CN112110934B - AZD 9291-based biomarker and preparation method and application thereof - Google Patents
AZD 9291-based biomarker and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to an AZD 9291-based biomarkerAnd a preparation method and application thereof, wherein the structural formula of the biomarker is as follows:
wherein n and m are integers of 2 to 20, R1Is H; r2Is H, C1‑C5Alkyl radical, C1‑C5One of alkoxy, amino, nitro, hydroxyl or halogen; the preparation method comprises the following steps: carrying out click chemical reaction on a compound with a structure shown as a formula (II) and a compound with a structure shown as a formula (III), and then carrying out post-treatment to obtain the biomarker,
compared with the prior art, the preparation method is simple, the operation is convenient, the condition is mild, and the prepared compound has application value in the prevention, diagnosis or treatment of the non-small cell lung cancer.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and relates to an AZD 9291-based biomarker and a preparation method and application thereof.
Background
The structural formula of AZD9291 (Osimetinib; AstraZeneca) is shown as follows, and the AZD9291 is a third-generation novel irreversible small-molecule inhibitor, is developed to target sensitized and resistant mutant forms of EGFR, and simultaneously retains a wild-type receptor. This mono-anilino-pyrimidine compound differs structurally and pharmacologically from all other TKIs. AZD9291 irreversibly binds EGFR kinase by covalent bond formation targeting cysteine-797 residues in the ATP binding site. Has activity against mutant EGFR, including T790M, but has selective borders on wild-type EGFR. The current AZD9291 is used in larger doses and thus leads to undesirable metabolism such as diarrhea, rash, nausea. Therefore, it is necessary to optimize the structure of the compound, improve the physical properties of the compound, enhance the anti-tumor activity, and reduce the dosage of the drug so as to reduce the toxic and side effects of the drug on the premise of achieving the required inhibitory effect. And carrying out alkynyl modification on the AZD9291, and carrying out click chemical reaction on the AZD9291 and an azide group-modified fluorescein compound to obtain a target product, namely the biomarker.
The biomarker (biomarker) can discuss pathogenesis from a molecular level, has unique advantages in accurately and sensitively evaluating early and low-level damage, can provide early warning, and provides a basis for auxiliary diagnosis for clinicians to a great extent. Examination of a disease-specific biomarker may be helpful in the identification, early diagnosis and monitoring of diseases during prevention and treatment.
With the continuous development of cancer biomarkers, the continuous knowledge of biological information in human beings, and the development of new therapeutic means, the research and treatment of tumors will eventually enter the era of individualized medical treatment. Based on the significant effect of AZD9291 in the treatment of anti-mutant EGFR in NSCLC and the important role of biomarkers in cancer diagnosis, biomarkers based on AZD9291 will be investigated for the prevention, diagnosis or treatment of EGFRm NSCLC.
Disclosure of Invention
The invention aims to provide an AZD 9291-based biomarker and a preparation method and application thereof.
The purpose of the invention can be realized by the following technical scheme:
an AZD 9291-based biomarker, which is a compound having a structure shown in formula (I):
wherein n and m are integers from 2 to 20; r1Is H; r2Includes H, C1-C5Alkyl radical, C1-C5One of alkoxy, amino, nitro, hydroxyl or halogen.
Specifically, when n is 2 and m is 6, the formula of the compound of formula (I) is as follows:
further, when said R is1、R2When all are H, the formula of the compound of formula (I) is as follows:
when said R is1Is H, R2When methyl, the compounds of formula (I) have the following structural formula:
when said R is1Is H, R2When amino, the formula of the compound of formula (I) is as follows:
when said R is1Is H, R2When a fluorine substituent, the formula of the compound of formula (I) is as follows:
specifically, when n is 2 and m is 20, the formula of the compound of formula (I) is as follows:
further, when said R is1Is H, R2When methyl, the compounds of formula (I) have the following structural formula:
specifically, when n is 20 and m is 2, the formula of the compound of formula (I) is as follows:
further, when said R is1Is H, R2When a fluorine substituent, the formula of the compound of formula (I) is as follows:
a preparation route of a biomarker based on AZD9291 is shown in figure 1, and the preparation method comprises the following steps: carrying out click chemical reaction on a compound with a structure shown as a formula (II) and a compound with a structure shown as a formula (III) in a catalytic system consisting of copper sulfate and sodium ascorbate at 18-25 ℃, and then carrying out post-treatment to prepare the biomarker,
furthermore, in the click chemistry reaction, the molar ratio of the compound with the structure shown in the formula (II) to the compound with the structure shown in the formula (III) to the copper sulfate to the sodium ascorbate is 1 (0.8-1.2) to (0.08-0.12) to (0.28-0.32); the reaction solvent comprises a mixed solution of water and isobutanol according to the volume ratio of 1 (0.8-1.2).
