CN113912560A - Oxazole histone deacetylase inhibitor and preparation method and application thereof - Google Patents

Oxazole histone deacetylase inhibitor and preparation method and application thereof Download PDF

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CN113912560A
CN113912560A CN202111445772.2A CN202111445772A CN113912560A CN 113912560 A CN113912560 A CN 113912560A CN 202111445772 A CN202111445772 A CN 202111445772A CN 113912560 A CN113912560 A CN 113912560A
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histone deacetylase
oxazole
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赵登高
张瑞强
马燕燕
张焜
莫华龙
陈亚军
徐学涛
盛钊君
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Abstract

The invention provides an oxazole histone deacetylase inhibitor, a preparation method and application thereof, belonging to the technical field of new drug compounds. The chemical structure of the inhibitor is shown as the formula (I), and the preparation method comprises the step of using NH2Dissolving the oxazole compound 1A in OK solution, adding hydroxylamine, stirring at room temperature, detecting the reaction end point by TLC, decompressing and removing the solvent, adding hydrochloric acid solution for acidification, extracting by dichloromethane, and evaporating to dryness to obtain a crude product. The oxazole compound has strong inhibition effect on histone deacetylase and can effectively inhibit cancer cells. Compared with the histone deacetylase inhibitor on the market, the oxazole compound provided by the invention has the advantages that the activity of the histone deacetylase is obviously improved, the effect on solid tumors such as lung cancer is better, and the problems of low activity, poor curative effect on the solid tumors and the like of the existing histone deacetylase inhibitor can be solved.

Description

Oxazole histone deacetylase inhibitor and preparation method and application thereof
Technical Field
The invention relates to the technical field of new medicine compounds, in particular to an oxazole histone deacetylase inhibitor and a preparation method and application thereof.
Background
Histone Deacetylases (HDACs) are a class of proteases that are widely found in eukaryotic cells and remove acetyl groups from histone lysines, thereby inhibiting gene transcription.
In addition, HDACs can remove acetyl groups from some non-histone proteins, such as transcription factors, structural proteins and inflammatory mediators, affecting their function. Inhibiting the enzyme activity of HDACs not only affects the cellular processes of gene expression, apoptosis, growth arrest, differentiation, etc., but also inhibits angiogenesis. Because HDACs play an extremely important role in gene expression and other cellular activities, HDAC inhibitors have tremendous research and development value in cancer therapy.
Vorinostat is the first HDAC inhibitor approved by the U.S. Food and Drug Administration (FDA) for the treatment of cutaneous T-cell lymphoma (CTCL), ruminants are FDA-approved for the treatment of CTCL and peripheral T-cell lymphoma (PTCL) in 2009 and 2011, respectively, and belinostat is FDA-approved for the treatment of PTCL in 2014. However, the efficacy of HDAC inhibitors for the treatment of B cell lymphoma is not yet clear.
In addition, the existing marketed HDAC inhibitors generally have the problems of low activity, poor curative effect on solid tumors and the like. Therefore, the development of a novel histone deacetylase inhibitor has wide application prospect.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides an oxazole histone deacetylase inhibitor and a preparation method and application thereof.
The technical scheme of the invention is as follows: an oxazole histone deacetylase inhibitor, which has a chemical structure shown in formula (I):
Figure BDA0003381702800000021
wherein R is H, Cl, CH3,CF3Or OMe; n is 6.
Further, the chemical structure of the inhibitor is as follows:
Figure BDA0003381702800000022
further, the chemical structure of the inhibitor is as follows:
Figure BDA0003381702800000023
further, the chemical structure of the inhibitor is as follows:
Figure BDA0003381702800000024
further, the chemical structure of the inhibitor is as follows:
Figure BDA0003381702800000031
further, the chemical structure of the inhibitor is as follows:
Figure BDA0003381702800000032
the invention also provides a preparation method of the oxazole histone deacetylase inhibitor, which comprises the following steps:
s1), placing 15mmol of hydroxylamine hydrochloride and 15mmol of KOH in a round-bottom flask, adding 25mL of anhydrous methanol for dissolving, stirring in ice bath for 20-40min, and filtering to obtain a hydroxylamine potassium solution NH2OK；
S2), using 25mL of NH2Dissolving 1mmol of oxazole compound 1A in OK solution, adding 20mmol of hydroxylamine, stirring at room temperature for 30min-1h, detecting the reaction end point by TLC, and removing the solvent under reduced pressure;
s3), then adding an appropriate amount of 2mol/L hydrochloric acid solution to acidify to PH 3-4, extracting with dichloromethane for 1-3 times, and then using anhydrous MgSO4Drying and evaporating to obtain a crude product;
the reaction formula is as follows:
Figure BDA0003381702800000033
wherein R is H, Cl, CH3,CF3Or OMe.
