CN115057856B - 3, 5-disubstituted-7-azaindole derivative and synthetic method and application thereof - Google Patents
3, 5-disubstituted-7-azaindole derivative and synthetic method and application thereof Download PDFInfo
- Publication number
- CN115057856B CN115057856B CN202210639390.1A CN202210639390A CN115057856B CN 115057856 B CN115057856 B CN 115057856B CN 202210639390 A CN202210639390 A CN 202210639390A CN 115057856 B CN115057856 B CN 115057856B
- Authority
- CN
- China
- Prior art keywords
- disubstituted
- pharmaceutically acceptable
- azaindole derivative
- azaindole
- gpx4
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- -1 3, 5-disubstituted-7-azaindole Chemical class 0.000 title abstract description 11
- 238000010189 synthetic method Methods 0.000 title description 3
- 239000003814 drug Substances 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 5
- 102100023410 Phospholipid hydroperoxide glutathione peroxidase Human genes 0.000 claims description 30
- 101000829725 Homo sapiens Phospholipid hydroperoxide glutathione peroxidase Proteins 0.000 claims description 29
- 230000000694 effects Effects 0.000 claims description 25
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 22
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- 230000034994 death Effects 0.000 claims description 13
- 229910052742 iron Inorganic materials 0.000 claims description 11
- 230000003859 lipid peroxidation Effects 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000002246 antineoplastic agent Substances 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims description 5
- 230000001413 cellular effect Effects 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- XPQIPUZPSLAZDV-UHFFFAOYSA-N 2-pyridylethylamine Chemical compound NCCC1=CC=CC=N1 XPQIPUZPSLAZDV-UHFFFAOYSA-N 0.000 claims description 3
- LPTVWZSQAIDCEB-UHFFFAOYSA-N 5-bromo-1h-pyrrolo[2,3-b]pyridine Chemical compound BrC1=CN=C2NC=CC2=C1 LPTVWZSQAIDCEB-UHFFFAOYSA-N 0.000 claims description 3
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims description 3
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000007884 disintegrant Substances 0.000 claims description 2
- 239000003995 emulsifying agent Substances 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 208000005017 glioblastoma Diseases 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000000375 suspending agent Substances 0.000 claims description 2
- 239000002562 thickening agent Substances 0.000 claims description 2
- 239000000080 wetting agent Substances 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 6
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 238000012360 testing method Methods 0.000 description 5
- 101100173542 Caenorhabditis elegans fer-1 gene Proteins 0.000 description 4
- 230000030833 cell death Effects 0.000 description 4
- UJHBVMHOBZBWMX-UHFFFAOYSA-N ferrostatin-1 Chemical compound NC1=CC(C(=O)OCC)=CC=C1NC1CCCCC1 UJHBVMHOBZBWMX-UHFFFAOYSA-N 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- TXJZRSRTYPUYRW-NQIIRXRSSA-N methyl (1s,3r)-2-(2-chloroacetyl)-1-(4-methoxycarbonylphenyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole-3-carboxylate Chemical compound C1([C@H]2C3=C(C4=CC=CC=C4N3)C[C@@H](N2C(=O)CCl)C(=O)OC)=CC=C(C(=O)OC)C=C1 TXJZRSRTYPUYRW-NQIIRXRSSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- IOOMXAQUNPWDLL-UHFFFAOYSA-N 2-[6-(diethylamino)-3-(diethyliminiumyl)-3h-xanthen-9-yl]-5-sulfobenzene-1-sulfonate Chemical compound C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=C(S(O)(=O)=O)C=C1S([O-])(=O)=O IOOMXAQUNPWDLL-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229940045835 RSL3 Drugs 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 101150077696 lip-1 gene Proteins 0.000 description 3
- YAFQFNOUYXZVPZ-UHFFFAOYSA-N liproxstatin-1 Chemical compound ClC1=CC=CC(CNC=2C3(CCNCC3)NC3=CC=CC=C3N=2)=C1 YAFQFNOUYXZVPZ-UHFFFAOYSA-N 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 102000004121 Annexin A5 Human genes 0.000 description 2
- 108090000672 Annexin A5 Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 238000008999 Glutathione Peroxidase assay kit Methods 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 108010033024 Phospholipid Hydroperoxide Glutathione Peroxidase Proteins 0.000 description 1
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001348 alkyl chlorides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 230000004900 autophagic degradation Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 238000007822 cytometric assay Methods 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 238000012137 double-staining Methods 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000009422 growth inhibiting effect Effects 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 208000024798 heartburn Diseases 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 208000024981 pyrosis Diseases 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 239000012723 sample buffer Substances 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 125000001554 selenocysteine group Chemical group [H][Se]C([H])([H])C(N([H])[H])C(=O)O* 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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 patent medicine 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 is a novel cell death mode discovered and named for the first time in 2012, and is significantly different from the cell death modes such as apoptosis, necrosis, autophagy and pyrosis in morphology, biological characteristics and regulatory mechanisms. Iron death is the triggering of cell death by lipid peroxidation of polyunsaturated fatty acids on cell membranes under the catalysis of ferrous iron, resulting in membrane rupture. Iron death plays an important role in the occurrence, development and treatment of tumors, cardiovascular and cerebrovascular diseases and neurodegenerative diseases.
