparation of pharmaceutically acceptable salts of Compound I
Figure 600456DEST_PATH_IMAGE004
Example 1-1, CompoundNPreparation of (E) -hydroxy-3- ((benzopyran-2-one-4-) amino) propionamide (JD 01)
Taking 2-hydroxyacetophenone (1.3 g, 10 mmol) and toluene (30 ml), cooling the reaction system with ice water bath, adding sodium hydride (2.0 g, 50 mmol) in 0oDiethyl carbonate (1.8 ml, 15 mmol) was added under C. Reacting at normal temperature, removing most of solvent under reduced pressure, and passing through a silica gel column after conventional treatment to obtain the intermediate 4-hydroxycoumarin.
4-Hydroxycoumarin (800 mg, 5 mmol) was dissolved in acetonitrile (30 ml) and TEABAC (4.7 g, 20 mmol), 40, was addedoC stirring for 30 min, then adding phosphorus oxychloride (3.2 g, 20 mmol), 80 oCStirring for 5 hours, and separating to obtain an intermediate 4-chlorocoumarin.
4-chlorocoumarin (300 mg, 2.05 mmol) was dissolved in ethanol (10 ml), triethylamine (1.1 ml, 8.2 mmol) and methyl glycinate (423 mg, 4.1 mmol) were added, and the reaction was heated to reflux. After 5 hours, the excess solvent was removed under reduced pressure and passed through a silica gel column after conventional treatment to obtain an ester intermediate.
At 40oC in methanol (10 ml) of hydroxylamine hydrochloride (3.82 g, 55 mmol) KOH (3.08 g, 55 mmol) was added and held for 10 min, then the reaction was cooled to 0oC was filtered and the ester was added to the filtrate followed by KOH (308 mg, 5.5 mmol) and the reaction was left at room temperature for 30 min. Extraction with EtOAc and conventional work-up followed by silica gel column gave the product JD01 (100 mg, 40.3%).1H NMR (600 MHz, DMSO) δ 10.50 (brs, 1H), 8.81 (brs, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.76-7.75 (m, 1H), 7.59 (dd, J = 6.6, 6.0 Hz, 1H), 7.33-7.30 (m, 2H), 5.19 (s, 1H), 3.49-3.47 (m, 2H), 2.36 (t, J = 6.6 Hz, 2H). HRMS (ESI): calcd for [C12H12N2O4 + H]+ 249.0797, found 249.0882。
Example 1-2, CompoundsNPreparation of (E) -hydroxy-6- ((benzopyran-2-one-4-) amino) hexanamide (JD 02)
Preparation of JD02 was carried out by changing methyl aminopropionate to methyl aminocaproate, according to the procedure for preparation of JD 01.
1H NMR (600 MHz, DMSO) δ 10.37 (brs, 1H), 8.69 (brs, 1H), 8.08 (d, J= 7.8 Hz, 1H), 7.64 (t, J = 5.4 Hz, 1H), 7.61 – 7.56 (m, 1H), 7.35 – 7.27 (m, 2H), 5.14 (s, 1H), 1.97 (t, J = 7.8 Hz, 2H), 1.68 – 1.59 (m, 2H), 1.55 (t, J= 7.2 Hz, 2H), 1.39 – 1.29 (m, 2H), 1.21 (t, J = 7.8 Hz, 2H)。HRMS (ESI): calcd for [C15H18N2O4 + H]+ 291.1267, found 291.1344。
Examples 1 to 3, CompoundsNPreparation of-hydroxy-6- ((benzopyran-2-one-7-methoxy-4-) amino) hexanamide (JD 03). The preparation of JD03 was carried out by replacing o-hydroxyacetophenone with paeonol and methyl aminopropionate with methyl aminopentanoate, according to the procedure for the preparation of JD 01.
