CN115057856A - 3, 5-disubstituted-7 azaindole derivative and synthesis method and application thereof - Google Patents
3, 5-disubstituted-7 azaindole derivative and synthesis method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a 3, 5-disubstituted-7 azaindole derivative, and a synthesis method and application thereof. The 3, 5-disubstituted-7 azaindole derivative has GPX inhibitory activity and good drug forming potential, and is expected to be used for preparing medicines for treating/preventing diseases related to GPX 4.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a 3, 5-disubstituted-7 azaindole derivative, and a synthesis method and application thereof.
Background
Iron death was the first discovered and named new cell death pattern in 2012, and it is significantly different from apoptosis, necrosis, autophagy and pyro-death in morphology, biological characteristics and regulatory mechanisms. Iron death is catalyzed by ferrous iron, lipid peroxidation of polyunsaturated fatty acids on cell membranes occurs, leading to membrane rupture and triggering cell death. Iron death plays an important role in the occurrence, development and treatment of tumors, cardiovascular and cerebrovascular diseases and neurodegenerative diseases.
Glutathione peroxidase 4(GPX4) reduces lipid peroxides to non-toxic water or alcohols, protecting cells from damage by lipid peroxidation. The existing research shows that GPX4 plays a key regulation role in the cell iron death process, and the inhibition of the activity of GPX4 promotes the death of tumor cells. The inhibitor of GPX4 is adopted to induce iron death, so that the inhibitor has great significance and good application prospect in the treatment of tumors which have resistance to chemotherapeutic drugs.
However, most of the existing GPX4 inhibitors including RSL3 inhibit GPX4 activity by forming a covalent bond between an activated alkyl chloride and a catalytic selenocysteine residue thereof, lack the stability and selectivity required by pharmacy, have poor pharmacokinetic properties and can only be used in vitro as a tool compound (reference: Eaton, J.K., et al, Nature chemical biology,2020.16(5): p.497-506.). On the other hand, GPX4 also has important physiological activity, and a safe and effective therapeutic window is also a difficulty in developing GPX4 inhibitor drugs. Therefore, the development of a novel GPX4 inhibitor with better drug performance has important significance for treating tumors.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art described above. Therefore, the invention provides a 3, 5-disubstituted-7 azaindole derivative and a synthesis method and application thereof. The 3, 5-disubstituted-7 azaindole derivative has GPX inhibitory activity and good drug forming potential, and is expected to be used for developing novel antitumor drugs.
The invention provides a 3, 5-disubstituted-7 azaindole derivative or a pharmaceutically acceptable salt thereof, wherein the structural formula of the 3, 5-disubstituted-7 azaindole derivative is as follows:
wherein when R is tert-butyloxycarbonyl, the 3, 5-disubstituted-7 azaindole derivative is numbered DA-5;
when R is a hydrogen atom, the 3, 5-disubstituted-7 azaindole derivative is numbered DA-6.
Specifically, the structural formulas of DA-5 and DA-6 are shown below:
the invention also provides a synthesis method of the 3, 5-disubstituted-7 azaindole derivative or pharmaceutically acceptable salt thereof, and a reaction route for preparing the 3, 5-disubstituted-7 azaindole derivative is as follows:
5-bromo-7 azaindole and oxalyl chloride are subjected to Friedel-crafts acylation to obtain an intermediate (1); condensing the intermediate (1) with 2- (2-pyridyl) ethylamine to obtain an intermediate (2); carrying out Suzuki coupling reaction on the intermediate (2) to obtain DA-5; carrying out Boc removal reaction on DA-5 to obtain DA-6;
the invention also provides application of the 3, 5-disubstituted-7 azaindole derivative or pharmaceutically acceptable salt thereof in preparing any one of the following products:
a. a medicament for the treatment/prevention of a GPX 4-related disease;
b. a product that inhibits GPX enzymatic activity;
c. products that induce cellular iron death;
d. products for modulating the degree of cellular lipid peroxidation.
Preferably, the GPX 4-associated disease comprises a tumor.
More preferably, the tumor species comprises breast cancer, lung cancer, liver cancer, glioblastoma.
Even more preferably, the tumor is breast cancer.
The invention also provides an anti-tumor medicament which comprises the 3, 5-disubstituted-7 azaindole derivative or pharmaceutically acceptable salt thereof.
Preferably, the anti-tumor medicine further comprises pharmaceutically acceptable auxiliary materials.
More preferably, the pharmaceutically acceptable adjuvant is at least one of a solvent, a wetting agent, an emulsifier, a thickener, an excipient, a suspending agent, a disintegrant, a filler, a lubricant, or a diluent.