Glutathione peroxidase 4 (GPX 4) can reduce lipid peroxides to non-toxic water or alcohols, protecting cells from lipid peroxidation. The prior study shows that GPX4 plays a key regulation role in the death process of cell iron, and inhibiting the activity of the GPX4 can promote the death of tumor cells. The inhibitor of GPX4 is used for inducing iron death, so that the method has great significance and good application prospect in the treatment of tumors which have drug resistance to chemotherapeutic drugs.
However, existing GPX4 inhibitors, including RSL3, mostly inhibit GPX4 activity by covalent bond formation of activated alkyl chloride with its catalytic selenocysteine residue, lack stability and selectivity for pharmaceutical requirements, and have poor pharmacokinetic properties and can only be used in vitro as tool compounds (ref: 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 treatment window is also a difficulty in developing GPX4 inhibitor drugs. Therefore, the development of the novel GPX4 inhibitor with better drug property has important significance for tumor treatment.
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 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 potential of patent medicine, and is expected to be used for developing and obtaining novel antitumor drugs.
The invention provides a 3, 5-disubstituted-7 azaindole derivative or pharmaceutically acceptable salt thereof, wherein the structural formula of the 3, 5-disubstituted-7 azaindole derivative is as follows:
wherein, when R is tert-butoxycarbonyl, the number of the 3, 5-disubstituted-7 azaindole derivative is 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 synthetic 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:
performing Friedel-crafts acylation on 5-bromo-7-azaindole and oxalyl chloride to obtain an intermediate (1); condensing the intermediate (1) with 2- (2-pyridyl) ethylamine to obtain an intermediate (2); the intermediate (2) is subjected to Suzuki coupling reaction to obtain DA-5; carrying out Boc removal reaction on the 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 treating/preventing a disease associated with GPX 4;
b. a product that inhibits GPX enzyme activity;
c. a product that induces cellular iron death;
d. a product that modulates the degree of lipid peroxidation of a cell.
Preferably, the disease associated with GPX4 comprises a tumor.
More preferably, the tumor comprises breast cancer, lung cancer, liver cancer, glioblastoma.
Even more preferably, the tumor is breast cancer.
The invention also provides an antitumor drug comprising a 3, 5-disubstituted-7 azaindole derivative or a pharmaceutically acceptable salt thereof.
Preferably, the antitumor drug further comprises pharmaceutically acceptable auxiliary materials.
More preferably, the pharmaceutically acceptable auxiliary material 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 completely different chemical structures from the existing GPX4 inhibitors, but also show good GPX4 activity inhibition effects. The 3, 5-disubstituted-7 azaindole derivative has killing effect on various tumor cells in vitro, shows anti-tumor activity on an animal model, does not have obvious adverse effect on the health condition of animals, and shows that the 3, 5-disubstituted-7 azaindole derivative has good drug properties different from the existing GPX4 inhibitor.