Further, the post-processing comprises: and adding water into the reaction system to quench the reaction, washing with water and a saturated sodium chloride solution in sequence, adding dichloromethane for extraction, combining organic phases, drying with anhydrous sodium sulfate, and concentrating and separating by column chromatography to obtain the biomarker.
Common procedures such as extraction, quenching, chromatography, etc., are well known in the art, and reagents employed are generally obtained from commercial sources or readily prepared using methods well known to those skilled in the art.
An application of a biomarker based on AZD9291 in preparing an anti-tumor drug; the tumor comprises lung cancer, breast cancer, gastrointestinal cancer, esophageal cancer, nasopharyngeal cancer, pancreatic cancer, ovarian cancer, glioma, prostatic cancer, epidermal squamous cell carcinoma, head and neck squamous cell carcinoma and the like. The prepared medicine can effectively prevent, diagnose or treat the tumors.
Preferably, the use of the AZD 9291-based biomarker for the preparation of a medicament for the prevention, diagnosis and/or treatment of an indication related to EGFR kinase function.
According to the invention, AZD9291 is subjected to alkynyl modification and then undergoes click chemical reaction with an azide group-modified fluorescein compound to obtain a target product, namely the biomarker. It has strong in vitro anti-tumor activity, and has strong affinity, strong storage capacity in cancer tissues and slow excretion speed due to the better positioning and distribution effect characteristics of fluorescein compounds on cancer cells, and can increase blood concentration and improve curative effect. Fluorescein has been reported to be used for diagnosing cancers abroad, and the fluorescein itself has a certain anticancer effect. Therefore, the biomarker obtained by carrying out click chemical reaction on the alkynyl-modified AZD9291 and the azide group-modified fluorescein compound not only changes the physical properties of the compound, but also enhances the in vitro anti-tumor activity of the compound, and has better inhibition effect on various tumor cells.
Preferably, the dosage form of the antitumor drug comprises freeze-dried powder, injection, liposome, emulsion, microcapsule, suspension or solution for intravenous injection, granule, tablet, capsule or syrup for oral administration, and suppository.
Compared with the prior art, the preparation method is simple, the operation is convenient, the condition is mild, the prepared compound can inhibit the activation or resistance mutation of the EGFR, can be used for treating EGFR sensitive type mutant cancer, is an ideal medicament for treating diseases caused by EGFR mutation, and has application value for preventing, diagnosing or treating non-small cell lung cancer.
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FIG. 1 is a preparation scheme of a compound having a structure shown in formula (I).
Detailed Description
The present invention will be described in detail with reference to specific examples.
An AZD 9291-based biomarker is a compound having a structure shown as formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, wherein n and m are integers of 2-20; r1Includes H, C1-C10Alkyl radical, C1-C10One of alkoxy or halogen; r2Includes H, C1-C5Alkyl radical, C1-C5One of alkoxy, amino, nitro, hydroxyl or halogen.
The preparation method comprises the following steps: carrying out click chemical reaction on a compound with a structure shown as a formula (II) and a compound with a structure shown as a formula (III) in a catalytic system consisting of copper sulfate and sodium ascorbate at 18-25 ℃, adding water into the reaction system to quench the reaction, sequentially washing with water and a saturated sodium chloride solution, adding dichloromethane to extract, combining organic phases, drying with anhydrous sodium sulfate, concentrating, and carrying out column chromatography separation to obtain the biomarker.
Wherein, the mol ratio of the compound with the structure shown in the formula (II), the compound with the structure shown in the formula (III), the copper sulfate and the sodium ascorbate is 1 (0.8-1.2) to (0.08-0.12) to (0.28-0.32), and the reaction solvent comprises mixed solution of water and isobutanol according to the volume ratio of 1 (0.8-1.2).
The following examples are given in detail to illustrate the embodiments and specific procedures of the present invention, but the scope of the present invention is not limited to the following examples.