Compared with the prior art, the invention has the following beneficial effects:
the 3, 5-disubstituted-7 azaindole derivatives (DA-5 and DA-6) provided by the invention have chemical structures completely different from those of the existing GPX4 inhibitors, but also show good GPX4 activity inhibition effect. The 3, 5-disubstituted-7 azaindole derivative has a killing effect on various tumor cells in vitro, shows anti-tumor activity on an animal model, does not obviously affect the health condition of the animal, and shows that the derivative has good drug forming property different from the existing GPX4 inhibitor.
Drawings
FIG. 1 shows the results of the GPX4 enzyme activity inhibition experiment at the cellular level;
FIG. 2 shows the results of the inhibitory activities of the DA-5 and DA-6 enzymes GPX4 in vitro;
FIG. 3 is a graph of the inhibitory effect of DA-5 on GPX4 at various doses;
FIG. 4 is a graph showing the growth inhibitory effect of DA-5 on various breast cancer cells;
FIG. 5 shows the relieving effect of lipid peroxidation scavengers, Fer-1 and Lip-1, on DA-5;
FIG. 6 shows the rescue effect of Fer-1 on DA-5 induced cell iron death;
FIG. 7 is a flow cytometric assay to detect the effect of DA-5 on apoptosis;
FIG. 8 shows the pharmacokinetic results of mice orally administered DA-5;
FIG. 9 shows the growth inhibition of MDA-MB-231 xenograft tumors by DA-5.
Detailed Description
In order to make the technical solutions of the present invention more apparent to those skilled in the art, the following examples are given for illustration. It should be noted that the following examples are only preferred embodiments of the present invention, and the claimed protection scope is not limited thereto, and any modification, substitution, combination made without departing from the spirit and principle of the present invention are included in the protection scope of the present invention.
The starting materials, reagents or apparatuses used in the following examples are, unless otherwise specified, either commercially available from conventional sources or can be obtained by known methods.
Example 1: chemical synthetic route of 3, 5-disubstituted-7 azaindole derivatives (DA-5) and (DA-6)
5-bromo-7 azaindole and oxalyl chloride are subjected to Friedel-crafts acylation to obtain an intermediate (1); condensing the intermediate (1) with 2- (2-pyridyl) ethylamine to obtain an intermediate (2); carrying out Suzuki coupling reaction on the intermediate (2) to obtain DA-5; carrying out Boc removal reaction on DA-5 to obtain DA-6; the specific reaction route is as follows:
wherein the reaction conditions and parameters are as follows: a. ether, 0 ℃ for 3 h; b.K 2 CO 3 And refluxing the mixture for 3 hours by using toluene; pd (dppf) Cl 2 (dichloro [1,1' -bis (diphenylphosphino) ferrocene)]Palladium), K 2 CO 3 ,H 2 O/DME,90℃；d&e.CH 2 Cl 2 ,rt.
Example 2: structures of 3, 5-disubstituted-7 azaindole derivatives (DA-5) and (DA-6)
The chemical structures, mass spectra and nuclear magnetic data of DA-5 and DA-6 are shown in Table 1:
TABLE 1
Example 3: cellular level GPX4 enzyme activity inhibition assay
Collecting 5X 10 5 1mL of sample Buffer (Beyotime, S0056) was added to MDA-MB-231 cells for breast cancer, and homogenized in an ice bath using a glass homogenizer. After 10. mu.L of each homogenate was treated with 1. mu.L of DMSO (VEH group), 1. mu.L of DA-5(DA-5 group, 5mM), 1. mu.L of RSL3(RSL group (a known GPX4 inhibitor), CAS No.:1219810-16-8, 10mM) for 1 hour, the activity of GPX4 (Beyotime, S0056) was measured using a glutathione peroxidase assay kit (NADPH method), and the results are shown in FIG. 1.
As is clear from FIG. 1, the 3, 5-disubstituted-7 azaindole derivative DA-5 of the present invention has a good inhibitory effect on the activity of GPX 4.
Example 4: study on in vitro GPX4 enzyme inhibitory Activity of DA-5 and DA-6
In this example, the inhibitory activity of DA-5 and DA-6 on the enzymatic activity of purified GPX4 was tested using a GPX enzymatic activity test kit, as follows: dividing 10 mu M of purified GPX4 protein into four groups, respectively adding 10 mu M of RSL3, DA-5 and DA-6, controlling the DMSO content of each group to be consistent and less than 1%, and testing the enzyme activity of GPX4 of each group according to the kit specification, wherein the test result is shown in figure 2. As can be seen from FIG. 2, both DA-5 and DA-6 have better enzyme inhibition effect on GPX4 than the known GPX4 inhibitor, RSL 3.
