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CN110759891B - SET8 lysine methyltransferase inhibitor and intermediate, preparation method and application thereof - Google Patents

SET8 lysine methyltransferase inhibitor and intermediate, preparation method and application thereof Download PDF

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CN110759891B
CN110759891B CN201911063266.XA CN201911063266A CN110759891B CN 110759891 B CN110759891 B CN 110759891B CN 201911063266 A CN201911063266 A CN 201911063266A CN 110759891 B CN110759891 B CN 110759891B
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lysine methyltransferase
set8
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苏学明
李玮
杨超
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Hainan Yiling Medical Industry & Development Co ltd
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Abstract

The invention provides a SET8 lysine methyltransferase inhibitor and an intermediate, a preparation method and application thereof, wherein the structural general formula of the inhibitor is as follows:

Description

SET8 lysine methyltransferase inhibitor and intermediate, preparation method and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a SET8 lysine methyltransferase inhibitor, an intermediate thereof, a preparation method and application thereof.
Background
Epigenetics is the change in gene expression that is independent of changes in gene sequence, but rather dependent on DNA methylation and chemical modification of histones. Genetic mutations, epigenetic mutations, lifestyle and environmental factors together affect human health and disease. The mutation of the coding epigenetic regulation gene is mainly reflected in four aspects of histone modification change, DNA promoter hypermethylation, DNA extensive hypomethylation and chromatin structure abnormality in the process of tumorigenesis and development. Aberrant methylation of DNA is likely to result in repression of oncogene transcription, genomic instability, and aberrant activation of oncogenes. Mutations in histone modification enzymes in tumors, including histone methylase, demethylase, acetylase mutations, etc., also cause abnormal gene expression and determine tumor cell phenotype. These epigenetic changes are directly related to the growth, immune escape, metastasis, heterogeneity, drug resistance, etc. of tumor cells, even leading to the development of tumors. Therapeutic strategies against epigenetic mutations have become new therapeutic approaches to tumors, and a variety of epigenetic drugs have begun clinical trials. In addition, the treatment strategy also has great application prospect in the aspects of autoimmunity, cardiovascular diseases, nerves, development, aging and the like.
SET8 lysine methyltransferase, also known as SETD8, PR-SET7 and KMT5a, is the only histone H found to be specifically monomethylated4Lysine 20 (histidine H)4lysine20，H4K20) Lysine methyltransferase of (1). SET8 participates in the biological processes of gene transcription regulation, genome stabilization, cell cycle progression and embryonic development in vivo through the methylation modification of histones. At present, a plurality of studies at home and abroad report the action mechanism of SET8 lysine methyltransferase for regulating and controlling tumorigenesis and development. For example, it was shown that SET8 can regulate apoptosis and proliferation of cells by methylation of non-histone Numb. Li et al found that SET8 lysine methyltransferase is a transduction mediator of the Wnt signaling pathway and is important for activating Wnt reporter and target genes in mammalian cells and zebrafish. Chen et al found that the hot miRNA was studied to regulate cell proliferation and cell cycle by directly targeting SET 8. SET8 is not only involved in regulating Wnt target gene expression and influencing Wnt3 a-mediated embryonic development, but also involved in Twist regulation and transformation of epithelial stroma, thereby influencing tumor formation and development. Moreaux et al first demonstrated in 2016 that SET8 is effective against multiple medullaThe importance of tumor cell survival, it was proposed that inhibition of SET8 lysine methyltransferase is a potential strategy for improving the treatment of multiple myeloma. In addition, it has been shown that the expression of SET8 is an independent prognostic marker for gastric cancer patients, and the expression level of SET8 lysine methyltransferase can help patients to determine the risk of having an adverse disease. In conclusion, SET8 lysine methyltransferase plays an important role in the life process of the body, participates in the regulation of the cell cycle, cell proliferation and apoptosis of cells in vivo, and is closely related to the occurrence, growth, metastasis and the like of many tumors. However, few compounds targeting SET8 lysine methyltransferase have been reported, and therefore, it is a difficult point and hot spot of the current research to develop a new class of compounds targeting SET8 lysine methyltransferase.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention provides a SET8 lysine methyltransferase inhibitor with a novel structure, which has obvious inhibitory activity on SET8 lysine methyltransferase and obvious in-vitro antitumor activity, and can be further developed into a targeted antitumor drug targeting SET 8.