Drawings
FIG. 1 shows the results of an experiment for inhibiting GPX4 enzyme activity at the cellular level;
FIG. 2 shows the results of the in vitro GPX4 enzyme inhibition activity of DA-5 and DA-6;
FIG. 3 shows the inhibitory effect of DA-5 on GPX4 at different doses;
FIG. 4 shows the growth inhibitory effect of DA-5 on a variety of breast cancer cells;
FIG. 5 is a graph showing the alleviating effects of lipid peroxidation scavengers Fer-1 and Lip-1 on DA-5;
FIG. 6 is a rescue effect of Fer-1 on DA-5 induced cellular 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 after oral administration of DA-5;
FIG. 9 shows the growth inhibition results of DA-5 on MDA-MB-231 xenograft tumors.
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: chemical synthetic route for 3, 5-disubstituted-7 azaindole derivatives (DA-5) and (DA-6)
Performing Friedel-crafts acylation on 5-bromo-7-azaindole and oxalyl chloride to obtain an intermediate (1); condensing the intermediate (1) with 2- (2-pyridyl) ethylamine to obtain an intermediate (2); the intermediate (2) is subjected to Suzuki coupling reaction to obtain DA-5; carrying out Boc removal reaction on the DA-5 to obtain DA-6; the specific reaction route is as follows:
wherein the reaction conditions and parameters are as follows: a. diethyl ether, 0 ℃,3h; b.K 2 CO 3 Toluene, reflux for 3h; pd (dppf) Cl 2 (dichloro [1,1' -bis (diphenylphosphine) ferrocene)]Palladium), K 2 CO 3 ,H 2 O/DME,90℃；d&e.CH 2 Cl 2 ,rt.
Example 2: structure of 3, 5-disubstituted-7-azaindole derivatives (DA-5) and (DA-6)
The chemical structural formulas, mass spectra and nuclear magnetic data of DA-5 and DA-6 are shown in Table 1:
TABLE 1
Example 3: cell level GPX4 enzyme Activity inhibition assay
Collect 5X 10 5 Fine MDA-MB-231 of breast cancerCells, 1mL of sample Buffer (Beyotime, S0056) was added 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, 5 mM) and 1. Mu.L of RSL3 (RSL group, a known GPX4 inhibitor, CAS No.:1219810-16-8, 10 mM) for 1 hour, GPX4 activity was detected by using a glutathione peroxidase assay kit (NADPH method) (Beyotime, S0056), and the detection results are shown in FIG. 1.
As shown in FIG. 1, the 3, 5-disubstituted-7-azaindole derivative DA-5 has good GPX4 activity inhibition effect.
Example 4: DA-5 and DA-6 in vitro GPX4 enzyme inhibition Activity Studies
The present example tested the ability of DA-5 and DA-6 to inhibit the activity of purified GPX4 enzyme using the GPX enzyme activity test kit, as follows: the purified GPX4 proteins are divided into four groups of 10 mu M, RSL3, DA-5 and DA-6 are respectively added into the four groups, the DMSO content of each group is controlled to be consistent and less than 1%, and according to the instruction of the kit, the GPX4 enzyme activity of each group is tested, and 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 (GPX 4 protein 10. Mu.M) at various doses (30, 20, 13.3,8.89,5.93,3.95,2.63. Mu.M) was tested, and the IC50 value of DA-5 for inhibition of GPX4 enzyme activity was calculated, and the test results are shown in FIG. 3. FIG. 3 shows that DA-5 inhibits the enzyme activity of GPX4 50 =10.90 μm, demonstrating a significant inhibitory effect of DA-5 on GPX 4.
Example 5: DA-5 in vitro anti-tumor Activity Studies
DA-5 was tested for inhibitory activity against proliferation of various breast cancer cells (Sk-Br-3, BT549, MDA-MB-468, MDA-MB-231, 4T 1) after 48 hours of action using a sulforhodamine B (SRB) colorimetric method, and the test results are shown in FIG. 4. As can be seen from fig. 4, DA-5 can significantly inhibit the growth of tumor cells, and its inhibition effect is enhanced with increasing dosage, and is characterized by dose dependency.