In addition, the inhibitory effect of DA-5 on GPX4(GPX4 protein 10. mu.M) at different doses (30, 20, 13.3, 8.89, 5.93, 3.95 and 2.63. mu.M) is tested, and the IC50 value of DA-5 on GPX4 enzyme activity inhibition is calculated, and the test result is thatAs shown in fig. 3. FIG. 3 shows the result that the enzymatic activity of GPX4 is inhibited by DA-5 IC 50 When the concentration was 10.90. mu.M, the inhibitory effect of DA-5 on GPX4 was significant.
Example 5: DA-5 in vitro antitumor Activity study
DA-5 is tested to inhibit the proliferation activity of various breast cancer cells (Sk-Br-3, BT549, MDA-MB-468, MDA-MB-231 and 4T1) after acting for 48 hours by using a sulforhodamine B (SRB) colorimetric method, and the test result is shown in figure 4. As can be seen from FIG. 4, DA-5 can significantly inhibit the growth of tumor cells, and the inhibition effect is enhanced with the increase of the dosage, which is characterized by the dependence of the dosage.
Example 6: DA-5 induces cellular iron death
Breast cancer cells were treated with DA-5 (5. mu.M) MDA-MB-23124 hours, stained with C11-BODIPY, and analyzed by flow cytometry. As can be seen from FIG. 5, DA-5 significantly increased the degree of lipid peroxidation, and lipid peroxidation scavengers, Fer-1(5 μ M) and Lip-1(5 μ M), could mitigate their effects. As can be seen in FIG. 6, the SRB experiment shows that this death can be rescued by the iron death inhibitor, Fer-1 (5. mu.M). As can be seen from FIG. 7, after PI + Annexin V double staining and flow cytometry analysis, early apoptotic cells (PI-, Annexin V +) are not obviously increased, the possibility of DA-5 causing apoptosis is eliminated, and the proportion of DA-5 induced cell death can be obviously reduced by a lipid peroxidation scavenging reagent Lip-1(5 μ M). The above results indicate that DA-5 induces iron death of the cells.
Example 7: pharmacokinetics study of DA-5 mice with oral drugs
33 KM female mice were treated with DA-5 at a dose of 30mg/kg (reference drug effect dose), fasted but freely drinkable water for 12 hours, then subjected to gastric lavage, and the eyeballs were removed at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours, and collected in heparin-treated tubes, 3 mice per time point. Plasma was collected by centrifugation, treated with four times the volume of organic solvent (methanol: acetonitrile 1: 1), centrifuged, the supernatant collected, quantitatively diluted with organic solvent, assayed by the LC-MS/MS assay method established in advance for DA-5 in mouse plasma, and analyzed by measuring DA-5 concentration in plasma after a single gavage of 30mg/kg DA-5, versus time data, as shown in fig. 8 and table 2. The detection result shows that the DA-5 mouse oral administration has more ideal bioavailability and more ideal prodrug potential.
TABLE 2
Example 8: DA-5 inhibits the growth of MDA-MB-231 xenograft tumors
DA-5 was gavaged at 30mg/kg/d for 3 weeks on a mouse model of MDA-MB-231 xenograft tumor, and the growth status and tumor progression of the mice were monitored, and the test results are shown in FIG. 9. As can be seen from fig. 9 (a), the overall health status of the animals was good and no significant weight loss was observed; as can be seen from FIG. 9 (B), DA-5 significantly reduced the growth rate of the tumor (B); as can be seen from (C) and (D) in FIG. 9, at the end of the experiment, the size and weight of the tumor were significantly reduced, and no obvious pathological abnormality was observed in the appearance of the tissues of each organ, which preliminarily indicates the safety and effectiveness of DA-5.
The embodiments of the present application have been described in detail with reference to the drawings, but the present application is not limited to the embodiments, and various changes can be made within the knowledge of those skilled in the art without departing from the gist of the present application. Furthermore, the embodiments and features of the embodiments of the present application may be combined with each other without conflict.