One technical scheme of the invention provides a SET8 lysine methyltransferase inhibitor shown in formula I, an optical isomer, a solvate or a pharmaceutically acceptable salt thereof,
Figure BDA0002257806100000031
wherein,
R1independently selected from C1-C3An alkyl group;
R2independently selected from C1-C6Alkyl, substituted C1-C6Alkyl, cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, heterocyclyl, or substituted heterocyclyl; said substitution C1-C6Alkyl is independently substituted with one or more substituents selected from halo, nitro, amino, hydroxy or cyano; said substituted phenyl or substituted benzyl each independentlyIs selected from halogen and C1-C6Alkyl radical, C1-C6Alkoxy, trifluoromethoxy, trifluoromethyl, nitro, amino, hydroxy, C1-C6Alkanoylamino, cyano, C1-C6Alkylamino or C1-C6Substituent substitution of alkoxy acyl; said substituted heterocyclyl is independently substituted with one or more substituents selected from halogen, C1-C6Alkyl radical, C1-C6Alkoxy, trifluoromethoxy, trifluoromethyl, phenyl, benzyl, nitro, amino, hydroxy, C1-C6Alkanoylamino, cyano, C1-C6Alkylamino or C1-C6Substituent substitution of alkoxy acyl;
R3independently selected from C1-C6Alkyl, substituted C1-C6Alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, heterocyclyl or substituted heterocyclyl; said substitution C1-C6Alkyl is independently substituted with one or more substituents selected from halo, nitro, amino, hydroxy or cyano; the substituted phenyl or substituted benzyl is independently substituted by one or more selected from halogen and C1-C6Alkyl radical, C1-C6Alkoxy, trifluoromethoxy, trifluoromethyl, nitro, amino, hydroxy, C1-C6Alkanoylamino, cyano, C1-C6Alkylamino or C1-C6Substituent substitution of alkoxy acyl; said substituted heterocyclyl is independently substituted with one or more substituents selected from halogen, C1-C6Alkyl radical, C1-C6Alkoxy, trifluoromethoxy, trifluoromethyl, phenyl, benzyl, nitro, amino, hydroxy, C1-C6Alkanoylamino, cyano, C1-C6Alkylamino or C1-C6Substituent of alkoxy acyl.
In a further development, R1Is methyl.
In a further development, R2Selected from phenyl, substituted phenyl, benzyl or substituted benzyl; said substituted phenyl or substituted benzyl each independentlyAll the ingredients are selected from C1-C4Alkyl or C1-C4Substituent substitution of alkoxy; preferably, said R is2Is a substituted benzyl group, said substituted benzyl group being substituted with one methoxy group;
preferably, R3Selected from methyl, phenyl, substituted benzyl, heterocyclic or substituted heterocyclic; each of said substituted phenyl or substituted heterocyclyl is independently substituted with one methyl group; said substituted benzyl group being substituted with one methoxy group; said heterocyclyl is selected from pyrazinyl, piperidinyl or pyridinyl, preferably, R3For substituted piperidinyl, the substituted piperidinyl group is substituted with one methyl group.
In a further refinement, the inhibitor is selected from compounds of formula i:
Figure BDA0002257806100000041
another technical scheme of the invention provides an intermediate shown in a formula C for preparing the SET8 lysine methyltransferase inhibitor shown in the formula I,
Figure BDA0002257806100000042
the invention also provides an intermediate shown in a formula II for preparing the SET8 lysine methyltransferase inhibitor shown in the formula I,
Figure BDA0002257806100000043
another embodiment of the present invention provides a method for preparing a SET8 lysine methyltransferase inhibitor represented by formula i, which comprises the following steps:
1) carrying out condensation reaction on carboxylic acid shown in a formula A or acyl chloride shown in a formula D and thioamide shown in a formula B in the presence of a catalyst to generate a thioimide intermediate shown in a formula C;
2) cyclizing a thioimide intermediate shown as a formula C and hydrazine shown as a formula E or a salt thereof under the catalysis of alkali to generate a SET8 lysine methyltransferase inhibitor shown as a formula I;
the reaction equation is as follows:
Figure BDA0002257806100000051
in a further improvement, the catalyst in step 1) is pyridine and 4-dimethylaminopyridine, wherein the molar ratio of the carboxylic acid represented by formula a or the acid chloride represented by formula D to the thioamide, pyridine and 4-dimethylaminopyridine represented by formula B is 1.05-1.2: 1: 0.1-0.2: 0.1-0.3.
In a further improved scheme, the alkali in the step 2) is sodium acetate; the molar ratio of the thioimide intermediate shown in the formula C to the hydrazine shown in the formula E or the salt and the alkali thereof is 1: 1.1-1.3: 1.25-2.6; preferably, the reaction solvent in the step 2) is a mixture of 1: 0.8-2 parts of acetic acid and 1, 4-dioxane.