Example 6: DA-5 induces cellular iron death
Breast cancer cells MDA-MB-231 h, stained with DA-5 (5. Mu.M), and analyzed by flow cytometry. As can be seen from FIG. 5, DA-5 significantly increases the degree of lipid peroxidation, and the lipid peroxidation scavengers Fer-1 (5. Mu.M) and Lip-1 (5. Mu.M) can alleviate the effects. As can be seen from FIG. 6, SRB experiments show that this death can be rescued by the iron death inhibitor, fer-1 (5. Mu.M). As can be seen from FIG. 7, the double-staining with PI+annexin V showed no significant increase in early apoptotic cells (PI-, annexin V+) by flow cytometry, eliminating the possibility of DA-5 induced apoptosis, and the lipid peroxidation scavenging reagent Lip-1 (5. Mu.M) significantly reduced the DA-5 induced cell death rate. The above results indicate that DA-5 induces iron death in cells.
Example 7: pharmacokinetic study of DA-5 mice
33 KM female mice were dosed with DA-5 at a dose of 30mg/kg (reference pharmacodynamic dose), fasted but free-standing for 12 hours, and then dosed by stomach irrigation, eyeballs were extracted at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours, and blood was collected in heparin-treated tubes, 3 mice at each time point. Plasma was collected by centrifugation, treated with four volumes of organic solvent (methanol: acetonitrile=1:1), centrifuged, and the supernatant was collected, quantitatively diluted with the organic solvent, and then detected by the LC-MS/MS assay method for DA-5 assay in mouse plasma established in advance, and analysis was performed by measuring DA-5 concentration-time data in plasma after single-dose gavage of 30mg/kg of DA-5, and the results are shown in fig. 8 and table 2. The detection result shows that the DA-5 mice have ideal bioavailability after oral administration and ideal potential of patent medicine.
TABLE 2
Example 8: DA-5 inhibits the growth of MDA-MB-231 xenograft tumors
DA-5 was intragastrically administered at 30mg/kg/d for 3 weeks on a MDA-MB-231 xenograft tumor mouse model, 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 of the animals was good, and no significant decrease in body weight was observed; as can be seen from fig. 9 (B), DA-5 significantly reduced the growth rate of tumor (B); as can be seen from fig. 9 (C) and (D), at the end of the experiment, the tumor size and weight were significantly reduced, and the appearance of each organ tissue was not seen to be significantly pathological, thus preliminarily indicating the safety and effectiveness of DA-5.
The embodiments of the present application have been described in detail above with reference to the accompanying drawings, but the present application is not limited to the above embodiments, and various changes can be made within the knowledge of one of ordinary skill in the art without departing from the spirit of the present application. Furthermore, embodiments of the present application and features of the embodiments 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 the 3, 5-disubstituted-7 azaindole derivative is selected from the group consisting of compounds of the structures:
2. the method for 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 as follows:
performing Friedel-crafts acylation on 5-bromo-7-azaindole and oxalyl chloride to obtain an intermediate (1); condensing the intermediate (1) with 2- (2-pyridyl) ethylamine to obtain an intermediate (2); the intermediate (2) is subjected to Suzuki coupling reaction to obtain DA-5; carrying out Boc removal reaction on the 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 treating/preventing a disease associated with GPX 4;
b. a product that inhibits GPX enzyme activity;
c. a product that induces cellular iron death;
d. a product that modulates the degree of lipid peroxidation of a cell.
4. The use according to claim 3, wherein the disease associated with GPX4 comprises a tumour.
5. The use according to claim 4, wherein the tumor comprises breast cancer, lung cancer, liver cancer, glioblastoma.
6. An antitumor agent comprising the 3, 5-disubstituted-7 azaindole derivative of claim 1 or a pharmaceutically acceptable salt thereof.
