CN108299255B - Histone deacetylase 8 selective inhibitor and preparation method and application thereof - Google Patents
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Abstract
The invention discloses a histone deacetylase 8 selective inhibitor, and a preparation method and application thereof. The selective inhibitor of the histone deacetylase 8 has a structure shown in the following general formula (I) or (II). The invention also provides a preparation method of the compound and application of the compound in preparing a medicament for preventing or treating diseases related to abnormal activity of HDAC 8.
Description
Technical Field
The invention relates to a histone deacetylase 8(HDAC8) selective inhibitor, and a preparation method and application thereof, and belongs to the technical field of organic compound synthesis and medical application.
Background
Histone Deacetylases (HDACs) are a class of proteases that catalyze deacetylation of histones, allowing them to bind tightly to negatively charged DNA, with compact chromatin coiling, thereby inhibiting transcription of related genes. Thus, HDACs play an important role in the structural modification and gene expression regulation of chromosomes. The HDACs family currently found in humans has 18 members, which are classified into four groups: class I (HDAC1, 2, 3, and 8); class II (IIa: HDAC4, 5, 7 and 9; IIb: HDAC6, 10); class III HDACs (SIRT1-7) and class IV (HDAC 11). Of these, class I, class II and class IV depend on zinc ion for function, while class III HDACs (SIRT1-7) depend on NAD+Functional (Zagni, C.; Floresta, G.; Monciino, G.; Rescifina, A., The Searchwor Poten, Small-molecular HDACIs in Cancer Treatment: A Decode AfterVorinostat. Med Res Rev 2017,37(6), 1373-1428). More and more studies have shown that abnormal expression of HDACs can lead to various diseases, such as cancer, viral infection, inflammation and neurodegenerative diseases. To date, a total of 5 HDACs inhibitors vorinostat (SAHA), romidepsin (FK228), belinostat (PXD101), panobinostat (LBH589) and cisdanide (CS055) have been approved for cancer therapy. However, these 5 approved drugs on the market are non-selective HDACs inhibitors and present more serious toxic side effects, such as: tiredness, diarrhea, erythropenia, leukopenia, thrombocytopenia and cardiotoxicity (Alokta Chakranti, J.M., Fiona R Kolbinger, Ina Oehme, Johanna Senger, Olaf Witt, Wolfgang Sippl)&Manual Jung, Targeting histone deacetylase 8 as a thermal approach to cancer and neuro-genic diseases, future medical Chemistry 2016,8(13), 1609-1634. Subtype selective HDACs inhibitors are expected to avoid the toxic side effects of the broad spectrum HDACs inhibitors.
HDAC8 is a 42kDa protein consisting of 377 amino acids, distributed mainly in the nucleus and cytoplasm, playing an important role in many physiological and pathological processes, although there is still controversy as to whether histone is a HDAC8 substrate, a large number of non-histones (such as SMC3, ERR α and p53) have been reported to be substrates for HDAC8 or to be ligands for their interactions, studies have shown that HDAC8 is a substrate for p53, and that low knock-out (knockdown) HDAC8 shows antiproliferative activity in cells with p53 mutations, which indicates that HDAC8 inhibitors are likely to be adjunctive therapeutic drugs with p53 mutations, furthermore, there is increasing evidence that HDAC8 activity or abnormal expression is essential in many diseases, in particular in T cell lymphomas, childhood neuroblastoma and Cornelide Lange syndrome (Cdng. LS), and that HDAC 3407, a highly potent inhibitor, such as a chemotherapeutic drug inhibitor, targeting, Scotc, and other chemotherapeutics, which are expected to have been developed as a highly effective inhibitor of tumors.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a histone deacetylase 8(HDAC8) selective inhibitor, and a preparation method and application thereof.