Example 1:
n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (1- (2- ((1- (6- ((3' -hydroxy-3-oxo-3H-spiro [ isobenzofuran-1, 9' -xanthine ] -6' -yl) oxy) hexyl) -1H-1,2, 3-triazol-4-yl) methoxy) ethyl) -1H-indol-3-yl) pyrimidin-2 yl) amino) -4-methoxyphenyl) acrylamide, a biomarker of structure (a), prepared by a process comprising:
56.7mg (0.1mmol) of the compound N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1- (2- (prop-2-yn-1-yloxy) ethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide is weighed and placed in a 100mL eggplant-shaped bottle, and CuSO is added4·5H2O2.5 mg, sodium ascorbate 5.9mg (0.03mmol), and finally 3' - ((6-azidohexyl) oxy) -6' -hydroxy-3H-cyclo [ isobenzofuran-1, 9' -xanthine]45.7mg (0.1mmol) of (E) -3-ketone, and further dropwise added with a solvent of (2 mL each of) isobutanol 1:1 (water and isopropanol), followed by reaction at ordinary temperature. TLC plate was monitored until the reaction was complete. After the reaction, water was added to quench the reaction, and the reaction solution was washed with water and a saturated sodium chloride solution in this order, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (DCM (dichloromethane): MeOH (methanol) ═ 3:1), to give the biomarker of structure (a) as a pink solid compound 97mg (yield 95%).
Example 2:
n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (1- (2- ((1- (6- ((3' -hydroxy-3-oxo-3H-spiro [ isobenzofuran-1, 9' -xanthine ] -6' -yl) oxy) hexyl) -1H-1,2, 3-triazol-4-yl) methoxy) ethyl) -7-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide, a biomarker of structure (b) prepared by a process comprising:
weighing the compound N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-56.7mg (0.1mmol) of methoxy-5- ((4- (7-methyl-1- (2- (2-yne-1-oxy) ethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide was placed in a 100ml eggplant-shaped bottle, and CuSO was added4·5H2O2.5 mg (0.01mol), sodium ascorbate 5.9mg (0.03mmol) and finally 3' - ((6-azidohexyl) oxy) -6' -hydroxy-3H-cyclo [ isobenzofuran-1, 9' -xanthine]45.7mg (0.1mmol) of (E) -3-ketone, and further dropwise added with a solvent of (2 mL each of) isobutanol 1:1 (water and isopropanol), followed by reaction at ordinary temperature. TLC plate was monitored until the reaction was complete. After the reaction, water was added to quench the reaction, and the reaction solution was washed with water and saturated sodium chloride solution in this order, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (DCM (dichloromethane): MeOH (methanol) ═ 3:1), to give the biomarker of structure (b) as a pink solid compound 93mg (yield 92%).
Example 3:
n- (5- ((4- (7-amino-1- (2- ((1- (6- ((3' -hydroxy-3-oxo-3H-spiro [ isobenzofuran-1, 9' -xanthine ] -6' -yl) oxy) hexyl) -1H-1,2, 3-triazol-4-yl) methoxy) ethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, i.e., a biomarker of structure (c), prepared by a method comprising:
56.7mg (0.1mmol) of the compound N- (5- ((4- (7-amino-1- (2- (2-propyl-1-oxy) ethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl acrylamide is weighed and placed in a 100mL eggplant-shaped bottle, and CuSO is added4·5H2O2.5 mg (0.01mol), sodium ascorbate 5.9mg (0.03mmol) and finally 3' - ((6-azidohexyl) oxy) -6' -hydroxy-3H-cyclo [ isobenzofuran-1, 9' -xanthine]45.7mg (0.1mmol) of (E) -3-ketone, and further dropwise added with a solvent of (2 mL each of) isobutanol 1:1 (water and isopropanol), followed by reaction at ordinary temperature. TLC plate was monitored until the reaction was complete. After the reaction is finished, adding water to quench the reaction, washing the reaction by using water and saturated sodium chloride solution in sequence, extracting the reaction by using dichloromethane, combining organic phases, drying the organic phases by using anhydrous sodium sulfate, concentrating the organic phases, and carrying out column chromatography separation (DCM: MeOH ═ 3:1) to obtain the biomarker with the structure (c) which is a pink solid compound89mg (yield 88%).
