CN116239610A - Pyrimidine derivative, preparation method thereof and application thereof in preparation of antitumor drugs - Google Patents
Pyrimidine derivative, preparation method thereof and application thereof in preparation of antitumor drugs Download PDFInfo
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- CN116239610A CN116239610A CN202310154871.8A CN202310154871A CN116239610A CN 116239610 A CN116239610 A CN 116239610A CN 202310154871 A CN202310154871 A CN 202310154871A CN 116239610 A CN116239610 A CN 116239610A
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- Prior art keywords
- pyrimidine derivative
- cancer
- acid
- pharmaceutically acceptable
- dna
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- -1 cyano, amino Chemical group 0.000 claims abstract description 7
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 150000002367 halogens Chemical class 0.000 claims abstract description 4
- 125000001424 substituent group Chemical group 0.000 claims abstract description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
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- 150000003839 salts Chemical class 0.000 claims description 14
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- 229950010773 pidilizumab Drugs 0.000 description 1
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- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and discloses a pyrimidine derivative, a preparation method thereof and application thereof in preparing antitumor drugs. The structural general formula of the pyrimidine derivative is shown as (I); wherein X, Y and Z are each independently selected from CH, N; r is R 1 Selected from the following substituted or unsubstituted: c (C) 5 ‑C 12 Saturated or unsaturated carboheterocyclyl, C 5 ‑C 12 Saturated or unsaturated spiroheterocyclyl, C 5 ‑C 12 Saturated or unsaturated fused heterocyclic groups, wherein the substituents refer to one or more groups selected from the group consisting of: hydroxy, halogen, cyano, amino. The pyrimidine derivative has good DNA-PK inhibition activity and pharmacokinetics stability, can effectively inhibit tumor growth, and synergistically enhance the effects of chemotherapy and radiotherapy;
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a pyrimidine derivative, a preparation method thereof and application thereof in preparing antitumor drugs.
Background
At present, clinical researches find that many tumor patients resist radiotherapy and chemotherapy, so that the search of low-toxicity high-efficiency targeted drugs and radiotherapy and chemotherapy sensitizers has important significance for tumor treatment formulas. The main mechanism of action of DNA damaging chemotherapeutics (e.g. bleomycin, topoisomerase II inhibitors such as etoposide and doxorubicin) and radiotherapy commonly used in tumor treatment at present is to cause lethal double strand break of DNA molecules, thereby inducing death of tumor cells. However, the existence of a DNA damage repair system in tumor cells, such as DNA-dependent protein kinase (DNA-dependent protein kinase, DNA-PK), can repair such breaks, thereby improving the viability of tumor cells, which is one of the mechanisms of tumor cells against chemoradiotherapy. Accordingly, the sensitivity of tumor cells to radiotherapy and chemotherapy can be improved only by inhibiting the repair of the DNA damage.
DNA-PK is a class of serine/threonine protein kinases that participate in and determine the overall process of connecting non-homologous ends to DNA damage repair pathways. DNA-PK is a complex consisting of catalytic subunits DNA-PKcs and Ku70/80 heterodimers, wherein the Ku70/80 heterodimers recognize DNA breaks (DSBs) and recruit activated kinase subunits DNA-PKcs that direct Artemis binding to the site of injury, followed by recruitment and binding of the XRCC4/DNA-Ligase IV complex by the activated DNA-PKcs and finally localization and ligation of broken DNA double stranded ends by DNA-Ligase IV, thereby completing the entire repair process. Research shows that high expression of DNA-PK is found in tumor tissues treated by radiotherapy and chemotherapy, and the increase of the activity of DNA-PKcs enhances the repair of damaged DNA to a certain extent, prevents death of tumor cells and leads to tolerance to radiotherapy and chemotherapy. In addition, cells surviving tumor tissues after radiotherapy and chemotherapy are often cells with high DNA-PKcs activity insensitive to treatment, which is also the reason of poor curative effect and poor prognosis. The DNA-PK inhibitor can inhibit the activity of DNA-PKcs by being combined with a chemoradiotherapy medicament, thereby greatly reducing the DNA repair of tumors and inducing cells to enter an apoptosis program so as to achieve better treatment effect.