7. The antitumor drug of claim 6, further comprising pharmaceutically acceptable excipients.
8. The antitumor drug of 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210639390.1A CN115057856B (en) | 2022-06-08 | 2022-06-08 | 3, 5-disubstituted-7-azaindole derivative and synthetic method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210639390.1A CN115057856B (en) | 2022-06-08 | 2022-06-08 | 3, 5-disubstituted-7-azaindole derivative and synthetic method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115057856A CN115057856A (en) | 2022-09-16 |
| CN115057856B true CN115057856B (en) | 2024-04-02 |
Family
ID=83200718
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210639390.1A Active CN115057856B (en) | 2022-06-08 | 2022-06-08 | 3, 5-disubstituted-7-azaindole derivative and synthetic method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115057856B (en) |
Citations (5)
| 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. |
| 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 |
| 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 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102008038221A1 (en) * | 2008-08-18 | 2010-02-25 | Merck Patent Gmbh | 7-azaindole derivatives |
| US10987353B2 (en) * | 2016-05-04 | 2021-04-27 | The Wistar Institute Of Anatomy And Biology | Methods of treating cancers overexpressing CARM1 with EZH2 inhibitors and platinum-based antineoplastic drugs |
-
2022
- 2022-06-08 CN CN202210639390.1A patent/CN115057856B/en active Active
Patent Citations (5)
| 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. |
| 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 |
| 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 |
|---|
| 7-氮杂吲哚及其类似物的合成与抗肿瘤和抗菌活性研究;谭雪;周莹;姚其正;;国外医药(抗生素分册);20100930;31(第05期);207-218 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115057856A (en) | 2022-09-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110382483A (en) | Condensed N- heterocyclic compound and its application method | |
| US10301273B2 (en) | Compounds and methods for treating cancer | |
| EA009196B1 (en) | Acetyl-2-hydroxy-1.3 diaminoalkanes | |
| Santos et al. | Synthesis, in vitro antimalarial activity and in silico studies of hybrid kauranoid 1, 2, 3-triazoles derived from naturally occurring diterpenes | |
| JP2010138192A (en) | Novel flavanoid and chalcone, as chemotherapeutic agent, chemopreventive agent, and antiangiogenic agent | |
| CN114315754B (en) | Hydroxamic acid compound and application thereof | |
| KR20210027382A (en) | Activator of the unfolded protein reaction | |
| CN108026141A (en) | Ligand of orphan nuclear receptor Nur77 and application thereof | |
| JP2020528076A (en) | Pharmaceutical compound | |
| CN110156822B (en) | Naphthol-phenylboronic acid compound and preparation method and application thereof | |
| KR101975299B1 (en) | Compounds containing core structure of indole acetic acid and uses thereof | |
| CN115057856B (en) | 3, 5-disubstituted-7-azaindole derivative and synthetic method and application thereof | |
| JPH09323928A (en) | Nerve differentiated induction agent | |
| CN110590778B (en) | 3, 10 di-p-methoxyphenyl 6, 12 diaza tetracubane compound, synthetic method and pharmaceutical composition | |
| CN110590779B (en) | 3, 10 di-p-chlorophenyl 6, 12 diazatetracubane compound, and synthetic method, application and pharmaceutical composition thereof | |
| JP5898768B2 (en) | Indene derivatives for use in the treatment of inflammatory bowel disease | |
| US11459313B2 (en) | Aziridinyl and amino dimeric naphthoquinone compounds and use for acute myeloid leukemia | |
| CN111518065A (en) | Parthenolide derivative and preparation method and application thereof | |
| CN113004268B (en) | Thiazole compound for inhibiting tumor cell growth and application thereof | |
| CN112979638B (en) | Thiazole compound and application thereof | |
| WO2004039797A1 (en) | A special kind of indole compounds, their preparation, and their use in treatment and prevention of those disease such as cancer | |
| CN112300235B (en) | Benzimidazole derivative BI321 and preparation method and application thereof | |
| CN112778201B (en) | Benzo [ b ] azepine-chalcone hybrid and preparation method and application thereof | |
| JP7348214B2 (en) | Crystal forms of HDAC6 selective inhibitors and uses thereof | |
| CN113768925A (en) | Preparation method of K252c derivative and application of K252c derivative in preparation of anti-tumor metastasis drugs |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |