CN115364079A - Application of benzyl naphthyl (sulfoxide) sulfone compound in preparing radioprotective medicament - Google Patents
Application of benzyl naphthyl (sulfoxide) sulfone compound in preparing radioprotective medicament Download PDFInfo
- Publication number
- CN115364079A CN115364079A CN202211074747.2A CN202211074747A CN115364079A CN 115364079 A CN115364079 A CN 115364079A CN 202211074747 A CN202211074747 A CN 202211074747A CN 115364079 A CN115364079 A CN 115364079A
- Authority
- CN
- China
- Prior art keywords
- sulfoxide
- radiation
- group
- irradiation
- benzyl naphthyl
- 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.)
- Pending
Links
- -1 benzyl naphthyl Chemical group 0.000 title claims abstract description 40
- 239000003814 drug Substances 0.000 title claims abstract description 35
- 150000003462 sulfoxides Chemical class 0.000 title claims abstract description 23
- 230000004223 radioprotective effect Effects 0.000 title claims abstract description 13
- 239000007924 injection Substances 0.000 claims abstract description 12
- 238000002347 injection Methods 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 230000037396 body weight Effects 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 2
- 239000011248 coating agent Substances 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 238000000576 coating method Methods 0.000 claims 1
- 230000005855 radiation Effects 0.000 abstract description 53
- 230000006378 damage Effects 0.000 abstract description 12
- 238000002360 preparation method Methods 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 9
- 230000002265 prevention Effects 0.000 abstract description 7
- 230000001154 acute effect Effects 0.000 abstract description 4
- 201000010099 disease Diseases 0.000 abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
- 231100000053 low toxicity Toxicity 0.000 abstract description 4
- 208000024891 symptom Diseases 0.000 abstract description 4
- 241000699670 Mus sp. Species 0.000 description 35
- PRFBWBYKWZVQJF-RRABGKBLSA-M sodium;4-[(e)-2-[(4-chlorophenyl)methylsulfonyl]ethenyl]benzoate Chemical compound [Na+].C1=CC(C(=O)[O-])=CC=C1\C=C\S(=O)(=O)CC1=CC=C(Cl)C=C1 PRFBWBYKWZVQJF-RRABGKBLSA-M 0.000 description 32
- 210000004027 cell Anatomy 0.000 description 21
- 230000004083 survival effect Effects 0.000 description 20
- 241000699666 Mus <mouse, genus> Species 0.000 description 13
- 238000004820 blood count Methods 0.000 description 12
- 230000005778 DNA damage Effects 0.000 description 11
- 231100000277 DNA damage Toxicity 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 11
- CHZJRGNDJLJLAW-RIQJQHKOSA-N (8r,9s,13s,14s,16r,17r)-3-cyclopentyloxy-17-ethynyl-13-methyl-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthrene-16,17-diol Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1C[C@@H](O)[C@@]4(O)C#C)C)CC2=CC=3OC1CCCC1 CHZJRGNDJLJLAW-RIQJQHKOSA-N 0.000 description 10
- 210000001772 blood platelet Anatomy 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 102000001554 Hemoglobins Human genes 0.000 description 8
- 108010054147 Hemoglobins Proteins 0.000 description 8
- 238000005286 illumination Methods 0.000 description 8
- 210000000265 leukocyte Anatomy 0.000 description 8
- 229950007863 nilestriol Drugs 0.000 description 8
- 210000003743 erythrocyte Anatomy 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 241000282414 Homo sapiens Species 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 238000003927 comet assay Methods 0.000 description 6
- 208000027418 Wounds and injury Diseases 0.000 description 5
- 231100000170 comet assay Toxicity 0.000 description 5
- 208000014674 injury Diseases 0.000 description 5
- 239000013642 negative control Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 239000007928 intraperitoneal injection Substances 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 3
- 208000019155 Radiation injury Diseases 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 238000001962 electrophoresis Methods 0.000 description 3
- 230000005865 ionizing radiation Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 206010073306 Exposure to radiation Diseases 0.000 description 2
- 208000002463 Sveinsson chorioretinal atrophy Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000005782 double-strand break Effects 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 210000000777 hematopoietic system Anatomy 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 239000000718 radiation-protective agent Substances 0.000 description 2