Accordingly, the present invention contemplates novel compounds having DNA-PK (DNA-dependent protein kinase) inhibiting function for better application in the treatment of tumors.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems in the prior art described above. Therefore, the invention provides a pyrimidine derivative, a preparation method thereof and application thereof in preparing antitumor drugs. The pyrimidine derivative has good DNA-PK inhibition activity and pharmacokinetics stability, can effectively inhibit tumor growth, and synergistically enhances the effects of chemotherapy and radiotherapy.
The invention provides a pyrimidine derivative or pharmaceutically acceptable salt and stereoisomer thereof, wherein the structural general formula of the pyrimidine derivative is shown as (I):
wherein X, Y and Z are each independently selected from CH, N; r is R 1 Selected from the following substituted or unsubstituted: c (C) 5 -C 12 Saturated or unsaturated carboheterocyclyl, C 5 -C 12 Saturated or unsaturated spiroheterocyclyl, C 5 -C 12 Saturated or unsaturated fused heterocyclic groups, wherein the substituents refer to one or more groups selected from the group consisting of: hydroxy, halogen, cyano, amino.
The pharmaceutically acceptable salts of the pyrimidine derivatives of the invention may be: acid addition salts with acids which carry nitrogen atoms in the chain or ring, acid addition salts with inorganic acids (e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, resulfuric acid, phosphoric acid or nitric acid), acid addition salts with organic acids (e.g. formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) -benzoic acid, camphoric acid, cinnamic acid, cyclopentanic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, maleic acid, fumaric acid, D-gluconic acid, heptonic acid, glyceric acid, salicylic acid, sulfuric acid, semi-sulfuric acid or sulfuric acid.
Preferably, said R 1 Selected from the following groups:
preferably, the pyrimidine derivative is selected from the following compounds:
the invention also provides a preparation method of the pyrimidine derivative, and the synthetic method is as follows:
in the above synthesis method, the first step is to use R for hydrogen in Z 1 The group is substituted, and the second step is to substitute on chlorine atom to prepare the final pyrimidine derivative.
The invention also provides application of the pyrimidine derivative or the pharmaceutically acceptable salt and stereoisomer thereof in preparing antitumor drugs. The pyrimidine derivative or pharmaceutically acceptable salt and stereoisomer thereof has the effect of inhibiting DNA-PK (DNA dependent protein kinase), and can be used for preventing and/or treating DNA-PK mediated diseases such as tumor.
Preferably, the tumor is selected from colon cancer, lung cancer, ovarian cancer, endometrial cancer, pancreatic cancer, head and neck cancer, esophageal cancer, breast cancer, colorectal cancer, lymphoma, leukemia, synovial sarcoma, melanoma, liver cancer, gastric cancer, bladder cancer, squamous cell carcinoma, medulloblastoma, renal cancer or glioma.
The invention provides an antitumor drug, which comprises the pyrimidine derivative or pharmaceutically acceptable salt and stereoisomer thereof as a first therapeutic agent. The antitumor drug can be used in combination with chemotherapy or radiotherapy (such as X-ray, gamma ray, and radiopharmaceuticals), and has good synergistic anticancer effect.
Preferably, the antitumor drug further comprises pharmaceutically acceptable auxiliary materials.
More preferably, the pharmaceutically acceptable adjuvant comprises cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyalcohols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifying agent
At least one of a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizing agent, an antioxidant, a preservative, or water.
Preferably, the antitumor drug further comprises a second therapeutic agent, the second therapeutic agent is selected from the group consisting of oxidastine, lu Kapa, nilapamide, methotrexate, capecitabine, gemcitabine, doxifluridine, pemetrexed disodium, pazopanib, imatinib, erlotinib, lapatinib, gefitinib, vandetanib, herceptin, bevacizumab, rituximab, trastuzumab, paclitaxel, vinorelbine, docetaxel, doxorubicin, hydroxycamptothecin, mitomycin, epirubicin, pirarubicin, bleomycin, letrozole, tamoxifen, fulvestrant, trastulin, fluzamide, leuprolide, azalide, busulfan, cyclophosphamide, mitoxantine at least one of carmustine, nimustine, semustine, nitrogen mustard, horse flange, onconine, carboplatin, cisplatin, oxaliplatin, carboplatin, topotecan, camptothecine, topotecan, everolimus, siromosi, tertiarycancer aptamer, 6-mercaptopurine, 6-thioguanine, azathioprine, mycomycin D, daunorubicin, doxorubicin, mitoxantrone, bleomycin, pramipexole or aminoglutethimide, nivolumab, pembrolizumab, ipilimumab, bevacizumab, dulvacizumab, at Zhu Shankang (atezolizumab), and Pidilizumab. The second therapeutic agent with anticancer effect can be added into the antitumor drug to inhibit tumor growth more effectively.