1H NMR (600 MHz, DMSO) δ 10.31 (brs, 1H), 8.63 (brs, 1H), 7.92 (d, J= 9.0 Hz, 1H), 7.47 (t, J = 5.4 Hz, 1H), 6.85 (dd, J = 8.4, 8.4 Hz, 1H), 6.81-6.80 (m, 1H), 4.95 (s, 1H), 3.79 (s, 3H), 2.51 – 2.40 (m, 2H), 1.92 (t, J = 7.8 Hz, 2H), 1.60 – 1.53 (m, 2H), 1.53 – 1.45 (m, 2H), 1.31-1.27 (m, 2H)。HRMS (ESI): calcd for [C16H20N2O5 + H]+ 321.1372, found 321.1378。
Examples 1-4 preparation of the compound N-hydroxy-7- ((chromen-2-one-7-methoxy-4-) amino) heptanamide (JD 04). The preparation of JD04 was carried out by replacing o-hydroxyacetophenone with paeonol and methyl aminopropionate with methyl aminoheptanoate, according to the procedure for the preparation of JD 01.
1H NMR (600 MHz, DMSO) δ 10.35 (brs, 1H), 8.67 (brs, 1H), 7.98 (d, J= 8.4 Hz, 1H), 7.53 (s, 1H), 6.91 (dd, J = 8.4, 2.4 Hz, 1H), 6.87-6.85 (m, 1H), 5.00 (s, 1H), 3.84 (s, 3H), 3.20 -3.16 (m, 2H), 1.95 (t, J = 7.2 Hz, 2H), 1.63 – 1.58 (m, 2H), 1.52-1.48 (m, 2H), 1.35 (t, J = 7.2 Hz, 2H), 1.31 – 1.24 (m, 2H)。HRMS (ESI): calcd for [C17H22N2O5 + H]+ 335.1529, found 335.1579。
Examples 1-5 preparation of the compound N-hydroxy-8- ((chromen-2-one-7-methoxy-4-) amino) octanamide (JD 05). The preparation of JD05 was carried out by replacing o-hydroxyacetophenone with paeonol and methyl aminopropionate with methyl aminocaprylate, according to the procedure for the preparation of JD 01.
1H NMR (600 MHz, DMSO) δ 10.35 (brs, 1H), 8.67 (brs, 1H), 7.97 (d, J= 8.4 Hz, 1H), 7.52 (s, 1H), 6.91 (dd, J = 8.4, 2.4 Hz, 1H), 6.87-6.85 (m, 1H), 5.00 (s, 1H), 3.84 (s, 3H), 3.20-3.18 (m, 2H), 1.94 (t, J = 7.2 Hz, 2H), 1.65 – 1.56 (m, 2H), 1.52 – 1.45 (m, 2H), 1.34-1.30 (m, 4H), 1.27 – 1.19 (m, 2H)。HRMS (ESI): calcd for [C18H24N2O5 + H]+ 349.1685, found 349.1747。
Examples 1 to 6, CompoundsNPreparation of-hydroxy-5- ((benzopyran-2-one-7-methoxy-4-) oxy) pentanamide (JD 06).
1H NMR (600 MHz, MeOD) δ 7.94 (brs, 1H), 7.73 (d, J = 8.4 Hz, 1H), 6.89 (dd, J = 8.4, 7.8 Hz, 1H), 6.84-6.83 (m, 1H), 5.62 (s, 1H), 4.18 (t, J = 6.0 Hz, 2H), 3.85 (s, 3H), 2.17 (t, J = 7.2 Hz, 2H), 1.89 (t, J = 6.0 Hz, 2H), 1.85 – 1.79 (m, 2H)。HRMS (ESI): calcd for [C15H17NO6 + H]+ 308.1056, found 308.1102。
Examples 1 to 7, CompoundsN-hydroxy-6- ((benzo)Preparation of pyran-2-one-7-methoxy-4-) oxy) hexanamide (JD 07). The preparation of JD07 was carried out by changing methyl bromovalerate to methyl bromohexanoate, according to the procedure for the preparation of JD 06.