- 229940124553 radioprotectant Drugs 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 230000005783 single-strand break Effects 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- 210000003606 umbilical vein Anatomy 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- 208000001395 Acute radiation syndrome Diseases 0.000 description 1
- 101150065175 Atm gene Proteins 0.000 description 1
- 230000005971 DNA damage repair Effects 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical group [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 206010068142 Radiation sickness syndrome Diseases 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000012820 cell cycle checkpoint Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 108091092356 cellular DNA Proteins 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 238000010205 computational analysis Methods 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000005251 gamma ray Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 238000009650 gentamicin protection assay Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- BEJNERDRQOWKJM-UHFFFAOYSA-N kojic acid Chemical compound OCC1=CC(=O)C(O)=CO1 BEJNERDRQOWKJM-UHFFFAOYSA-N 0.000 description 1
- 229960004705 kojic acid Drugs 0.000 description 1
- WZNJWVWKTVETCG-UHFFFAOYSA-N kojic acid Natural products OC(=O)C(N)CN1C=CC(=O)C(O)=C1 WZNJWVWKTVETCG-UHFFFAOYSA-N 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- OLSOLSGWNZJLDL-UHFFFAOYSA-N n'-[ethoxy(hydroxy)phosphinothioyl]oxypropane-1,3-diamine Chemical compound CCOP(O)(=S)ONCCCN OLSOLSGWNZJLDL-UHFFFAOYSA-N 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002633 protecting effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000003537 radioprotector Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 210000001626 skin fibroblast Anatomy 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 150000003752 zinc compounds Chemical class 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
- A61K31/10—Sulfides; Sulfoxides; Sulfones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Toxicology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to an application of benzyl naphthyl (sulfoxide) sulfone compounds in preparation of radioprotective medicines. The invention discloses an application of a benzyl naphthyl (sulfoxide) sulfone compound in preparation of a radiation protection medicament, wherein the benzyl naphthyl (sulfoxide) sulfone compound has a structure shown in a formula I. The benzyl naphthyl (sulfoxide) sulfone compound has the characteristics of high efficiency, low toxicity, prevention and treatment, stable quality, convenient taking, effective oral injection and the like, can directly resist multi-system damage caused by radiation, effectively relieves the symptoms of acute radiation diseases, wins precious time for subsequent comprehensive treatment and provides a new thought and direction for developing efficient and safe radiation protection medicaments.
Description
The application is a divisional application of Chinese patent application with the application date of 2018, 06 and 26 months, and the application number of 201810666530.8 is the application number of 'the application of benzyl naphthyl (sulfoxide) sulfone compounds in the preparation of radioprotective medicines'.
The present application also claims priority from the chinese patent office filed on 12.02/2018, and having application number CN201810146424.7, the entire contents of which are incorporated herein by reference.
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an application of a benzylnaphthyl (sulfoxide) sulfone compound in preparation of a radiation protection medicine.
Background
Prevention and treatment of radiation damage caused by nuclear radiation is always a great medical problem of high concern at home and abroad. In recent years, with the development of nuclear weapon technology, the development and application of nuclear energy and radiation diagnosis and treatment technology, the dangers of nuclear diffusion, nuclear accidents, nuclear terrorism and the like are difficult to eliminate, the risk of radiation leakage is not neglected, and the national safety and health face potential serious threats.