The invention also provides application of the oxazole histone deacetylase inhibitor in aspects of being used as a histone deacetylase inhibitor, an anti-cancer drug and a cell cycle drug.
The invention has the beneficial effects that:
1. the oxazole compound provided by the invention has strong inhibition effect on histone deacetylase, can effectively inhibit cancer cells, and can form a new generation of anticancer lead compound;
2. compared with the histone deacetylase inhibitor on the market, the oxazole compound provided by the invention has the advantages that the activity of the histone deacetylase is obviously improved, the effect on solid tumors such as lung cancer is better, and the problems of low activity, poor curative effect on the solid tumors and the like of the existing histone deacetylase inhibitor can be solved;
3. the oxazole compound of the invention can be prepared into tablets, powder injection, emulsifying agents, capsules and the like under the preparation combination which can be accepted by pharmaceutical specifications, and has wide application prospect in the aspects of histone deacetylase inhibitors, anti-cancer drugs, cell cycle drugs and the like.
Detailed Description
The technical solutions of the present invention will be further described with reference to the following embodiments, and it should be apparent that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. The methods and procedures used in the examples are conventional in the art and, unless otherwise indicated. The starting materials used in the examples are all commercially available and are all the same species used in parallel experiments.
Example 1
The embodiment provides a preparation method of an oxazole histone deacetylase inhibitor, which comprises the following steps:
s1), respectively placing 15mmol of hydroxylamine hydrochloride and 15mmol of KOH in a round-bottom flask, adding 25mL of anhydrous methanol for dissolving, stirring in ice bath for 30min, and filtering to obtain hydroxylamine potassium (NH)2OK) solution, sealing for standby;
s2), 1mmol of methyl 7- (5-phenyloxazole-2-amide) heptanoate was used with the prepared 25mL NH2Dissolving OK solution, adding 20mmol of hydroxylamine, stirring at room temperature for 1h, detecting the reaction end point by TCL, and removing the solvent under reduced pressure;
s3), acidifying to PH 3-4 by adding appropriate 2mol/L hydrochloric acid solution, extracting with dichloromethane (3 × 20mL), anhydrous MgSO4Drying and evaporating to dryness to obtain a crude product which is recorded as 10 d.
This example prepares the reaction as follows:
Figure BDA0003381702800000051
the crude product was purified by column chromatography on silica gel (eluent chloroform: methanol 10:1), recrystallized from ethanol and dried in vacuo to give 0.35mmol of the desired product 10d, with a yield of about 35%.
Target product 10 d: white powder solid.1H NMR(500MHz,DMSO-d6)δ10.34(s,1H),8.98(s,1H),8.67(s,1H),7.90(s,1H),7.83(d,J＝7.2Hz,2H),7.52(t,J＝7.6Hz,2H),7.44(t,J＝7.4Hz,1H),3.24(q,J＝6.7Hz,2H),1.93(t,J＝7.4Hz,2H),1.53–1.47(m,4H),1.30–1.24(m,4H)；13C NMR(126MHz,DMSO-d6)δ169.18,154.68,154.45,152.36,129.51,129.32,126.87,124.69,123.70,38.98,32.32,28.93,28.40,26.21,25.18。
Example 2
The embodiment provides a preparation method of an oxazole histone deacetylase inhibitor, which comprises the following steps:
s1) respectively putting 15mmol of hydroxylamine hydrochloride and 15mmol of KOH into a round-bottom flask, adding 25mL of anhydrous methanol for dissolving, stirring in ice bath for 30min, and filtering to obtain hydroxylamine potassium (NH)2OK) solution, sealed for use.
S2), 1mmol of methyl 7- (5- (4-methoxyphenyl oxazole) -2-amide) heptanoate was used with a prepared 25mL of NH2Dissolving OK solution, adding 20mmol of hydroxylamine, stirring at room temperature for 1h, detecting the reaction end point by TCL, and removing the solvent under reduced pressure;
s3), acidifying to PH 3-4 by adding appropriate 2mol/L hydrochloric acid solution, extracting with dichloromethane (3 × 20mL), anhydrous MgSO4Dried and evaporated to dryness to give 9g of crude product.