1H NMR (600 MHz, DMSO) δ 10.36 (brs, 1H), 8.69 (brs, 1H), 7.69 (d, J= 8.4 Hz, 1H), 6.98-6.96 (m, 1H), 6.95 (dd, J = 8.4, 2.4 Hz, 1H), 5.73 (s, 1H), 4.18 (t, J = 6.0 Hz, 2H), 3.86 (s, 3H), 1.99 (t, J = 7.2 Hz, 2H), 1.86 – 1.76 (m, 2H), 1.63 – 1.53 (m, 2H), 1.45-1.42 (m, 2H)。HRMS (ESI): calcd for [C16H19NO6 + H]+ 322.1212, found 322.1268。
Examples 1 to 8, CompoundsNPreparation of-hydroxy-7- ((benzopyran-2-one-7-methoxy-4-) oxy) heptanamide (JD 08). The preparation of JD08 was carried out by replacing methyl bromovalerate with methyl bromoheptanoate, according to the procedure for the preparation of JD 06.
1H NMR (600 MHz, MeOD) δ 7.93 (brs, 2H), 7.72 (d, J = 8.4 Hz, 1H), 6.89 (dd, J = 8.9, 8.4 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 5.61 (d, J = 4.3 Hz, 1H), 4.15 (t, J = 6.6 Hz, 2H), 3.84 (s, 3H), 2.07 (t, J = 7.2 Hz, 2H), 1.90 – 1.84 (m, 2H), 1.68 – 1.59 (m, 2H), 1.56 – 1.48 (m, 2H), 1.39 (t, J = 7.8 Hz, 2H)。HRMS (ESI): calcd for [C17H21NO6 + H]+ 336.1369, found 336.1433。
Examples 1 to 9, CompoundsNPreparation of-hydroxy-8- ((benzopyran-2-one-7-methoxy-4-) oxy) octanamide (JD 09). The preparation of JD09 was carried out by replacing methyl bromovalerate with methyl bromooctanoate, according to the procedure for the preparation of JD 06.
1H NMR (600 MHz, MeOD) δ 7.75 (d, J = 8.4 Hz, 1H), 6.94 (dd, J = 8.4, 8.4 Hz, 1H), 6.89-6.88 (m, 1H), 5.65 (s, 1H), 4.20 (t, J = 6.6 Hz, 2H), 3.89 (s, 3H), 2.10 (t, J = 7.2 Hz, 2H), 1.94 – 1.87 (m, 2H), 1.64 (t, J = 7.4 Hz, 2H), 1.58 – 1.52 (m, 2H), 1.45 (t, J = 7.4 Hz, 2H), 1.42 – 1.37 (m, 2H)。HRMS (ESI): calcd for [C18H23NO6 + H]+ 350.1525, found 350.1543。
Examples 1 to 10, CompoundsNPreparation of-hydroxy-9- ((benzopyran-2-one-7-methoxy-4-) oxy) nicotinamide (JD 10). The preparation of JD10 was carried out by changing methyl bromovalerate to methyl bromolaurate, corresponding to the preparation of JD 06.
1H NMR (600 MHz, DMSO) δ 10.33 (brs, 1H), 8.66 (brs, 1H), 7.69 (d, J= 8.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.96 (dd, J = 8.4, 2.4 Hz, 1H), 5.73 (s, 1H), 4.18 (t, J = 6.0 Hz, 2H), 3.85 (s, 3H), 1.94 (t, J = 7.2 Hz, 2H), 1.85 – 1.75 (m, 2H), 1.53 – 1.46 (m, 2H), 1.46 – 1.41 (m, 2H), 1.37 – 1.32 (m, 2H), 1.30 – 1.27 (m, 2H), 1.26 – 1.21 (m, 2H)。HRMS (ESI): calcd for [C19H25NO6 + H]+ 364.1682, found 364.1630。
Examples 1 to 11, CompoundsNPreparation of-hydroxy-8- ((benzopyran-2-one-4-) oxy) octanamide (JD 11). The preparation of JD11 was carried out by replacing methyl bromovalerate with methyl bromooctanoate, according to the procedure for the preparation of JD 06.