Unless otherwise indicated, the following terms appearing in the present invention have the following meanings:
the term "halogen", "halo" refers to fluorine, chlorine, bromine or iodine.
The term "carboheterocyclyl" refers to a cyclic alkyl group containing a specified number of heteroatoms including carbon atoms and 1, 2, 3 or 4 heteroatoms, especially nitrogen, oxygen and/or sulfur, wherein the heteroatoms are the same or different, which may be monocyclic (e.g., C 5 -C 10 Cycloalkyl) may also be in the form of a bicyclic or tricyclic ring, such as bridged, fused or spiro ring (e.g., C 5 -C 10 Bridged cycloalkyl, C 5 -C 10 Condensed ring alkyl, C 5 -C 10 Spirocycloalkyl) forms.
The term "substituted" means that one or more hydrogens on the designated atom are replaced with a selection from the indicated groups, provided that: no more than the normal valency of the atom specified in the prior art, and this substitution results in a stable compound. Substituents and/or variables may be combined so long as such combination can result in a stable compound.
Compared with the prior art, the invention has the following beneficial effects:
(1) The pyrimidine derivative has excellent DNA-PK inhibition effect, shows good pharmacokinetic property in organisms, and can synergistically enhance the effects of chemotherapy and radiotherapy, thereby playing a good role in resisting tumor.
(2) The pyrimidine derivative has the advantages of short synthetic route, simple preparation process and easy mass industrial production.
Detailed Description
In order to make the technical solutions of the present invention more apparent to those skilled in the art, the following examples will be presented. It should be noted that the following embodiments are only preferred embodiments of the present invention, and the scope of the present invention is not limited to the following embodiments, and any modifications, substitutions, and combinations made without departing from the spirit and principles of the present invention are included in the scope of the present invention.
The starting materials, reagents or apparatus used in the following examples are all available from conventional commercial sources or may be obtained by methods known in the art unless otherwise specified.
Example 1
This example provides a pyrimidine derivative T-01, the synthetic route of which is shown below:
the preparation method comprises the following steps:
(1) To the reaction flask were added compound 1 (350 mg), tetrahydrofuran (10 mL), triphenylphosphine (972 mg) and compound 2 (241 mg), stirred and cooled to 0 ℃, diisopropyl azodicarboxylate DIAD (749 mg) was added dropwise, and after the addition, the mixture was heated to 70 ℃ and reacted for 16 hours, cooled, concentrated, purified by column chromatography on silica gel, ethyl acetate: petroleum ether system elution gives compound 3 (373 mg) as a pale yellow solid. LCMS: (MS-ESI, M/z) [ M+H ]] + ＝267。
(2) To the reaction flask were added compound 3 (25 mg), compound 4 (14 mg), palladium acetate (5 mg), cesium carbonate (61 mg), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthenes Xanthos (6 mg) and dioxane (2 mL), and the mixture was stirred and heated to 100℃under nitrogen protection, reacted for 2 hours, cooled to 25℃and filtered, and the filtrate was subjected to reverse phase preparative liquid phase HPLC [ Waters Sunfire C18,10 μm,
column,gradient 10-95％ B(solvent A,0.02％ TFA in water；solvent B,CH 3 CN)]purification gave white compound T-01 (2 mg).