The technical scheme of the invention is as follows:
one, selective inhibitors of histone deacetylase 8(HDAC8)
The histone deacetylase 8(HDAC8) selective inhibitor is a compound with a structure shown in the following structural general formula (I) or (II), and an optical isomer, diastereoisomer and racemate mixture thereof, and pharmaceutically acceptable salt, solvate or prodrug thereof:
wherein: n is 0-8;
R1is an aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclyl, substituted heterocyclyl;
R2is hydrogen, aliphatic hydrocarbon group, aromatic hydrocarbon group;
R3is hydrogen, aliphatic hydrocarbon group, aromatic hydrocarbon group;
is in the S or R configuration, or a racemate thereof.
Preferred according to the invention, wherein:
n＝0-3；
R1is phenyl, substituted phenyl;
R2is-H, -CH3,-CH(CH3)2,
R3Is that
Is in the S configuration.
According to a further preferred embodiment of the invention, the above compound is one of the following:
II, preparation method of histone deacetylase 8(HDAC8) selective inhibitor
The preparation of the selective inhibitor of histone deacetylase 8(HDAC8) of the present invention comprises the following steps: the raw material 1 and methanol are subjected to esterification reaction to generate a compound 2, then the compound 2 is reacted with thionyl chloride to obtain a key intermediate 3, and the intermediate 3 is condensed with compounds 4a-4q respectively to obtain compounds 5a-5 q; finally, reacting the compounds 5a-5q with hydroxylamine potassium in a methanol solution to obtain target compounds 6a-6 q;
the synthetic route is as follows:
wherein, n, R1，R2，R3Is as defined in general formula (I) and general formula (II);
reagents and reaction conditions in the above synthetic route: a, methanol, hydrochloric acid and sodium bicarbonate; b, thionyl chloride, N, N-dimethylformamide; c, triethylamine and methylbenzene; d, potassium hydroxide, hydroxylamine hydrochloride and methanol.
According to a preferred embodiment of the present invention, the preparation of compounds 6a-6q, which are selective inhibitors of histone deacetylase 8(HDAC8), is performed by the following steps, taking compound 6b as an example:
intermediate 2: 3-Methoxycarbonylbenzenesulfonic acid sodium salt
Refluxing 11.2g of raw material 3-carboxyl sodium benzenesulfonate, 145mL of anhydrous methanol and 34mL of 12mol/L concentrated hydrochloric acid at the normal temperature of 25 ℃ for 4-6h, filtering the reaction solution after the reaction is finished, removing white residues, reacting the filtrate with 10g of anhydrous sodium bicarbonate at the normal temperature for 1h, filtering out precipitates, washing the filter residues with a small amount of methanol, combining the filtrates, concentrating, adding 135mL of methanol, filtering twice, and evaporating to dryness to obtain an intermediate 2 for later use; 9.8g of solid is obtained, and the yield is 82%;
intermediate 3: methyl-3-chlorosulfonyl benzoate
Refluxing 10g of the intermediate 2, 180mL of thionyl chloride and 0.2mL of N, N-dimethylformamide at 80 ℃ for 4-6 hours, after the reaction is finished, cooling the reaction solution, evaporating half of the solvent, slowly adding an ice-water mixture into the rest material under the stirring of an ice bath, filtering after complete quenching, and drying by a vacuum diaphragm pump to obtain 8g of a white solid compound with the yield of 85%; the intermediate 3 is unstable and is quickly put into the next reaction;
intermediate 5b methyl-3- (N-benzylsulfonamide) benzoate
At the normal temperature of 25 ℃,4.2g of raw material benzylamine (4b) and 100mL of methylbenzene are put into a 500mL round-bottom flask, the intermediate 3 is dissolved in 100mL of methylbenzene, the obtained product is filtered, the obtained filtrate is dripped into a reaction bottle under stirring, the reaction is continued for 2-3h at the room temperature of 25 ℃, after TLC detection reaction is finished, part of solvent is evaporated, the obtained product is filtered, and a filter cake is respectively leached by water and a small amount of methylbenzene, so that 4.2g of white solid is obtained, and the yield is 65%.