The radiation protection medicament, namely the radiation injury prevention medicament and/or the radiation injury treatment medicament can directly resist multi-system injury caused by ionizing radiation, effectively relieve the symptoms of acute radiation diseases and win precious time for subsequent comprehensive treatment. Therefore, the development of the high-efficiency and safe radiation protection medicine has great practical significance. The ideal and practical radiation protection medicine needs to meet the conditions of high efficiency, low toxicity, prevention and treatment, stable quality, convenient taking, effective oral administration and injection, and the like. So far, no ideal medicine meeting all the requirements is developed at home and abroad.
The development of the radiation protection medicament is a worldwide problem, and the medicaments developed at home and abroad for preventing and treating the radiation damage have a plurality of defects in practical application, such as unclear target points, weak medicinal effect or large side effect. The radiation protection medicament has the characteristics of high efficiency, low toxicity, prevention and treatment, stable quality, convenient taking, effectiveness in oral injection and the like, and is the research and development direction in the field.
Disclosure of Invention
The invention aims to provide the application of a benzyl naphthyl (sulfoxide) compound in preparing a radiation protection medicament aiming at the technical defects in the prior art.
In order to achieve the above purpose, the invention provides the following technical scheme:
the invention provides a radioprotective pharmaceutical composition, which comprises a benzyl naphthyl (sulfoxide) compound, a geometric isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; and a pharmaceutical carrier or excipient;
the benzyl naphthyl (sulfoxide) compound has a structure shown in a formula I:
the pharmaceutical composition is an injection, the dosage is 200-400 mg/Kg (body weight)/day, and the injection is used once each for 24 hours and 15min before irradiation.
Preferably, the medicament is a pharmaceutical composition containing the benzylnaphthyl (sulfoxide) sulfone compound, a geometric isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate compound thereof and a pharmaceutically acceptable carrier or excipient.
Preferably, the medicament is tablets, pills, granules, capsules, coating agents, oral liquid, emulsion, powder, injection or suppository.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides application of benzyl naphthyl (sulfoxide) sulfone compounds serving as protein tyrosine kinase inhibitors in preparation of radioprotective medicaments. The invention discovers that the benzyl naphthyl (sulfoxide) sulfone compound with the structure shown in the formula I has better radiation protection activity, and comprises the functions of improving the survival rate of HUVECs (human umbilical vein endothelial cells) after irradiation, effectively repairing DNA damage caused by ionizing radiation, effectively improving the survival rate of C57/BL mice after irradiation and improving the hemogram index of the mice. The experimental results can reveal that the compounds can be used as radioprotective medicines, and are suitable for preventing and treating radiation injury, and body injury caused by radiation, including early symptoms such as dizziness, fatigue, appetite decrease and the like, DNA injury, digestive tract injury, hematopoietic system injury, brain injury and the like caused by different radiation doses to human beings or animals.
The benzyl naphthyl (sulfoxide) sulfone compound with the structure shown in the formula I has the characteristics of high efficiency, low toxicity, prevention and treatment, stable quality, convenient taking, effective oral injection and the like, can directly resist multi-system damage caused by radiation, effectively relieves the symptoms of acute radiation diseases, wins precious time for subsequent comprehensive treatment and provides a new thought and direction for developing efficient and safe radiation protection medicaments.
Drawings
FIG. 1 is a bar graph showing the results of a comet assay for compounds of the present invention;
FIG. 2 shows a microscope photograph of comet assay of the compound of the present invention;
FIG. 3 is a graph showing the change in body weight of a mouse in an animal experiment using the compound of the present invention;
FIG. 4 is a graph showing the change in survival rate of mice in an animal experiment using the compound of the present invention;
FIG. 5 is a graph showing the white blood cell count of mice 1d to 30d after the irradiation;
FIG. 6 is a graph showing a mouse red blood cell count curve from 1d to 30d after the light;
FIG. 7 is a graph showing the hemoglobin content of a mouse hemogram from 1d to 30d after the irradiation;
FIG. 8 is a graph showing the platelet count of mice 1d to 30d after the irradiation.