Another embodiment of the present invention provides a method for preparing a SET8 lysine methyltransferase inhibitor represented by formula i, which comprises the following steps:
1) reacting acetyl chloride or acetic acid with 2- (4-methoxyphenyl) thioacetamide in the presence of a catalyst to prepare an intermediate shown in a formula II;
2) reacting an intermediate shown in a formula II with 4-hydrazino-1 methylpiperidine or salt thereof under the catalysis of alkali to generate a compound shown in a formula I;
the reaction equation is as follows:
Figure BDA0002257806100000061
in a further refinement, the catalyst of step 1) is pyridine and 4-dimethylaminopyridine, wherein the molar ratio of acetyl chloride or acetic acid to 2- (4-methoxyphenyl) thioacetamide, pyridine and 4-dimethylaminopyridine is from 1.05 to 1.2: 1: 0.1-0.2: 0.1-0.3.
In a further improved scheme, the alkali in the step 2) is sodium acetate; the molar ratio of the intermediate shown in the formula II to the 4-hydrazino-1 methylpiperidine or the salt and the alkali thereof is 1: 1.1-1.3: 1.25-2.6.
In a further improved scheme, the reaction solvent in the step 2) is a mixture of the solvents with the volume ratio of 1: 0.8-2 parts of acetic acid and 1, 4-dioxane.
Another embodiment of the present invention provides a pharmaceutical composition comprising a SET8 lysine methyltransferase inhibitor represented by formula i, an optical isomer, solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
The SET8 lysine methyltransferase inhibitor shown in the formula I or the pharmaceutically acceptable salt thereof can also exist in crystals, and the invention comprises any crystal form of the SET8 lysine methyltransferase inhibitor shown in the formula I, an optical isomer, a solvate or an acceptable salt thereof.
The SET8 lysine methyltransferase inhibitor represented by the formula i of the present invention, an optical isomer, solvate or acceptable salt thereof, can be administered by the following routes: topical, intravenous, oral, subcutaneous, etc.
The SET8 lysine methyltransferase inhibitor represented by the formula I, an optical isomer, a solvate or a pharmaceutically acceptable salt thereof can be prepared into various suitable dosage forms according to the administration route.
When administered orally, the compounds of the present invention may be formulated into any orally acceptable dosage form, including but not limited to tablets, capsules, granules. Wherein, the carrier or excipient includes but is not limited to lactose, glucose, microcrystalline cellulose and the like as a filler; carboxymethyl cellulose, povidone, methyl cellulose, etc. as a binder; sodium carboxymethylcellulose, crospovidone, and the like as a disintegrant; magnesium stearate, talc, silica and the like are used as lubricants.
When applied topically to the skin, the compounds of the present invention may be formulated in the form of suitable ointments and the like, carriers or excipients selected from petrolatum, propylene glycol, polyethylene oxide and the like.
The SET8 lysine methyltransferase inhibitor, the optical isomer, the solvate or the pharmaceutically acceptable salt thereof can also be used for medicines in the form of sterile injection preparations, including sterile injection, and can also be in a freeze-dried form. Among the carriers and solvents that may be used are water, isotonic sodium chloride solution and the like.
The invention also provides application of the SET8 lysine methyltransferase inhibitor shown in the formula I, an optical isomer, a solvate or a pharmaceutically acceptable salt thereof in preparing a medicament for treating tumors. In particular to application of the compound in preparing a targeted antitumor drug targeting SET 8. Such tumors include, but are not limited to, liver cancer, glioma, colorectal cancer, gastric cancer, breast cancer, melanoma, lung cancer, prostate cancer, pancreatic cancer, bladder cancer, kidney cancer, multiple myeloma, cervical cancer, and the like.
The invention synthesizes and identifies a targeted SET8 lysine methyltransferase inhibitor for the first time. The in vitro activity evaluation results show that: the inhibitor has obvious inhibitory activity on SET8 lysine methyltransferase, has obvious in-vitro anti-tumor activity and low toxicity, and can be further developed into a targeted anti-tumor medicament taking SET8 lysine methyltransferase as a target.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available. And when the dosage or the yield of each substance is calculated, part of the data is carried out.