1H NMR (600 MHz, DMSO) δ 10.34 (brs, 1H), 8.67 (brs, 1H), 7.80 (d, J= 7.8 Hz, 1H), 7.68 – 7.64 (dd, J = 7.8, 7.8 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 7.8, 7.2 Hz, 1H), 5.89 (s, 1H), 4.21 (t, J = 6.6 Hz, 2H), 1.95 (t, J = 7.2 Hz, 2H), 1.83-1.79 (m, 2H), 1.52-1.49 (m, 2H), 1.47-1.43 (m, 2H), 1.37 – 1.32 (m, 2H), 1.30-1.26 (m, 2H)。
Example two, inhibition of HDAC enzymatic activity by the compounds of the present invention at the molecular level.
Ac-Lys-Tyr-Lys (Ac) -AMC is used as a substrate, and the enzyme activity is detected in a 96-hole or 384-hole flat-bottom microplate by adopting a fluorescence detection method. After the substrate Ac-Lys-Tyr-Lys (Ac) -AMC is deacetylated by HDAC1, the product AMC obtained by pancreatin hydrolysis can be detected as a fluorescent signal under the excitation of 355nm of a fluorescence detector and the emission of 460 nm. The initial reaction speed is calculated by detecting the change of the fluorescence signal with time. The results are shown in Table 1. From table 1, it can be seen that the compounds all have certain inhibitory activity on HDAC, wherein the inhibitory activity of compounds JD03, JD08 and JD09 is better than that of SAHA, and particularly the inhibitory activity of JD09 is about 30 times higher than that of SAHA.
Figure 157339DEST_PATH_IMAGE005
EXAMPLE III inhibition of proliferation of different tumor cells by Compounds of the invention
Detecting the survival rate of the cells by an SRB method; tumor cells at 5 x 103The mixture is inoculated to a 96-well plate at one/well density, after the mixture is cultured for 24 hours conventionally, the compounds of the invention with different concentrations are sequentially added to ensure that the final concentration is 5.0 mu mol/L, the same amount of DMSO is added to a control group, and 6 multiple wells are arranged in each group. After further culturing for 48 h, the cells were fixed, SRB stained, and the OD was measured in a 96-well plate at 440 nm wavelength in a microplate reader. The effect of the drug on cell viability was statistically analyzed. The results are shown in table 2, and it can be seen that the sensitivity of liver cancer cell HepG2 to the compound is poor, the inhibitory activity of compound JD05 and SAHA to cervical cancer Hela cell are significantly better than the inhibitory activity of compounds JD05 and JD09 to lung cancer a549 cell.
Meanwhile, as can be seen from fig. 2, the compounds JD03, JD04, JD05, JD06, JD07, JD08 and JD09 of the present invention selected from lung cancer H157 cells and breast cancer MCF7 cells have the same inhibitory effect on the proliferation of different tumor cells at different concentrations as the currently used drug SAHA.
Figure 955531DEST_PATH_IMAGE006
EXAMPLE four Compounds of the invention increase the acetylation level of Histone H3
Inoculating cells into a six-hole plate, adding compounds to be detected with different concentrations when the cells grow to 70% of density, washing twice with PBS after 24 hours, collecting the cells with cell lysate, quantifying protein, performing polyacrylamide gel electrophoresis, and performing membrane conversion with a polyvinylidene fluoride membrane. After one hour of bovine serum albumin blocking, the corresponding antibody was added and incubated overnight at 4 ℃ and washed three times with PBST. Secondary antibodies were incubated for one hour at room temperature, washed three times with PBST and exposed. The experimental results are shown in fig. 2, and the compounds JD05 and JD09 used in the present invention can significantly improve the acetylation of histone H3 at the concentrations of 0.2 μ M, 0.5 μ M and 1 μ M, and are dose-dependent, and have a more significant improvement effect than the positive control SAHA.

Claims (6)

1. A hydroxamic acid micromolecule organic compound containing a coumarin structure is characterized by comprising a compound I and derivatives thereof, wherein the structure of the compound I is as follows:
Figure DEST_PATH_IMAGE002
wherein: r = H or OCH3(ii) a n = 2-6; x = NH or O;
excluding: n-hydroxy-3- ((chromen-2-one-4-) amino) propionamide and the compound N-hydroxy-5- ((chromen-2-one-7-methoxy-4-) oxy) pentanamide;
the derivative is an acid addition salt formed by the compound I and an acid; wherein the acid is hydrobromic acid, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, salicylic acid, tartaric acid, methanesulfonic acid, citric acid, lactic acid, p-toluenesulfonic acid, succinic acid, maleic acid, pyruvic acid.