This example prepares the reaction as follows:
Figure BDA0003381702800000061
the crude product prepared in this example was purified by column chromatography on silica gel (eluent chloroform: methanol ═ c)
10:1), ethanol recrystallization and vacuum drying to obtain 9g of 0.42mmol of target product, and the yield is about 42 percent.
9g of target product: white powder solid.1H NMR(500MHz,DMSO-d6)δ10.34(s,1H),8.92(s,1H),8.67(s,1H),7.79–7.71(m,3H),7.08(d,J＝8.9Hz,2H),3.81(s,3H),3.22(s,2H),1.93(s,2H),1.53–1.45(m,4H),1.31–1.22(m,4H)；13C NMR(126MHz,DMSO-d6)δ169.19,160.20,154.76,153.86,152.55,126.39,122.07,119.49,114.79,55.46,38.95,32.32,28.96,28.41,26.22,25.19。
Example 3
The embodiment provides a preparation method of an oxazole histone deacetylase inhibitor, which comprises the following steps:
s1), respectively placing 15mmol of hydroxylamine hydrochloride and 15mmol of KOH in a round-bottom flask, adding 25mL of anhydrous methanol for dissolving, stirring in ice bath for 30min, and filtering to obtain hydroxylamine potassium (NH)2OK) solution, sealed for use.
S2), 1mmol of methyl 7- (5- (4-chlorophenyloxazole) -2-amide) heptanoate was used with the prepared 25mL NH2Dissolving OK solution, adding 20mmol of hydroxylamine, stirring at room temperature for 1h, detecting the reaction end point by TCL, and removing the solvent under reduced pressure;
s3), acidifying to PH 3-4 by adding appropriate 2mol/L hydrochloric acid solution, extracting with dichloromethane (3 × 20mL), anhydrous MgSO4Drying and evaporating to dryness to obtain a crude product which is recorded as 10 m.
This example prepares the reaction as follows:
Figure BDA0003381702800000071
the crude product prepared in this example was purified by column chromatography on silica gel (eluent chloroform: methanol 10:1), recrystallized from ethanol and dried in vacuo to give 0.28mmol of the desired product 10m, with a yield of about 28%.
Target product 10 m: white powder solid.1H NMR(500MHz,DMSO-d6)δ10.34(s,1H),9.00(s,1H),8.67(s,1H),7.94(s,1H),7.85(d,J＝8.6Hz,2H),7.60(d,J＝8.6Hz,2H),3.25(s,2H),1.93(s,2H),1.51(s,4H),1.27(s,4H)；13C NMR(126MHz,DMSO-d6)δ169.18,154.60,154.57,151.32,133.96,129.43,126.46,125.77,124.34,39.00,32.32,28.92,28.40,26.21,25.18。
Example 4
The embodiment provides a preparation method of an oxazole histone deacetylase inhibitor, which comprises the following steps:
s1), respectively placing 15mmol of hydroxylamine hydrochloride and 15mmol of KOH in a round-bottom flask, adding 25mL of anhydrous methanol for dissolving, stirring in ice bath for 30min, and filtering to obtain hydroxylamine potassium (NH)2OK) solution, sealed for use.
S2), 1mmol of methyl 7- (5- (4-methyloxazole) -2-amide) heptanoate was used with the prepared 25mL NH2Dissolving OK solution, adding 20mmol of hydroxylamine, stirring at room temperature for 1h, detecting the reaction end point by TCL, and removing the solvent under reduced pressure;
s3), then acidified to PH 3-4 by adding an appropriate amount of 2mol/L hydrochloric acid solution, extracted with dichloromethane (3 × 20mL), anhydrous MgSO4Drying and evaporating to dryness to obtain a crude product which is recorded as 10 n.
This example prepares the reaction as follows:
Figure BDA0003381702800000072
the crude product prepared in this example was purified by column chromatography on silica gel (eluent chloroform: methanol)
10:1), ethanol recrystallization, and vacuum drying to obtain 0.30mmol of the target product 10n, with a yield of about 30%.