EXAMPLE 1 preparation of N- (2- (4-methoxyphenyl) thioacetyl) acetamide (formula II)
Figure BDA0002257806100000081
The starting materials, 2- (4-methoxyphenyl) thioacetamide (1.0mmol, 181mg), 4-dimethylaminopyridine (0.1mmol, 12mg), and pyridine (0.15mmol, 12mg) were dissolved in 8mL of dry acetonitrile, and acetyl chloride (1.1mmol, 86mg) was added dropwise to the above system under nitrogen protection in a room-temperature water bath, followed by reaction at room temperature for 1 day. The reaction mixture was diluted with 50mL of ethyl acetate, washed with 20mL of water and a saturated ammonium chloride solution in this order, dried over anhydrous sodium sulfate, and the reaction mixture was concentrated and then subjected to column chromatography [ V (petroleum ether): V (ethyl acetate) ═ 8:1 to 6:1], to give 38mg of pale yellow oily substance II with a yield of 17%.
EXAMPLE 2 preparation of 4- (3- (4-methoxybenzyl) -5-methyl-1H-1, 2, 4-triazol-1-yl) -1-methylpiperidine (formula I)
Figure BDA0002257806100000082
After the compound of formula II (0.16mmol, 36mg), 4-hydrazino-1-methylpiperidine (0.19mmol, 25mg) and sodium acetate (0.2mmol, 16mg) were dissolved in a mixed solvent of 1mL of acetic acid and 1mL of 1, 4-dioxane in this order, they were sealed and then reacted with heating at 80 ℃ until the reaction of formula II was completed. The reaction mixture was diluted with 20mL of ethyl acetate, washed with 20mL of a saturated sodium carbonate solution and a saturated sodium chloride solution in this order, dried over anhydrous sodium sulfate, and concentrated, followed by column chromatography [ V (dichloromethane solution of ammonia): V (methanol): 25:1-20:1] to obtain 16mg of a pale yellow oily substance I with a yield of 33%.
1H NMR(400MHz,CDCl3):δ7.25(d,J＝8.7Hz,2H),6.82(d,J＝8.6Hz,2H),4.03–3.88(m,3H),3.77(s,3H),3.05(s,2H),2.39(s,3H),2.36(m,3H),2.31–2.11(m,4H),1.91(s,2H).13C NMR(400MHz,CDCl3):δ161.8,158.2,151.4,130.7,129.9,113.9,55.4,54.7,46.1,34.0,31.6,29.8,12.3.ESI-MS:m/z 301.1[M+H]+。
Experimental example 1 in vitro inhibition of lysine methyltransferase SET8 Activity by Compounds of formula I
The steps for activity detection were performed entirely with Cayman SET8 methyltransferase inhibitor screening kit. Briefly, the reagents of the kit were added to a 96-well plate to be tested according to the following table.
Figure BDA0002257806100000091
After that, 10. mu.L of SET8 protein was added to each well and the reaction was started. After incubation at 37 ℃ for 10 minutes, the fluorescence intensity (A) values were determined at an excitation wavelength of 535nm and an absorption wavelength of 590 nm. The inhibition of the compound was calculated according to the following formula: inhibition ratio%Is normal-ASample (I))/)Is normal*100％。
The results show that the compound of the formula I has a remarkable inhibition effect on lysine methyltransferase (the inhibition rate is 76.9%).
EXAMPLE 2 study of antitumor Activity of Compound of formula I
1. The experimental method comprises the following steps: respectively culturing glioma cell strain SH-SY5Y, colorectal cancer cell strain SW480 and liver cancer cell strain HepG2 in RPMI-1640 culture medium containing 10% calf serum at 37 deg.C and 5% CO2Culturing in an incubator. The CCK-9 method is adopted to carry out cell proliferation inhibition test, and the main operations are as follows: collecting tumor cell strain in logarithmic growth phase, digesting with 0.25% trypsin, and concocting with 10% newborn calf serum RPMI-1640 culture solution to 6 × 104Cell suspension per mL, seeded in 96-well plates at 100 μ L per well. At 37 ℃ 5% CO2Culturing for 12h under saturated humidity condition. After their adherence, the culture supernatants were aspirated from the wells, and a sample solution prepared with RPMI-1640 medium containing 1% calf serum was added to each well so that the final concentrations of the samples were 100. mu.M, 30. mu.M, 10. mu.M, 3. mu.M, 1. mu.M and 0.3. mu.M, respectively. Each concentration was 3 wells in parallel, and after further culturing for 48h, 10. mu.L of CCK-8 solution (Dalian Meiren, MA0218) was added to each well at 37 ℃ with 5% CO2Incubation was continued for 4h under these conditions. 470nm is selected on an enzyme-linked immunosorbent assay instrument, the light absorption value of each well is measured, meanwhile, a blank group (only culture solution containing cells is added) and a control group (the culture solution replaces drugs) are arranged, and the cell proliferation inhibition rate is calculated. Inhibition (%) × (1 — average OD value of 3 wells in experimental group/average OD value of 3 wells in control group) × 100%. The inhibition rate is used as the ordinate to make the regression curve, and the calculation is carried outSample IC50The value is obtained. And performing data processing and statistical analysis by using Graphpad prism 7.0 software.