Detailed Description
The present invention will be described more specifically and further illustrated with reference to specific examples, which are by no means intended to limit the scope of the present invention.
The invention provides a radiation protection pharmaceutical composition, which comprises benzyl naphthyl (sulfoxide) compound, geometric isomer, pharmaceutically acceptable salt, hydrate or solvate thereof; and a pharmaceutical carrier or excipient;
the benzyl naphthyl (sulfoxide) compound has a structure shown in a formula I:
the pharmaceutical composition is an injection, the dosage is 200-400 mg/Kg (body weight)/day, and the injection is used once each for 24 hours and 15min before irradiation.
The invention provides a benzyl naphthyl (sulfoxide) sulfone compound (M) with a structure shown in a specific formula I 18 ) Is a compound with protein tyrosine kinase inhibitory activity, and the preparation thereof is described in the examples in the published document CN 104892471A.
The invention provides application of a benzyl naphthyl (sulfoxide) compound with a structure shown in a formula I as a protein tyrosine kinase inhibitor in preparation of radioprotective medicaments.
The current classical radioprotective agent is S-2-3 (3-aminopropylamino) ethyl thiophosphate (see Wasserman T H, brizel D M. The role of amino acids a radioprotector [ J ]. Oncology,2001,15 (10): 1349-1354.) for the structure of WR-2721, but is more toxic (sweet amino et al. Kojic acid and its manganese and zinc compounds as reactive radioprotectants [ J. Bioorg. Med. Chem. Lett.17 (2007) 45-48). Ex-RAD ((E) -4-carboxystyryl-4-chlorobenzyl methyl sulfone sodium salt) recently developed by Onck Norwa (Onconoya) pharmaceutical company in America can be used for preventing and treating lethal dose exposure acute radiation disease, and has safety superior to WR-2721, and in an in vitro experiment, the Ex-RAD can obviously improve the survival rate of three human normal cells, namely Human Umbilical Vein Endothelial Cells (HUVECs), human lung fibroblasts (HFL-1) and human skin fibroblasts (AG 1522) after irradiation; in vivo experiments, the radioprotective preparation for mice is a novel radioprotective preparation developed by the company, and can obviously reduce the damage of radiation to the mice by performing prophylactic administration (subcutaneous injection and intraperitoneal injection) on the mice.
The invention discovers that the benzyl naphthyl (sulfoxide) sulfone compound with the structure shown in the formula I has radiation prevention and control activity.
The following experiments prove that the benzyl naphthyl (sulfoxide) sulfone compound with the structure shown in the formula I can improve the survival rate of HUVECs after irradiation, effectively repair DNA damage caused by ionizing radiation, effectively improve the survival rate of C57/BL mice after irradiation and improve the hemogram index of the mice, and the compound with the structure shown in the formula I can be used as a radiation protection medicament. Experimental groups and data computational analysis were processed according to statistical methods. All radiation exposures (cells and mice) were performed using 8.0Gy, institute of radiation medicine, national institute of liberated military medical science, ministry of China 60 Co gamma or 10.0Gy 60 And a Co gamma irradiation device.
The first experimental example: evaluation experiment of radioprotectant active cells
The radioprotective activity of the compounds was determined by measuring the proliferation activity of HUVECs cells after exposure to radiation using the MTS method by means of prophylactic administration.