Target product 10 n: white powder solid.1H NMR(500MHz,DMSO-d6)δ10.34(s,1H),8.95(s,1H),8.67(s,1H),7.82(s,1H),7.71(d,J＝8.1Hz,2H),7.33(d,J＝8.0Hz,2H),3.23(s,2H),2.35(s,3H),1.93(s,2H),1.51(s,4H),1.26(s,4H)；13C NMR(126MHz,DMSO-d6)δ169.21,154.73,154.16,152.58,139.26,129.87,124.68,124.17,123.02,38.98,32.33,28.95,28.41,26.23,25.20,21.07。
Example 5
The embodiment provides a preparation method of an oxazole histone deacetylase inhibitor, which comprises the following steps:
s1), respectively placing 15mmol of hydroxylamine hydrochloride and 15mmol of KOH in a round-bottom flask, adding 25mL of anhydrous methanol for dissolving, stirring in ice bath for 30min, and filtering to obtain hydroxylamine potassium (NH)2OK) solution, sealed for use.
S2), 1mmol of methyl 7- (5- (4-trifluoromethyloxazole) -2-amide) heptanoate was used with a prepared 25mL of NH2Dissolving OK solution, adding 20mmol of hydroxylamine, stirring at room temperature for 1h, detecting the reaction end point by TCL, and removing the solvent under reduced pressure;
s3), acidifying to PH 3-4 by adding appropriate 2mol/L hydrochloric acid solution, extracting with dichloromethane (3 × 20mL), anhydrous MgSO4Drying and evaporating to dryness to obtain a crude product which is recorded as 10 p.
This example prepares the reaction as follows:
Figure BDA0003381702800000081
the crude product prepared in this example was purified by column chromatography on silica gel (eluent chloroform: methanol)
10:1), recrystallizing with ethanol, and drying in vacuum to obtain 0.30mmol of the target product 10p with the yield of about 20%.
Target product 10 p: white powder solid.1H NMR(500MHz,DMSO-d6)δ10.34(s,1H),9.06(s,1H),8.67(s,1H),8.10(s,1H),8.05(d,J＝8.2Hz,2H),7.89(d,J＝8.3Hz,2H),3.25(q,J＝6.7Hz,2H),1.93(t,J＝7.4Hz,2H),1.57–1.43(m,4H),1.27(s,4H).13C NMR(126MHz,DMSO-d6)δ169.18,155.13,154.51,150.88,130.64,126.32,126.29,125.80,125.31,39.04,32.32,28.91,28.40,26.21,25.18。
Example 6
Study on Activity of oxazole histone deacetylase inhibitor prepared in examples 1 to 5 on human histone deacetylase 1(HDAC1)
(1) Experimental Material
Target compound and positive control vorinostat (SAHA), human histone DebAcylase 1(HDAC1) kit (Abnova, Catalog Number KA1320), enzyme labeling instrument (Biotek NEO)2) And black 96-well plates.
(2) Experimental methods
The procedure was as provided by HDAC1 kit manufacturing. The black 96-well plate contains 3 systems of blank, negative and sample sets, 3 parallel sets per system. Wherein blank group (Bw): 150 μ L buffer, 10 μ L DMSO, and 10 μ L HDAC1 substrate; negative group (F)0): 140 μ L buffer, 10 μ L HDAC1 enzyme, 10 μ L DMSO, and 10 μ L HDAC1 substrate; sample set (F): 140 μ L buffer, 10 μ L HDAC1 enzyme, 10 μ L of different concentrations of compound, and 10 μ L HDAC1 substrate. Then incubating in a microplate constant temperature oscillator at 37 deg.C for 30min, adding 40 μ L of developer to each well, incubating for 15min, and using Biotek NEO2Measuring fluorescence intensity values of an enzyme-labeling instrument under the conditions that the excitation wavelength is 350nm and the emission wavelength is 450nm, calculating the inhibition rate of compounds with different concentrations on HDAC1 enzyme, and performing nonlinear curve fitting analysis on the inhibition rate of each concentration to obtain half inhibition concentration IC50The value is obtained. Median inhibitory concentration IC50Lower values represent a stronger inhibition of HDAC1 enzyme by the compound.
As shown in table 1, the half inhibitory concentration of the positive control SAHA to human histone deacetylase 1(HDAC1) was 214.8nM, and the half inhibitory concentrations of the compounds 9g, 10d, 10m, 10n and 10p were 40.07nM, 36.42nM, 31.38nM, 44.41nM and 42.82nM, respectively, which were superior to the positive control, showing that the target compound had a strong inhibitory activity to HDAC 1.