2. The following compounds or pharmaceutically acceptable salts thereof:
N-hydroxy-6- ((chromen-2-one-4-) amino) hexanamide;
N-hydroxy-6- ((chromen-2-one-7-methoxy-4-) amino) hexanamide;
N-hydroxy-7- ((chromen-2-one-7-methoxy-4-) amino) heptanamide;
N-hydroxy-8- ((chromen-2-one-7-methoxy-4-) amino) octanoamide;
N-hydroxy-6- ((benzopyran)Pyran-2-one-7-methoxy-4-) oxy) hexanamide;
N-hydroxy-7- ((chromen-2-one-7-methoxy-4-) oxy) heptanamide;
N-hydroxy-8- ((chromen-2-one-7-methoxy-4-) oxy) octanamide;
N-hydroxy-9- ((chromen-2-one-7-methoxy-4-) oxy) anthranilamide;
N-hydroxy-8- ((chromen-2-one-4-) oxy) octanamide.
3. The use of a compound according to claim 1 or 2 as a histone deacetylase inhibitor in a medicament for the prevention and treatment of diseases caused by imbalance in histone acetylation regulation, wherein the diseases include cancer or inflammation; can also be used in the drugs for inducing the acquired drug resistance to cause the anti-tumor therapy after chemotherapy failure.
4. A process for preparing a compound of claim 1, wherein R = H and X = NH, comprising the steps of:
Figure DEST_PATH_IMAGE004
compound 1 and diethyl carbonate are buckled to generate compound 2, compound 2 is chloridized in solvent A to obtain compound 3, compound 3 reacts with amino acid ester with different chain lengths to generate compound 4, the compound 4 reacts with hydroxylamine hydrochloride in solvent B to generate target compound 5, ice water is generally used for quenching after the reaction is finished, extraction is carried out, water and saturated saline water are sequentially used for washing, drying, the solvent is removed by low temperature and reduced pressure, and the final product is obtained by column chromatography.
5. A process for the preparation of a compound according to claim 1, wherein R = OCH3X = O, comprising the steps of:
Figure DEST_PATH_IMAGE006
the compound 6 and diethyl carbonate are subjected to ring closure to generate a compound 7, the compound 7 reacts in a solvent A to obtain a compound 8, the compound 8 reacts with hydroxylamine hydrochloride in a solvent B to generate a target compound 9, the target compound is generally quenched by ice water after the reaction is finished, extracted, washed by water and saturated saline solution in sequence, dried, subjected to low-temperature reduced pressure to remove the solvent, and subjected to column chromatography to obtain a final product.
6. The production method according to claim 4 or 5, wherein the solvent A is dimethylformamide, dioxane, toluene, benzene or tetrahydrofuran; the solvent B is dichloromethane, methanol, ethanol, dimethyl sulfoxide or toluene; the extraction liquid is ethyl acetate, dichloromethane or diethyl ether.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014196328A1 (en) * 2013-06-04 2014-12-11 日本理化学工業株式会社 Hydroxamic acid derivative or salt thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014196328A1 (en) * 2013-06-04 2014-12-11 日本理化学工業株式会社 Hydroxamic acid derivative or salt thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Antitumor agents 278. 4-Amino-2H-benzo[h]chromen-2-one (ABO) analogs as potent in vitro anti-cancer agents";Yizhou Dong;《Bioorganic & Medicinal Chemistry Letters》;20100524;第4085-4087页 *
"Design and synthesis of novel and highly-active pan-histone deacetylase (pan-HDAC) inhibitors";Toshihiko Tashima;《Bioorganic & Medicinal Chemistry》;20140514;第22卷;第3720-3731页 *
"Synthesis and evaluation of aliphatic-chain hydroxamates capped with osthole derivatives as histone deacetylase inhibitors";Wei-Jan Huang;《European Journal of Medicinal Chemistry》;20110612;第46卷;第4042-4049页 *

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