Compounds 5a, 5c-5q are prepared analogously to Compound 5 b;
target compound 6 b: 3- (N-benzylsulfonamido) -N-hydroxybenzamide
Dissolving 1.5g of the intermediate 5b in 15mL of newly prepared hydroxylamine potassium solution, stirring at room temperature of 25 ℃ for 1-2h, detecting by TLC at any time, stopping the reaction when the reaction is complete and no by-product is generated, adjusting the pH of the reaction solution to 5-6 by using 1M hydrochloric acid aqueous solution, filtering the obtained precipitate, and recrystallizing ethyl acetate to obtain the final product 6b, wherein the white solid is 0.9g, and the yield is 61%.
Application of selective inhibitor of histone deacetylase 8(HDAC8)
The invention also provides application of the selective inhibitor of histone deacetylase 8(HDAC8) in preparing a medicament for preventing or treating diseases related to abnormal activity or expression of HDAC 8; the diseases related to the abnormal activity or expression of HDAC8 comprise: various hematological tumors (e.g., T cell lymphoma, etc.), solid tumors (e.g., neuroblastoma, etc.), viral infections (e.g., influenza virus infection, human immunodeficiency virus infection, etc.), parasitic diseases (e.g., schistosomiasis, etc.), and the like.
Furthermore, the invention also comprises a pharmaceutical composition suitable for oral or parenteral administration comprising a compound of formula (I) or (II) and one or more pharmaceutically acceptable carriers or excipients.
Detailed Description
The present invention will be further described with reference to the following examples, but is not limited thereto.
Example 1 preparation of Compounds 6a-6q, exemplified by Compound 6b
The specific synthetic method and steps are as follows:
intermediate 2: 3-Methoxycarbonylbenzenesulfonic acid sodium salt
The preparation method comprises the steps of carrying out reflux reaction on raw materials of 3-carboxyl sodium benzenesulfonate (11.2g and 50mmol), anhydrous methanol (145mL) and concentrated hydrochloric acid (34mL) for 4-6h at normal temperature, filtering reaction liquid after the reaction is finished, removing white residues, reacting filtrate with 10g of anhydrous sodium bicarbonate for 1h at normal temperature, filtering out precipitates, washing filter residues with a small amount of methanol, combining the filtrate, concentrating, adding 135mL of methanol, filtering twice, and then evaporating to dryness to obtain an intermediate 2 for later use. 9.8g of a solid was obtained in 82% yield.
Intermediate 3: methyl-3-chlorosulfonyl benzoate
Refluxing the intermediate 2(10g, 42.0mmol), thionyl chloride (180mL) and N, N-dimethylformamide (0.2mL) at 80 ℃ for 4-6 hours, after the reaction is finished, cooling the reaction solution, evaporating half of the solvent, slowly adding an ice-water mixture into the rest under the stirring of an ice bath, filtering after complete quenching, and pumping to dryness by a vacuum diaphragm pump to obtain 8g of a white solid compound with the yield of 85%. This intermediate 3, which is unstable, is rapidly charged to the next reaction.
Intermediate 5b methyl-3- (N-benzylsulfonamide) benzoate
At normal temperature, raw materials of benzylamine (4b,4.2g and 40mmol) and 100mL of methylbenzene are put into a 500mL round-bottom flask, the intermediate 3 is dissolved in 100mL of methylbenzene, the filtering is carried out, the filtrate is dripped into a reaction bottle while stirring, the reaction is continued for 2-3h at room temperature after dripping, after TLC detection reaction is finished, part of solvent is evaporated, the filtering is carried out, and a filter cake is respectively leached by water and a small amount of methylbenzene, so that 4.2g of white solid is obtained, and the yield is 65%.1H NMR(400MHz,DMSO-d6)δ8.38(s,1H),8.27(t,J＝1.7Hz,1H),8.15(m,1H),8.06–7.99(m,1H),7.71(t,J＝7.8Hz,1H),7.22(m,5H),4.02(s,2H),3.90(s,3H)。
Compounds 5a, 5c-5q were prepared in analogy to Compound 5 b.