Example 4:
n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (6-fluoro-1- (2- ((1- (6- ((3' -hydroxy-3-oxo-3H-spiro [ isobenzofuran-1, 9' -xanthine ] -6' -yl) oxy) hexyl) -1H-1,2, 3-triazol-4-yl) methoxy) ethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide prepared by a process comprising:
56.7mg (0.1mmol) of the compound N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (6-fluoro-1- (2- (2-propyl-1-ethoxy) ethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide is weighed and placed in a 100mL eggplant-shaped bottle, and CuSO is added4·5H2O2.5 mg (0.01mol), sodium ascorbate 5.9mg (0.03mmol) and finally 3' - ((6-azidohexyl) oxy) -6' -hydroxy-3H-cyclo [ isobenzofuran-1, 9' -xanthine]45.7mg (0.1mmol) of (E) -3-ketone, and further dropwise added with a solvent of (2 mL each of) isobutanol 1:1 (water and isopropanol), followed by reaction at ordinary temperature. TLC plate was monitored until the reaction was complete. After the reaction, water was added to quench the reaction, and the reaction solution was washed with water and a saturated sodium chloride solution in this order, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (DCM: MeOH ═ 3:1), to obtain the biomarker with the structure (d) as a pink solid compound 98mg (yield 97%).
Example 5:
n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (1- (2- ((1- (20- ((3' -hydroxy-3-oxo-3H-spiro [ isobenzofuran-1, 9' -xanth ] -7' -yl) oxy) octadecyl) -1H-1,2, 3-triazol-4-yl) methoxy) ethyl) -7-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide prepared by a process comprising:
56.7mg (0.1mmol) of the compound N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (7-methyl-1- (2- (2-yn-1-oxy) ethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide is weighed and placed in a 100mL eggplant-shaped bottle, and CuSO is added4·5H2O1.56 mg (0.01mol), sodium ascorbate 5.79mg (0.03mmol) and finally 2'- ((20-azidoheterocycle) oxy) -6' -hydroxy-3H-spiroCyclo [ isobenzofuran-1, 9' -xanthane]63.73mg (0.1mmol) of (E) -3-ketone, and further added dropwise with a solvent of isobutanol 1:1 (water, isopropanol, 2mL each), followed by reaction at ordinary temperature. TLC plate was monitored until the reaction was complete. After the reaction is finished, water is added to quench the reaction, the reaction solution is washed by water and saturated sodium chloride solution in sequence, then dichloromethane is used for extraction, organic phases are combined, after being dried by anhydrous sodium sulfate, concentration and column chromatography separation (DCM: MeOH ═ 3:1), and finally the biomarker with the structure (e) is obtained, and is 99mg of pink solid compound (yield is 85%).
Example 6:
n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (7-fluoro-1- (20- ((1- (2- ((3' -hydroxy-3-oxo-3H-spiro [ isobenzofuran-1, 9' -xanthen ] -7' -yl) oxy) ethyl) -1H-1,2, 3-triazol-4-yl) methoxy) -1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide prepared by a process comprising:
56.7mg (0.1mmol) of the compound N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (7-fluoro-1- (20- (prop-2-yn-1-oxy) ethoxy) -1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide is weighed and placed in a 100mL eggplant-shaped bottle, and CuSO is added4·5H2O1.08 mg (0.01mol), sodium ascorbate 4.02mg (0.03mmol), and finally 2' - (2-azidoethoxy) -6' -hydroxy-3H-spiro [ isobenzofuran-1, 9' -xanthogen]27.15mg (0.1mmol) of (E) -3-ketone, and further added dropwise with a solvent of isobutanol 1:1 (water, isopropanol, 2mL each), followed by reaction at ordinary temperature. TLC plate was monitored until the reaction was complete. After the reaction, water was added to quench the reaction, and the reaction solution was washed with water and a saturated sodium chloride solution in this order, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (DCM: MeOH ═ 3:1), to obtain the biomarker with the structure (f) as a pink solid compound 82mg (yield 98%).
Example 7:
this example conducted pharmacodynamic tests on six AZD 9291-based biomarkers a, b, c, d, e, f from examples 1-6.
First, compound enzyme activity test
1. Test method
The half-inhibitory concentration of a compound, IC50 (the concentration of compound required to inhibit enzyme activity to 50%) was determined by mixing a specific substrate with a fixed enzyme and varying concentrations of the test compound. The Assay used was Caliper Shift analysis (Caliper Mobility Shift Assay) and the kinase measured was EGFR790M/L858RThe standard reference compound used was staurosporine.