TABLE 1 comparison of experimental results for inhibition of histone deacetylase 1(HDAC1) by oxazoles
Figure BDA0003381702800000101
Example 7
Study on the Effect of the oxazole histone deacetylase inhibitor prepared in examples 1 to 5 on cancer cell proliferation
(1) Experimental Material
Target compoundAnd positive control vorinostat (SAHA), pancreatin, cleaning solution PBS, fetal bovine serum, human lung cancer cell A549, double antibody (penicillin, streptomycin), CCK-8 kit (Biyuntian), and enzyme-labeling instrument (Biotek NEO)2) And 96-well plates.
(2) Experimental methods
Human lung cancer cell a549 was from shanghai institute of biochemistry and cell biology. The cells were cultured in the presence of 5% CO2In the 37 ℃ incubator, DMEM medium containing 10% serum and 1% diabase (penicillin, streptomycin) was used.
When tested by the SRB method, cells in the logarithmic growth phase are first digested and counted. Cells were seeded into 96-well plates overnight. After the cells are attached to the wall, compounds with different concentrations are added, wherein 7 concentrations are set for each compound, and 3-5 concentrations are set for each compound in parallel. The cells and the drug are cultured for 72h and then taken out, 50 mu L of 50% (m/v) trichloroacetic acid is added into each hole to fix the cells, and the cell plate needs to be placed at room temperature for 5min and then placed at 40 ℃ for 1 h. The stationary liquid was discarded, washed with distilled water 5 times, and naturally dried in the air. Then, 100 pieces of 0.4% SRB solution were added to each well, left at room temperature for 30min, washed with 1% acetic acid solution more than 10 times, and air-dried. Finally, 150. mu.L of Tris solution was added using Biotek NEO2The absorbance was measured by a microplate reader, and the absorption wavelength was set at 570 nm. Carrying out nonlinear curve fitting analysis on the inhibition rate of each concentration to obtain half inhibition concentration IC50The value is obtained.
As shown in table 2, the half inhibitory concentration of SAHA of the positive control to a549 in human lung cancer cells was 2.043 μm, and the half inhibitory concentrations of compounds 9g, 10d, 10m, 10n and 10p were 0.6087 μm, 0.4195 μm, 0.5139 μm, 0.6601 μm and 0.6410 μm, respectively, which were superior to the positive control, showing that the target compound had a strong inhibitory activity against cancer cells.
TABLE 2 comparison of experimental results of half inhibitory concentrations of oxazoles on A549 lung cancer cells
Figure BDA0003381702800000111
It is demonstrated by the above examples that the oxazole compounds provided according to the present invention have strong inhibitory effects on histone deacetylase and cancer cells. Compared with the histone deacetylase inhibitor on the market, the oxazole compound provided by the invention has obviously improved activity and can be developed into a new generation of anticancer drugs.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.

Claims (8)

1. An oxazole histone deacetylase inhibitor, which has a chemical structure represented by formula (I):
Figure FDA0003381702790000011
wherein R is H, Cl, CH3,CF3Or OMe; n is 6.
2. An oxazole histone deacetylase inhibitor according to claim 1, wherein: the chemical structure of the inhibitor is shown as follows:
Figure FDA0003381702790000012
3. an oxazole histone deacetylase inhibitor according to claim 1, wherein: the chemical structure of the inhibitor is shown as follows:
Figure FDA0003381702790000013
4. an oxazole histone deacetylase inhibitor according to claim 1, wherein: the chemical structure of the inhibitor is shown as follows:
Figure FDA0003381702790000021
5. an oxazole histone deacetylase inhibitor according to claim 1, wherein: the chemical structure of the inhibitor is shown as follows:
Figure FDA0003381702790000022
6. an oxazole histone deacetylase inhibitor according to claim 1, wherein: the chemical structure of the inhibitor is shown as follows:
Figure FDA0003381702790000023
7. a method for preparing an oxazole histone deacetylase inhibitor as described in any one of claims 1 to 6, wherein the method comprises the following steps: with 25mL of NH2Dissolving 1mmol of oxazole compound 1A in OK solution, adding 20mmol of hydroxylamine, stirring at room temperature for 30min-1h, detecting the reaction end point by TLC, and removing the solvent under reduced pressure; then adding a proper amount of 2mol/L hydrochloric acid solution to acidify until the PH value is 3-4, extracting with dichloromethane for 1-3 times, and evaporating to dryness to obtain a crude product;
the reaction formula is as follows:
Figure FDA0003381702790000024
wherein R is H, Cl, CH3,CF3Or OMe; n is 6.
8. An oxazole histone deacetylase inhibitor as defined in any one of claims 1 to 6 for use as a histone deacetylase inhibitor, an anticancer drug and a cell cycle drug.
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