Target compound 6 b: 3- (N-benzylsulfonamido) -N-hydroxybenzamide
Dissolving 1.5g of the intermediate 5b in 15mL of newly prepared hydroxylamine potassium solution, stirring at room temperature for 1-2h, detecting by TLC at any time, stopping the reaction when the reaction is complete and no by-product is generated, adjusting the pH of the reaction solution to 5-6 by using 1M hydrochloric acid aqueous solution, filtering the obtained precipitate, and recrystallizing by ethyl acetate to obtain the final product 6b, wherein the white solid is 0.9g, and the yield is 61%.1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝1.8Hz,1H),7.96(dd,J＝7.8,1.5Hz,1H),7.91(m,1H),7.65(t,J＝7.8Hz,1H),7.25(m,5H),4.01(s,2H)。13C NMR(101MHz,DMSO-d6)δ163.09,141.61,137.97,134.22,130.80,129.93,129.29,128.69,128.03,127.64,125.65,46.56。HRMS(AP-ESI)m/z calcdfor C14H14N2O4S,[M+H]+307.0753,found 307.0750。
Compounds 6a, 6c-6q were prepared in analogy to compound 6 b.
Example 2 evaluation of inhibitory Activity of target Compounds in vitro HeLa cell Nuclear extracts (mainly comprising HDAC1 and HDAC2)
The experimental steps are as follows: blank and control groups were set: setting three multiple wells for each concentration, adding 60 microliters of buffer solution into a blank group, incubating at 37 ℃ for 5min, then adding 40 microliters of substrate, continuing to incubate at 37 ℃ for 30min, then adding 100 microliters of stop solution, continuing to incubate for 20min, taking out and measuring the fluorescence intensity at 390nm/460nm to serve as a blank fluorescence value. And (3) mixing 50 microliters of buffer solution with 10 microliters of HDACs enzyme solution in a 100% control group, arranging three multiple holes, incubating for 5min, adding 40 microliters of substrate into each hole, continuing to incubate for 30min, finally adding 100 microliters of stop solution, after incubating for 20min, ending the action, and determining the fluorescence value. Taking 50 microliters of prepared solutions to be tested with various concentrations of the compounds and the positive medicines, setting three multiple holes for each concentration of each compound, mixing the solutions with 10 microliters of HDACs enzyme solution, incubating for 5min, carrying out subsequent operation with a control group, finally measuring fluorescence intensity at 390nm/460nm, calculating inhibition rate under corresponding concentration, and carrying out S curve fitting calculation by using Origin software to obtain half inhibition concentration of the compounds, namely IC50。
Inhibition rate calculation formula:
the inhibitory activity of the approved vorinostat (SAHA), belinostat (PXD101) and 6a-6q in vitro HeLa nuclear extracts of the invention (comprising mainly HDAC1 and HDAC2) was tested according to the above method.
The test results (table 1) show that the non-selective HDACs inhibitors SAHA and PXD101 show strong inhibitory effect on HeLa nuclear extracts. In contrast, compounds 6a-6q of the present invention did not significantly inhibit HeLa cell nuclear extracts at a concentration of 20. mu.M, suggesting that compounds 6a-6q have a weak inhibitory activity against HDAC1 and HDAC 2.
TABLE 1 evaluation results of in vitro HeLa cell nucleus extract inhibitory activitya
aValues are expressed as the mean of three independent replicates.
Example 3 evaluation of the subtype selectivity of HDACs in vitro for the Compounds of interest
The procedure for the HDACs subtype selectivity assay was identical to that of example 2. The results of the experiments (Table 2) show that the non-selective HDACs inhibitor SAHA has strong inhibitory activity (IC) on HDAC2 and HDAC6500.22. mu.M and 0.09. mu.M, respectively), but weak inhibitory activity against HDAC8 (IC)50> 5. mu.M); in contrast, compounds 6a-6c,6e-6g,6k-6l and 6p-6q showed varying degrees of inhibition and selectivity for HDAC8, with compounds 6a-6c having a strong inhibitory activity against HDAC8 and IC50Values were 0.05 μ M,0.08 μ M and 0.06 μ M, respectively, and the subtype selectivity to HDAC2 of the class I subfamily and HDAC6 of the class IIb subfamily was up to 180-fold and 30-fold, respectively.