2. Test results
Table 1 shows the results of the inhibition experiments of the enzymatic activity of the compounds. The results show that the target compounds (a, b, c, d, e, f) have strong inhibitory effects on two EGFR kinases, and that the results show that the target compounds (a, b, c, d, e, f) have good selective inhibitory activities. This selective inhibition has important therapeutic implications for acquired-resistant tumors carrying the T790M mutation.
TABLE 1 results of inhibition experiment of enzyme Activity of Compounds
Second, tumor cell inhibition test
The tumor cell inhibition tests of the biomarkers d, e and f based on AZD9291 in examples 4, 5 and 6 were carried out to examine the inhibition effects, specifically:
1. test method
(1) A compound: in vitro studies test compounds were first dissolved in 100% DMSO and then diluted to the desired concentration, with a final DMSO concentration of 0.1 vol%. 0.1 vol% DMSO was added to the medium as a solvent control for a total of 9 concentration gradients and the test was repeated twice.
(2) Tumor cell lines: the tumor cell lines tested were cultured in 10 RPM medium containing 10% fetal bovine serum in 5% CO2And culturing in an incubator at 37 ℃. The tumor cell lines tested were: MCF7 (human breast cancer cells), HT29 (human colon cancer cells), HCC827 (human non-small cell carcinoma cells), H1975 (human lung adenocarcinoma cells) and a549 (human lung cancer cells).
(3) The MTS method comprises the following steps: cells were seeded in 96-well plates, 3000 per wellCells and at 5% CO2Incubated overnight in a humidified incubator at 37 ℃. The next day test compounds were added to the wells and incubated for a further 72 hours. The activity of the cells was measured using MTS.
IC50 (the concentration of drug required to inhibit cell growth by 50% compared to DMSO control, calculated using non-linear regression analysis of GraphPad Prism software) was calculated.
2. Test results
The inhibitory activities of the target compounds d, e and f on MCF7, HT29, HCC827, H1975 and A549 tumor cells are shown in Table 2.
TABLE 2 tumor cell inhibition test results
As can be seen from Table 2, the compounds d, e and f of the present invention showed inhibitory activity against various tested tumor cells, especially HCC827 and H1975.
The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.
Claims (10)
1. An AZD 9291-based biomarker, which is a compound having a structure represented by formula (I):
wherein n and m are integers from 2 to 20; r1Is H; r2Is H, C1-C5Alkyl radical, C1-C5One of alkoxy, amino, nitro, hydroxyl or halogen.
2. A method for the preparation of AZD 9291-based biomarkers according to claim 1, comprising: carrying out click chemical reaction on a compound with a structure shown as a formula (II) and a compound with a structure shown as a formula (III), and then carrying out post-treatment to obtain the biomarker,
3. the method for preparing the AZD 9291-based biomarker according to claim 2, wherein the molar ratio of the compound having the structure shown in the formula (II) to the compound having the structure shown in the formula (III) in the click chemistry reaction is 1 (0.8-1.2).
4. The method for preparing AZD 9291-based biomarkers according to claim 2, wherein in the click chemistry reaction, the catalytic systems used are copper sulfate and sodium ascorbate, wherein the addition amount of copper sulfate is 0.08-0.12mol/mol of the compound having the structure shown in formula (II), and the addition amount of sodium ascorbate is 0.28-0.32mol/mol of the compound having the structure shown in formula (II).
5. The method for preparing AZD 9291-based biomarkers according to claim 2, wherein the reaction temperature in the click chemistry reaction is 18-25 ℃.
6. The method for preparing AZD 9291-based biomarkers according to claim 2, wherein in the click chemistry reaction, the reaction solvent is a mixed solution of water and isobutanol according to a volume ratio of 1 (0.8-1.2).
7. The method for preparing AZD 9291-based biomarkers according to claim 2, wherein said post-treatment comprises: and adding water into the reaction system to quench the reaction, washing with water and a saturated sodium chloride solution in sequence, adding dichloromethane for extraction, combining organic phases, drying with anhydrous sodium sulfate, and concentrating and separating by column chromatography to obtain the biomarker.
8. Use of an AZD 9291-based biomarker according to claim 1, in the preparation of an anti-tumour medicament.
9. The use of AZD9291 based biomarkers according to claim 8 wherein said antineoplastic agent is a prophylactic, diagnostic or therapeutic agent for non-small cell lung cancer.
10. The use of AZD 9291-based biomarkers according to claim 8, wherein said antineoplastic agents are in the form of lyophilized powder, injection, liposomes, emulsions, microcapsules, suspension, solution, granules, tablets, capsules, syrup or suppositories.
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