Pyrimidine derivative T-01 was detected as follows:
LCMS：(MS-ESI,m/z):[M+H] + ＝379。 1 H NMR：(400MHz,DMSO-d6,ppm):δ8.92(s,1H),
8.87(s,1H),8.78(d,J＝1.8Hz,1H),8.73(d,J＝1.8Hz,1H),8.64(s,1H),8.41(s,1H),4.61(s,1H),3.98(s,2H),3.56(s,2H),2.55(s,3H),2.21(d,J＝7.8Hz,2H),2.00(s,2H)。
example 2
This example provides a pyrimidine derivative T-02, which is synthesized in substantially the same manner as in example 1, except that:
by using
Alternative embodiment 1 +.>
Thereby preparing pyrimidine derivative->
Pyrimidine derivative T-02 was detected as follows:
LCMS：(MS-ESI,m/z):[M+H] + ＝349。 1 H NMR：(400MHz,DMSO-d6,ppm):δ8.81(s,1H),
8.72(dd,J＝4.2,1.6Hz,1H),8.47(s,1H),8.34(s,1H),8.18(d,J＝7.7Hz,1H),7.84(s,1H),4.60(dd,J＝8.0,3.9Hz,1H),4.00(dd,J＝11.4,4.1Hz,2H),3.48(d,J＝11.9Hz,2H),2.51(s,3H),2.29(dd,J＝12.3,4.3Hz,2H)。
example 3
This example provides a pyrimidine derivative T-03, which is synthesized in substantially the same manner as in example 1, except that:
by using
Alternative embodiment 1 +.>
Adopts->
Alternative embodiment 1 +.>
Thereby preparing pyrimidine derivative->
Pyrimidine derivative T-03 was detected as follows:
LCMS：(MS-ESI,m/z):[M+H] + ＝352。 1 H NMR：(400MHz,DMSO-d6,ppm):δ8.92(s,1H),
8.87(s,1H),8.64(s,1H),8.41(s,1H),7.90(s,1H),4.61(s,1H),3.98(s,2H),3.56(s,2H),2.55(s,3H),2.21(d,J＝7.8Hz,2H),2.00(s,2H)。
example 4
This example provides a pyrimidine derivative T-04, which is synthesized in substantially the same manner as in example 1, except that:
by using
Alternative embodiment 1 +.>
Adopts->
Alternative embodiment 1 +.>
Thereby preparing pyrimidine derivative->
Pyrimidine derivative T-04 was detected as follows:
LCMS：(MS-ESI,m/z):[M+H] + ＝350。 1 H NMR：(400MHz,DMSO-d6,ppm):δ9.14(s,1H),
8.92(s,1H),8.36(s,1H),8.35(s,1H),7.70(s,1H),4.56-4.53(m,1H),3.99-3.95(m,2H),3.47(s,2H),2.37(s,3H),2.17(dd,J＝12.1,4.1Hz,1H),1.96(d,J＝10.1Hz,1H)。
example 5
This example provides a pyrimidine derivative T-05, which is synthesized in substantially the same manner as in example 1, except that:
by using
Alternative embodiment 1 +.>
Thus preparing pyrimidine derivative
Pyrimidine derivative T-05 was detected as follows:
LCMS：(MS-ESI,m/z):[M+H] + ＝380。 1 H NMR：(400MHz,DMSO-d6,ppm):δ9.11(s,1H),
8.72(s,1H),8.31(s,1H),8.05(s,1H),7.39(s,1H),4.61(s,1H),3.98(s,2H),3.56(s,2H),2.55(s,3H),2.21(d,J＝7.8Hz,2H),2.00(s,2H)。
example 6
This example provides a pyrimidine derivative T-06, which is synthesized in substantially the same manner as in example 1, except that:
by using
Alternative embodiment 1 +.>
Adopts->
Alternative embodiment 1 +.>
Thereby preparing pyrimidine derivative->
Pyrimidine derivative T-06 was detected as follows:
LCMS：(MS-ESI,m/z):[M+H] + ＝392。 1 H NMR：(400MHz,DMSO-d6,ppm):δ9.04(s,1H),
8.82(s,1H),8.16(s,1H),7.95(s,1H),7.65(s,1H),4.57-4.51(m,1H),3.91-3.85(m,2H),3.47(m,2H),2.51(s,3H),2.31(m,2H),2.16(dd,J＝11.3,3.1Hz,2H),1.46(m,J＝10.1Hz,4H).