Claims (8)
1. A 3, 5-disubstituted-7 azaindole derivative or a pharmaceutically acceptable salt thereof, wherein said 3, 5-disubstituted-7 azaindole derivative is selected from the group consisting of compounds of the following structures:
2. a method of synthesizing a 3, 5-disubstituted-7 azaindole derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the reaction scheme for preparing the 3, 5-disubstituted-7 azaindole derivative is:
5-bromo-7 azaindole and oxalyl chloride are subjected to Friedel-crafts acylation to obtain an intermediate (1); condensing the intermediate (1) with 2- (2-pyridyl) ethylamine to obtain an intermediate (2); carrying out Suzuki coupling reaction on the intermediate (2) to obtain DA-5; carrying out Boc removal reaction on DA-5 to obtain DA-6;
3. use of a 3, 5-disubstituted-7 azaindole derivative according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of any one of the following products:
a. a medicament for the treatment/prevention of a GPX 4-related disease;
b. a product that inhibits GPX enzymatic activity;
c. products that induce cellular iron death;
d. products for modulating the degree of cellular lipid peroxidation.
4. The use of claim 3, wherein the GPX 4-related disease comprises a tumor.
5. The use of claim 4, wherein the tumor species comprises breast cancer, lung cancer, liver cancer, glioblastoma.
6. An antitumor agent comprising the 3, 5-disubstituted-7 azaindole derivative according to claim 1 or a pharmaceutically acceptable salt thereof.
7. The antitumor drug as claimed in claim 6, further comprising a pharmaceutically acceptable excipient.
8. The antitumor agent as claimed in claim 7, wherein the pharmaceutically acceptable adjuvant is at least one of a solvent, a wetting agent, an emulsifier, a thickener, an excipient, a suspending agent, a disintegrant, a filler, a lubricant or a diluent.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6482832B1 (en) * | 1998-05-25 | 2002-11-19 | Abbott Laboratories | Heterocyclically substituted amides, their production and their use |
| CN1805960A (en) * | 2003-04-24 | 2006-07-19 | 埃尔比昂股份公司 | 7-azaindoles and use thereof as therapeutic agents. |
| US20110166175A1 (en) * | 2008-08-18 | 2011-07-07 | Merck Patent Gesellschaft Mit Beschrankter Haftung | 7-azaindole derivatives |
| CN106957315A (en) * | 2016-01-08 | 2017-07-18 | 中国人民解放军第二军医大学 | N- replaces benzenesulfonyl-azaindole oxybenzamide class compound and its prepares the purposes of medicine |
| US20190134025A1 (en) * | 2016-05-04 | 2019-05-09 | The Wistar Institute Of Anatomy And Biology | Methods of Treating Cancers Overexpressing Carm1 With EZH2 Inhibitors and Platinum-Based Antineoplastic Drugs |
| CN112794851A (en) * | 2021-01-26 | 2021-05-14 | 复旦大学 | 3- (pyridine-3-yl) -7-azaindole derivative PI3K delta inhibitor and preparation method and application thereof |
| WO2022093770A1 (en) * | 2020-10-27 | 2022-05-05 | Memorial Sloan Kettering Cancer Center | Combination therapy with pi3k-akt-mtor inhibitors and ferroptosis inducing agents to treat cancer |
-
2022
- 2022-06-08 CN CN202210639390.1A patent/CN115057856B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6482832B1 (en) * | 1998-05-25 | 2002-11-19 | Abbott Laboratories | Heterocyclically substituted amides, their production and their use |
| CN1805960A (en) * | 2003-04-24 | 2006-07-19 | 埃尔比昂股份公司 | 7-azaindoles and use thereof as therapeutic agents. |
| US20110166175A1 (en) * | 2008-08-18 | 2011-07-07 | Merck Patent Gesellschaft Mit Beschrankter Haftung | 7-azaindole derivatives |
| CN106957315A (en) * | 2016-01-08 | 2017-07-18 | 中国人民解放军第二军医大学 | N- replaces benzenesulfonyl-azaindole oxybenzamide class compound and its prepares the purposes of medicine |
| US20190134025A1 (en) * | 2016-05-04 | 2019-05-09 | The Wistar Institute Of Anatomy And Biology | Methods of Treating Cancers Overexpressing Carm1 With EZH2 Inhibitors and Platinum-Based Antineoplastic Drugs |
| WO2022093770A1 (en) * | 2020-10-27 | 2022-05-05 | Memorial Sloan Kettering Cancer Center | Combination therapy with pi3k-akt-mtor inhibitors and ferroptosis inducing agents to treat cancer |
| CN112794851A (en) * | 2021-01-26 | 2021-05-14 | 复旦大学 | 3- (pyridine-3-yl) -7-azaindole derivative PI3K delta inhibitor and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 谭雪;周莹;姚其正;: "7-氮杂吲哚及其类似物的合成与抗肿瘤和抗菌活性研究", 国外医药(抗生素分册), vol. 31, no. 05, 30 September 2010 (2010-09-30), pages 207 - 218 * |
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