The experiment was divided into a blank group, a negative control group, a negative irradiation group (blank group containing neither cells nor irradiation, negative control group containing cells without irradiation, negative irradiation group containing cells with irradiation), an Ex-RAD group and Compound M 18 And (4) grouping. The blank contained no cells and 100. Mu.L of blank medium was added per well.HUVECs in logarithmic growth phase were taken, adjusted to 4000 cell concentration/mL, and seeded in 96-well plates at 100. Mu.L per well (400 cells per well). Day 2 negative control and negative irradiation groups 100 μ L of blank medium was added per well. Ex-RAD group and M 18 Cells were dosed per well. Ex-RAD was made up in DMSO to 50mM stock, M 18 Preparing 100mM mother liquor with DMSO, and preparing to the required concentration with culture medium before adding drugs. Ex-RAD group and M 18 The group was prepared by adding 100. Mu.L of a 20. Mu. Mol. L solution to each well -1 Ex-RAD solution of (A) and M 18 And (3) solution. On day 3 (24 hours after dosing), the negative irradiation group, ex-RAD group and M 18 Cells of the group were placed in 8Gy 60 And (5) irradiating the cells by Co gamma rays for one time, and immediately returning the cells to the cell culture box after the irradiation is finished, wherein the cells are observed. On the 4 th day after the irradiation, the cell proliferation activity was measured by MTS method, 20. Mu. LMTS was added to each well, and after 3 hours, OD value at 490nm was measured by a microplate reader to calculate the survival rate.
Survival rate (%) =100 × (negative irradiation group OD value-blank OD value)/(negative control group OD value-blank OD value)
The experimental results are expressed in x +/-s, the single-factor variance analysis is carried out on the survival rate data by using SPSS 13.0 software in the group comparison, and the difference is significant in statistical significance when P is less than 0.05. The results are shown in Table 1.
TABLE 1M 18 And cell survival after Ex-RAD irradiation
Note: * P is less than 0.05, and is compared with a negative irradiation group; # P < 0.05, x compared to Ex-RAD group
The data in Table 1 show that at a concentration of 20. Mu.M, M is 18 Can obviously improve the survival of HUVECs after irradiation, and the radiation protection effect is obviously better than that of Ex-RAD.
Experiment example two: experiment of single cell gel electrophoresis (comet electrophoresis)
Detection of M with comet assay kit 18 Repair of radiation-induced DNA damage. The grouping situation is as follows: to be free from radiation and use medicineTreating the material as a blank control group to receive radiation but not using a medicament as a negative control group; to receive radiation and to treat with drugs into corresponding drug groups, e.g. Ex-Rad groups, M 18 And (4) grouping.
The ATM gene located in chromosome 11q 22-23 is a key central regulatory factor in the reaction conduction path after cell DNA damage, and initiates multiple cell cycle check points through proteins such as p53 and the like to participate in DNA damage repair, thereby playing a role in radiation protection.
Comet assay is a common method for measuring DNA damage in single cells. The effect of the above compounds in protecting HUVECs cells from radiation-induced DNA damage was monitored using the basic comet assay. During electrophoresis, damaged cellular DNA (including fragments and strand breaks) separates from intact DNA, migrating farther than intact DNA, and a typical comet tail shape is observed under a microscope. The degree of DNA damage is usually judged by measuring the length of the comet tail. Radiation-induced DNA damage can lead to an increase in the number of Single Strand Breaks (SSBs), double Strand Breaks (DSBs), and alkali-labile damage. The degree of DNA damage was judged by calculating the tail length using CASP (commercial Software Project Lab) Software. At least 50 cells were randomly selected for analysis.
The experimental results show that M 18 Has the function of reducing DNA damage, and the experimental results are shown in table 2, figure 1 and figure 2.
TABLE 2 comet electrophoresis test results
| Group of | Tail space (mum) |
| Blank control group | 14.62±6.18 |
| Negative irradiation group | 36.48±11.07 |
| Ex-RAD | 33.6±10.24* |
| M 18 | 18.40±3.60 # |
Note: * P is less than 0.05, and is compared with a negative irradiation group; # P < 0.05, compared to Ex-RAD group
It can be seen that the comet tail of the negative shot group is significantly increased; and M 18 The comet tail distance was significantly smaller than that of the negative shot group and that of the Ex-RAD group, indicating M 18 Can obviously reduce DNA damage, and the activity is higher than that of Ex-RAD.