product effect test
1. In vitro detection of enzymatic Activity assay for DNA-PK inhibitors
The inhibition of DNA-PK by compounds was examined using a DNA-PK kinase kit, and the specific procedures were as follows:
1. melting DNA-dependent protein Kinase, DNA-dependent protein Kinase peptide substrate (10 mg/mL), ATP (contained in ADP-Glo Kinase Assay kit) on ice, and placing the above reagents on ice all the time in the experimental process, wherein the unused stock solution needs to be split-packed and stored, so as to avoid repeated freeze thawing;
2. taking pyrimidine derivatives T-01 to T-06 in examples 1-6 as samples to be tested, taking DNA-PK inhibitor (code AZD 7648) of the company of Ashikan as a positive sample, dissolving by using 1 Xbuffer (assay buffer) containing 5% DMSO, and adding 1 mu L/well into a microplate; blank control 1 Xbuffer (assay buffer) was added to the microplate at 1. Mu.L/well; the specific structure of the DNA-PK inhibitor AZD7648 is shown below:
after complete solubilization of the DNA-dependent protein kinase, the enzyme solution was added to the microplate at 2. Mu.L/well after dilution to 2.5 unit/. Mu.L with 1 Xbuffer, and the 1 Xbuffer was added to the blank wells at 2. Mu.L/well, and the microplate was centrifuged at 1000 rpm for 1 minute.
4. Preparing a mixed solution of a substrate and ATP: diluting the DNA-dependent protein kinase peptide substrate (10 mg/mL) with 1 Xbuffer solution, adding ATP to make the concentration of ATP 125 mu M and the concentration of the DNA-dependent protein kinase peptide substrate 0.5 mu g/mu L, and placing the mixed solution of the substrate and ATP on ice for later use;
5. adding a mixed solution of a substrate and ATP into a microplate at a concentration of 2 mu L/well, centrifuging the microplate at 1000 revolutions for 1 minute, wherein the concentration of the DNA-dependent protein kinase peptide substrate is 0.2 mu g/mu L, the concentration of ATP is 50 mu M, and the concentration of DMSO is 1%; sealing the membrane by a microplate, and incubating at 25 ℃ for 60min;
ADP-GloTM reagent and Kinase Detection require equilibration to room temperature prior to use;
after the incubation is finished, adding an ADP-GloTM reagent into a microplate at a concentration of 5 mu L/hole, centrifuging the microplate at 1000 revolutions for 1 minute, sealing the microplate, and then placing the microplate at 25 ℃ for incubation for 40 minutes;
7. after the incubation is finished, adding Kinase Detection into a microplate at 10 mu L/hole, centrifuging the microplate at 1000 revolutions for 1 minute, sealing the microplate, and then placing the microplate at 25 ℃ for incubation for 30 minutes; after the incubation is finished, luminescence detection is performed by using Nivo, and Luminescence value (RLU) is read;
8. and (3) calculating the enzyme activity rate:
enzyme activity% = (RLU (sample) -RLU (blank))/(RLU (1% dmso) -RLU (blank))) ×100%
The results of the binding force experiment between the DNA-PK inhibitor and the protein are shown in Table 1.
TABLE 1 determination of enzymatic Activity of DNA-PK inhibitors
As is clear from Table 1, the pyrimidine derivatives in examples 1 to 6 of the present invention all have the effect of inhibiting DNA-PK kinase, and a part of the pyrimidine derivatives have the activity equivalent to or better than AZD7648.
2. MTT cytotoxicity test (LoVo cell)
The inhibition of LoVo cell (human colon cancer cell) growth by pyrimidine derivatives of examples 1-6 was determined using MTT assay. The experimental procedure was as follows:
LoVo cells were seeded at about 5000 cells/well in 96-well plates and incubated at 37℃for 24h. The pyrimidine derivatives of examples 1 to 6 were diluted in a serum-free medium and then added to 96-well plates at a dose of 50. Mu.L/well. After 48h of drug treatment, 10. Mu.L MTT solution was added to each well and incubated for 4h at 37 ℃. The supernatant was carefully aspirated, 150 μl DMSO was added to each well, and gently shaken to dissolve the formazan. OD value was measured with an ELISA reader at 570nm of detection wavelength within 1 h. Analytical calculations were performed using Graphpad Prism software. Inhibition ratio = (100-OD Sample of /OD Solvent(s) ) X100%, where OD Sample of For absorbance values detected after addition of each concentration of the test substance, OD Solvent(s) Absorbance values detected for vehicle group (vehicle added, no test substance added). The positive control was a DNA-PK inhibitor from the company Aspirikang, code AZD7648. The results of the cytotoxicity test of each compound on LoVo cells are shown in table 2.
Table 2 results of the cytotoxicity test of each Compound against LoVo cells
As shown in Table 2, the pyrimidine derivatives in examples 1-6 have a good inhibitory effect on human colon cancer cells, and exhibit a good anti-colonic tumor effect.