TABLE 2 evaluation of HDACs subtype Selectivity in vitro experiments for representative target Compoundsa
aValues are expressed as the mean of three independent replicates.
EXAMPLE 4 in vitro antiproliferation assay of target Compounds
The experimental principle is as follows: MTT method is mostly adopted to measure the in vitro anti-tumor cell proliferation activity of the small molecular compound. MTT (thiazolyl blue) is 3- (4, 5-dimethylthiazolyl-2) -2,5-diphenyl tetrazolium bromide (3- (4, 5-dimethylthiazolyl-2-yl) -2,5-diphenylterazolium bromide) in a chemical name, is a dye capable of developing color and is commonly used for detecting cell viability. MTT acts with Succinate Dehydrogenase (SDH) in mitochondria in living cells, so that yellow MTT is reduced to generate formazan (formazan) which is a blue-violet substance. The substance is insoluble in water but soluble in DMSO, and after the experiment is finished, the formazan is dissolved by DMSO, and the absorbance is measured at 540nm of an microplate reader. Because the generation amount of the formazan is positively correlated with the number of viable cells in the culture solution, and the absorbance of the formazan solution is directly proportional to the concentration of the formazan, the cell number can be determined by measuring the absorbance of the formazan, and the anti-tumor cell proliferation effect of the compound to be detected is calculated by the absorbance of the formazan.
The experimental steps are as follows: taking the logarithmic growth-period cells, 7000/100 microliter suspension cells and 3500/100 microliter adherent cells per well, inoculating into 96-well cell culture plate, and culturing at 37 deg.C and 5% CO2After culturing for 6h in an incubator, 100 microliters of prepared compounds with different concentration gradients are added, and each concentration is provided with three multiple holes. After 48 or 72h of incubation, 20. mu.l of freshly prepared MTT stock was added to each well at 37 ℃ in 5% CO2And (3) continuing incubation for 4h in the incubator, then centrifuging to remove the culture medium, adding 200 microliters of DMSO into each hole, measuring the absorbance at 540nm, and calculating the inhibitory activity of the compound on the cells according to the value of the absorbance.
S curve fitting calculation is carried out by using Origin software to obtain the half Inhibitory Concentration (IC) of the compound50。
The experimental results (Table 3) show that, similar to the HDAC8 selective inhibitor PCI-34051, compounds 6a, 6b and 6c exhibit strong selective cytotoxicity on T-cell leukemia cell Jurkat, acute lymphoblastic leukemia cell Molt-4 and neuroblastoma cell SK-N-BE- (2). However, this selective cytotoxicity was not observed in the non-selective HDAC inhibitors SAHA and PXD 101. Notably, IC of Compound 6c on Jurkat and Molt-4 cell lines50The values are respectively 7.9 mu M and 6.2 mu M, are equivalent to PCI-34051, and are expected to be further developed into anti-tumor drugs with HDAC8 selectivity.
TABLE 3 in vitro antiproliferation assay of representative Compoundsa
aValues are expressed as the mean of three independent replicates.
bAnd (4) not measuring.
Claims (8)
1. The selective inhibitor of histone deacetylase 8 is a compound with a structure shown in the following structural general formula (I) or (II), and a pharmaceutically acceptable salt thereof:
wherein: n is 0-8; when n is 0, R1Is not phenyl;
R1is phenyl;
R2is-H, -CH3,-CH(CH3)2,
R3Is that
Is in the S configuration.