Experimental example three: mouse survival assay
M 18 As the test compound, male C57/BL was selected as the test animal. The test was conducted in 4 groups of 10 individuals, each of which was a radiation control group (20% of HPCD-containing physiological saline), a positive control group (nilestriol 5mg/kg, ex-RAD300 mg/kg), M 18 Group (300 mg/kg). Nilestriol is administrated once in 24 hours before the administration, 0.2 mL/patient, in a intragastric manner (nilestriol is an estrogen drug used for early treatment of acute radiation sickness); the other groups are administered by intraperitoneal injection once respectively 24h and 30min before the administration, and each time is 0.2 mL. The irradiation dose was 8.0Gy. Mouse body weight and 30-day survival were recorded and counted.
The experimental results show that M 18 Has the function of prolonging the survival of mice, and the experimental results are shown in a table 3 and figures 3 to 4.
Table 3 table of weight changes of mice in mice survival experiments
Note: * p is less than 0.05, compared with a radiation control group; # p < 0.05, x compared to Ex-Rad group; x ± s, n =10
As can be seen from the above results, the estradiol nilates and M are present from day 14 to day 22 18 The weight of the mice in the group is obviously higher (P is less than 0.05) than that of the radiation control group and the Ex-RAD group; the survival rate of the radiation control group is 50%, the survival rate of the nilestriol group is 100%, the survival rate of the Ex-RAD group is 60%, and the survival rate of the M group is 18 The group survival rate was 100%. Nilestriol and M compared to Ex-RAD group 18 The survival rate of the mice after irradiation can be obviously improved by all the groups, which shows that M 18 The radioprotective effect of the composition can reach the nilestriol level and is obviously stronger than that of Ex-RAD.
Experimental example four: mouse hemogram determination experiment
M 18 Ex-RAD and nilestriol were used as positive controls for test compounds. The experimental animals were adult male C57 mice, bred by Schbefu (Beijing) Biotechnology Ltd. The weight of the mouse is 18.0-22.0 g. Experimental animal license number: SCXK (Ko) 2016-0002. The experimental animals are bred in an SPF laboratory of the animal center of the military medical research institute, 5 mice are bred in each cage, and the mice are fed with feed specially prepared for the mice and are fed with water freely. The temperature in the animal laboratory is kept at about 25 ℃, the relative humidity is kept at 40-70%, and the illumination is carried out for 12 hours every day.
Irradiation conditions: 60 co gamma-ray is irradiated to the whole body once, the absorption dose rate is 53.04cGy/min, and the absorption dose of the irradiated mice is 6.5Gy. The experiment was set up in 4 groups of 10 animals each. Respectively, a radiation control group (20% HPCD-containing physiological saline), a positive control nitrol group (5 mg/kg), a positive control Ex-Rad group (300 mg/kg), M 18 Group (300 mg/kg). The nilestriol is administrated once by intragastric gavage 24 hours before the control, and each nilestriol is 0.2 mL; in other groups, the medicine is respectively administrated by intraperitoneal injection once in 24h and 30min before the irradiation, and each time is 0.2 mL. The time and schedule of administration are shown in table 4.
And (3) hemogram determination: collecting blood from tail vein of mouse, wherein the day of irradiation is 0 day, and collecting blood from tail vein before irradiation and after irradiation for 1,4,7, 10, 14, 18, 22 and 30 days, and detecting peripheral blood leukocyte, erythrocyte, platelet count and hemoglobin content.
The experimental results show that M 18 The mouse hemogram index after the control has the effect of increasing, and the experimental results are shown in tables 5-8 and figures 5-8.
TABLE 4 dosing Schedule
Note: ip: the administration is carried out by intraperitoneal injection; po, oral administration.