3. MTT cytotoxicity test (U373 cell)
The inhibition of the growth of U373 cancer cells (U373 astrocytes) by pyrimidine derivatives of examples 1-6 was determined using the MTT assay. The experimental procedure was as follows:
LoVo cells were seeded at about 5000 cells/well in 96-well plates and incubated at 37℃for 24h. The pyrimidine derivatives of examples 1 to 6 were diluted in a serum-free medium and then added to 96-well plates at a dose of 50. Mu.L/well. After 48h of drug treatment, 10. Mu.L MTT solution was added to each well and incubated for 4h at 37 ℃. The supernatant was carefully aspirated and 150. Mu.L of DMS was added to each wellO, gently shake to dissolve formazan. OD value was measured with an ELISA reader at 570nm of detection wavelength within 1 h. Analytical calculations were performed using Graphpad Prism software. Inhibition ratio = (100-OD Sample of /OD Solvent(s) ) X100%, where OD Sample of For absorbance values detected after addition of each concentration of the test substance, OD Solvent(s) Absorbance values detected for vehicle group (vehicle added, no test substance added). The positive control was a DNA-PK inhibitor from the company Aspirikang, code AZD7648. The results of the cytotoxicity test on U373 cancer cells of each compound are shown in table 3.
Table 3 results of the cytotoxicity test of each Compound against LoVo cells
As shown in Table 2, the pyrimidine derivatives in examples 1 to 6 have a good inhibitory effect on U373 astroglioma cells, and exhibit a good glioma-resistant effect.
4. Effects of DNA-PK inhibitors and irradiation combinations on U373 cancer cells (U373 astroglioma cells)
It is known that the combination of the DNA-PK inhibitor and the irradiation may exert the irradiation sensitization effect, so that the pyrimidine derivatives in examples 1 to 6 are combined with the irradiation and the inhibition effect on U373 cancer cells (U373 astroglioma cells) is examined, and the experimental method and steps are as follows:
cell line U373 at 37℃with 5% CO 2 Is cultured in an incubator, and cells in a logarithmic growth phase are periodically passaged and plated. U373 was inoculated at 5000 cells/well into 96-well plates and incubated at 37℃for 24h. The pyrimidine derivatives of examples 1 to 6 were diluted in a serum-free medium and then added to 96-well plates at a dose of 50. Mu.L/well. After the dosing procedure was completed, the 96-well plate was placed in an incubator, 1 hour later, placed in a RadSource 2000X-ray instrument, irradiated at an irradiation intensity of 2.4Gy, and the 96-well cell plate was returned to the incubator for 9 days after the irradiation was completed. Cell activity assay using CellTiter-Glo luminescence method, the following formula was used to calculate assay compoundsInhibition Rate (IR): IR (%) = (1- (RLU) Compounds of formula (I) –RLU Blank control )/(RLU Vehicle control –RLU Blank control ) Inhibition IC of 100% of the resulting compound 50 The results are shown in Table 4.
TABLE 4 inhibition Activity of DNA-PK inhibitors and irradiation combinations on U373 cell growth
As shown in Table 4, the pyrimidine derivatives of examples 1 to 6 also have a stronger inhibitory effect on U373 cancer cells when used in combination with irradiation, and the combination of both shows a good synergistic effect, as compared with AZD7648.
5. In vivo pharmacokinetics in rats
Healthy SD rats were randomly divided into 6 groups of 3 each. Plasma kinetics studies were performed in each group of rats with a single intragastric administration of the pyrimidine derivative of example 5, the pyrimidine derivative of example 6, and AZD7648. The plasma dynamics characteristics of the drug in the rat body are analyzed, including the exposure degree, absorption characteristics and the like of the original drug.
The oral administration dose is 5mg/kg, blood is collected at 7.5min, 15min, 30min, 1h, 2h, 4h, 8h and 24h respectively, EDTA is used as anticoagulant for whole blood collection, centrifugation is carried out at 4 ℃ and 10000 revolutions per minute for 1 min, blood plasma is separated in 1h, the blood is preserved at-20 ℃ to be detected, and the blood collection to centrifugation process is operated under ice bath condition. Sucking 30 mu L of plasma sample to be detected, adding 300 mu L of acetonitrile solution containing an internal standard (20 ng/mL of apixaban), shaking and uniformly mixing for 5 minutes, centrifuging at 13000rpm for 10 minutes, taking 80 mu L of supernatant, adding 80 mu L of ultrapure water for dilution, uniformly mixing, sucking 2 mu L of the supernatant for liquid chromatography-mass spectrometry analysis and determination, and calculating the drug generation parameters. The test results are shown in Table 5.
Each of table 5 represents the pharmacokinetic parameters of a compound
As can be seen from Table 5, the pyrimidine compounds of examples 5-6 have good absorption in the drug generation and have significant pharmacokinetic advantages.
While the embodiments of the present invention have been described in detail, the present invention is not limited to the above embodiments, and various changes can be made without departing from the spirit of the present invention within the knowledge of those skilled in the art. Furthermore, embodiments of the invention and features of the embodiments may be combined with each other without conflict.
Claims (10)
1. A pyrimidine derivative or pharmaceutically acceptable salts and stereoisomers thereof, which is characterized in that the pyrimidine derivative has a structural general formula shown in (I):
wherein X, Y and Z are each independently selected from CH, N; r is R 1 Selected from the following substituted or unsubstituted: c (C) 5 -C 12 Saturated or unsaturated carboheterocyclyl, C 5 -C 12 Saturated or unsaturated spiroheterocyclyl, C 5 -C 12 Saturated or unsaturated fused heterocyclic groups, wherein the substituents refer to one or more groups selected from the group consisting of: hydroxy, halogen, cyano, amino.
2. Pyrimidine derivative or a pharmaceutically acceptable salt, stereoisomer thereof according to claim 1, wherein R is 1 Selected from the following groups:
3. pyrimidine derivative according to claim 2, or a pharmaceutically acceptable salt, stereoisomer thereof, wherein the pyrimidine derivative is selected from the group consisting of:
4. a process for the preparation of a pyrimidine derivative or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 3, wherein the process for the synthesis of the pyrimidine derivative is as follows:
5. use of a pyrimidine derivative according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer thereof, in the preparation of an antitumor drug.
6. The use according to claim 5, wherein the tumour is selected from colon cancer, lung cancer, ovarian cancer, endometrial cancer, pancreatic cancer, head and neck cancer, oesophageal cancer, breast cancer, colorectal cancer, lymphoma, leukaemia, synovial sarcoma, melanoma, liver cancer, stomach cancer, bladder cancer, squamous cell carcinoma, medulloblastoma, renal cancer or glioma.
7. An antitumor drug comprising as a first therapeutic agent the pyrimidine derivative of any one of claims 1 to 3 or a pharmaceutically acceptable salt, stereoisomer thereof.
8. The antineoplastic agent of claim 7, further comprising a pharmaceutically acceptable adjuvant.
9. The antineoplastic agent of claim 8, wherein the pharmaceutically acceptable excipients comprise at least one of cellulose and its derivatives, gelatin, talc, solid lubricants, calcium sulfate, vegetable oils, polyols, emulsifiers, wetting agents, colorants, flavors, stabilizers, antioxidants, preservatives, or water.
10. The antineoplastic agent of claim 7, wherein said antineoplastic agent further comprises a second therapeutic agent, the second therapeutic agent is selected from the group consisting of oxidastine, lu Kapa, nilapamide, methotrexate, capecitabine, gemcitabine, doxifluridine, pemetrexed disodium, pazopanib, imatinib, erlotinib, lapatinib, gefitinib, vandetanib, herceptin, bevacizumab, rituximab, trastuzumab, paclitaxel, vinorelbine, docetaxel, doxorubicin, hydroxycamptothecin, mitomycin, epirubicin, pirarubicin, bleomycin, letrozole, tamoxifen, fulvestrant, tratrelin, fluzaorelin, leuprolide, alfuzosin, and fluvalvulgare at least one of ifosfamide, busulfan, cyclophosphamide, carmustine, nimustine, semustine, nitrogen mustard, marflange, buflunine, carboplatin, cisplatin, oxaliplatin, cisplatin, topotecan, camptothecine, topotecan, everolimus, siromosi, tetroxide, 6-mercaptopurine, 6-thioguanine, azathioprine, biotin D, daunorubicin, doxorubicin, mitoxantrone, bleomycin, plicamycin or aminoglutethimide, nivolumab, pemetuzumab, ipilimumab, avermectin, dimetuzumab, alt Zhu Shan antibody, pirimuzumab.
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