2. Experimental results on antitumor Activity
IC of compound of formula I on glioma cell line SH-SY5Y, colorectal cancer cell line SW480, liver cancer cell line HepG250And IC% at 100. mu.M are shown in Table 1.
TABLE 1 antitumor Activity of Compounds of formula I
Figure BDA0002257806100000101
As can be seen from the table, the compound of formula I shows good tumor cell proliferation inhibition activity on the liver cancer cell line HepG2, colorectal cancer cell line SW480 and glioma cell line SH-SY 5Y.

Claims (10)

1. A SET8 lysine methyltransferase inhibitor of formula I, or a pharmaceutically acceptable salt thereof,
Figure FDA0003416733500000011
wherein,
R1independently selected from C1-C3An alkyl group; r2Is a substituted benzyl group independently substituted with one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy;
R3for substituted piperidinyl, the substituted piperidinyl group is substituted with one methyl group.
2. The SET8 lysine methyltransferase inhibitor of formula i of claim 1, wherein R is an alkyl group, or a pharmaceutically acceptable salt thereof1Is methyl.
3. A SET8 lysine methyltransferase inhibitor of formula i, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein the inhibitor is selected from compounds of formula i:
Figure FDA0003416733500000012
4. an intermediate shown in formula C for preparing a SET8 lysine methyltransferase inhibitor shown in formula I,
Figure FDA0003416733500000021
R1independently selected from C1-C3An alkyl group; r2Is a substituted benzyl group, which is independently substituted with one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy.
5. A method of preparing a SET8 lysine methyltransferase inhibitor of formula one of claim 1, comprising the steps of:
1) carrying out condensation reaction on carboxylic acid shown in a formula A or acyl chloride shown in a formula D and thioamide shown in a formula B in the presence of a catalyst to generate a thioimide intermediate shown in a formula C;
2) cyclizing a thioimide intermediate shown as a formula C and hydrazine shown as a formula E or a salt thereof under the catalysis of alkali to generate a SET8 lysine methyltransferase inhibitor shown as a formula I;
the reaction equation is as follows:
Figure FDA0003416733500000022
6. the method of claim 4, wherein the catalyst of step 1) is pyridine and 4-dimethylaminopyridine, and wherein the molar ratio of the carboxylic acid of formula A or the acid chloride of formula D to the thioamide of formula B, pyridine and 4-dimethylaminopyridine is from 1.05 to 1.2: 1: 0.1-0.2: 0.1-0.3.
7. The method according to claim 4, wherein the base in step 2) is sodium acetate; the molar ratio of the thioimide intermediate shown in the formula C to the hydrazine shown in the formula E or the salt and the alkali thereof is 1: 1.1-1.3: 1.25-2.6.
8. The method according to claim 7, wherein the reaction solvent of step 2) is a mixture of solvents in a volume ratio of 1: 0.8-2 parts of acetic acid and 1, 4-dioxane.
9. A pharmaceutical composition comprising a SET8 lysine methyltransferase inhibitor of formula one of claims 1-3, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
10. Use of a SET8 lysine methyltransferase inhibitor of formula one of claims 1-3, a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a tumor associated with SET8 lysine methyltransferase.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105198828A (en) * 2015-08-26 2015-12-30 中国药科大学 Heterocyclic anthracene ketone histone methyltransferase inhibitor and medical application thereof
WO2017140743A1 (en) * 2016-02-16 2017-08-24 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of multiple myeloma
CN109293599A (en) * 2018-11-29 2019-02-01 福建医科大学 A kind of method for synthesizing benzothiazole by microwave irradiation of benzothioamide compounds in aqueous phase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105198828A (en) * 2015-08-26 2015-12-30 中国药科大学 Heterocyclic anthracene ketone histone methyltransferase inhibitor and medical application thereof
WO2017140743A1 (en) * 2016-02-16 2017-08-24 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of multiple myeloma
CN109293599A (en) * 2018-11-29 2019-02-01 福建医科大学 A kind of method for synthesizing benzothiazole by microwave irradiation of benzothioamide compounds in aqueous phase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Investigations on synthesis and structure elucidation of novel [1,2,4]triazolo[1,2-a]pyridazine-1-thiones and their inhibitory activity against inducible nitric oxide synthase";Ulrike Schulz等;《Bioorganic & Medicinal Chemistry》;20130901;第21卷(第17期);第5519页 *

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