2. A histone deacetylase 8 selective inhibitor according to claim 1, which is one of the following compounds:
3. the method for preparing the selective inhibitor of histone deacetylase 8 according to claim 1, comprising the steps of: the raw material 1 and methanol are subjected to esterification reaction to generate a compound 2, then the compound 2 is reacted with thionyl chloride to obtain a key intermediate 3, and the intermediate 3 is condensed with compounds 4b-4q respectively to obtain compounds 5b-5 q; finally, reacting the compounds 5b-5q with hydroxylamine potassium in a methanol solution to obtain target compounds 6b-6 q;
the synthetic route is as follows:
reagents and reaction conditions in the above synthetic route: a, methanol, hydrochloric acid and sodium bicarbonate; b, thionyl chloride, N, N-dimethylformamide; c, triethylamine and methylbenzene; d, potassium hydroxide, hydroxylamine hydrochloride and methanol.
4. The method for preparing a selective inhibitor of histone deacetylase 8 according to claim 3, wherein the compound 6b is prepared by a method comprising the steps of:
intermediate 2: 3-Methoxycarbonylbenzenesulfonic acid sodium salt
Refluxing 11.2g of raw material 3-carboxyl sodium benzenesulfonate, 145mL of anhydrous methanol and 34mL of 12mol/L concentrated hydrochloric acid at the normal temperature of 25 ℃ for 4-6h, filtering the reaction solution after the reaction is finished, removing white residues, reacting the filtrate with 10g of anhydrous sodium bicarbonate at the normal temperature of 25 ℃ for 1h, filtering out precipitates, washing the filter residues with a small amount of methanol, combining the filtrates, concentrating, adding 135mL of methanol, filtering twice, and evaporating to dryness to obtain an intermediate 2 for later use; 9.8g of solid is obtained, and the yield is 82%;
intermediate 3: methyl 3-chlorosulfonyl benzoate
Refluxing 10g of the intermediate 2, 180mL of thionyl chloride and 0.2mL of N, N-dimethylformamide at 80 ℃ for 4-6 hours, after the reaction is finished, cooling the reaction solution, evaporating half of the solvent, slowly adding an ice-water mixture into the rest material under the stirring of an ice bath, filtering after complete quenching, and drying by a vacuum diaphragm pump to obtain 8g of a white solid compound with the yield of 85%; the intermediate 3 is unstable and is quickly put into the next reaction;
intermediate 5b methyl-3- (N-benzylsulfonamide) benzoate
Adding 4.2g of raw materials of benzylamine (4b) and triethylamine (5.0g) into 100mL of toluene at the normal temperature of 25 ℃, dissolving the intermediate 3 into 100mL of toluene, filtering, dripping the filtrate into a reaction bottle while stirring, continuing to react for 2-3h at the room temperature of 25 ℃, evaporating part of the solvent after TLC detection reaction is finished, filtering, and leaching the filter cake with water and a small amount of toluene respectively to obtain 4.2g of white solid with the yield of 65%;
target compound 6 b: 3- (N-benzylsulfonamido) -N-hydroxybenzamide
Dissolving 1.5g of the intermediate 5b in 15mL of newly prepared hydroxylamine potassium solution, stirring at room temperature of 25 ℃ for 1-2h, detecting by TLC at any time, stopping the reaction when the reaction is complete and no by-product is generated, adjusting the pH of the reaction solution to 5-6 by using 1M hydrochloric acid aqueous solution, filtering the obtained precipitate, and recrystallizing ethyl acetate to obtain the final product 6b, wherein the white solid is 0.9g, and the yield is 61%.
5. Use of a histone deacetylase 8 selective inhibitor according to claim 1 or 2 for the manufacture of a medicament for the prevention or treatment of a disease associated with abnormal HDAC8 activity or expression.
6. The use according to claim 5, wherein the disease associated with abnormal HDAC8 activity or expression is a hematological neoplasm, solid tumor, viral infection, parasitic disease.
7. The use of claim 6, wherein the hematological neoplasm is T-cell lymphoma; the solid tumor is neuroblastoma; the virus infection is influenza virus infection and human immunodeficiency virus infection; the parasitic disease is schistosomiasis.
8. A pharmaceutical composition suitable for oral or parenteral administration comprising a histone deacetylase 8 selective inhibitor of claim 1 or 2 and one or more pharmaceutically acceptable carriers or excipients.
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