TABLE 5 white blood cell count table for mice 1d-30d after lighting
Note: * P is less than 0.05, compared with a radiation control group; # P < 0.05, compared to Ex-RAD group; x ± s, n =10
As can be seen from Table 5 and FIG. 5, the white blood cell count of each group of mice was significantly reduced 1 to 4 days after the light, and M was significantly reduced 7 to 18 days after the light 18 The mean white blood cell count of the group was consistently higher (P < 0.05) than that of the radiation control group and Ex-RAD group. The mean white blood cell count of each group of mice was significantly increased 22 to 30 days after the control, and the difference in the mean was not statistically significant. The results show that M 18 The white blood cell count level of 7 to 18 days after the mice are irradiated can be obviously improved.
TABLE 6 mouse erythrocyte counts 1d-30d post-illumination
Note: * P is less than 0.05, compared with a radiation control group; # P < 0.05, compared to Ex-RAD group; x ± s, n =10
As seen from Table 6 and FIG. 6, the mean red blood cell count of each group of mice was significantly reduced 1 to 10 days after the irradiation, and M was observed 10 to 18 days after the irradiation 18 Of group (a)The mean red cell count was consistently higher (P < 0.05) than the control and Ex-RAD groups. The mean red blood cell count of each group of mice returned to approximately pre-illumination levels 22 to 30 days post-illumination. The results show that M 18 Can significantly improve the red blood cell count level of 10 to 18 days after the mice are irradiated.
TABLE 7 hemoglobin content of mice after 1d-30d
Note: * P is less than 0.05, compared with a radiation control group; # P < 0.05, compared to Ex-RAD group; x ± s, n =10
As seen from Table 7 and FIG. 7, the mean hemoglobin content of each group of mice was significantly reduced 1 to 10 days after the irradiation, and M was found to be significantly reduced 10 to 18 days after the irradiation 18 The mean hemoglobin content of the groups was consistently higher (P < 0.05) than that of the radiation control group and Ex-RAD group. The mean hemoglobin content of each group of mice returned to almost pre-illumination levels 22 to 30 days after illumination. The results show that M 18 Can obviously improve the hemoglobin content level of 10 to 18 days after the mice are irradiated.
TABLE 8 platelet counts from 1d to 30d post-illumination in mice
Note: * P is less than 0.05, compared with a radiation control group; # P < 0.05, compared to Ex-RAD group; x ± s, n =10
As seen from table 8 and fig. 8, the mean platelet count values of each group were significantly reduced 1 to 7 days after the irradiation. 7-10 days after the irradiation, the mean value of the platelet count of the irradiation control group and the Ex-RAD group is continuously reduced; and M 18 The mean platelet count values in the group started to rise significantly, and the nilestriol group was more stable, with platelet counts significantly higher (P < 0.05) than in the radiation control group and the Ex-RAD group. From 10 to 18 days after the light, M 18 The mean platelet count of the groups was significantly higher (P < 0.05) than the radiation control and Ex-RAD groups. 22 to 30 days after the irradiation, the blood volume of each group is smallThe plate count mean returned to almost pre-illumination levels. The results show that M 18 The platelet count level of the mice can be obviously improved after 10 to 18 days of irradiation.
Through the analysis of the indexes of the hemogram of the mouse after the irradiation, the white blood cell count, the red blood cell count, the hemoglobin and the platelet count of the mouse are obviously reduced 1 to 14 days after the irradiation, which indicates that the irradiation causes serious damage to the hematopoietic system of the mouse during the period. Administration of M to mice 18 After that, the four indexes are obviously increased 10-18 days after the irradiation, which is obviously higher than that of a (P < 0.05) radiation control group and an Ex-RAD group, and the result shows that M is 18 Can relieve hematopoietic toxicity caused by radiation, has good radiation protection effect, and has application prospect as a radiation protective agent.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the content of the present invention.
Claims (3)
1. A radioprotective pharmaceutical composition comprising a benzylnaphthyl (thio) sulfone, a geometric isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof; and a pharmaceutical carrier or excipient;
the benzyl naphthyl (sulfoxide) compound has a structure shown in a formula I:
the pharmaceutical composition is an injection, the dosage is 200-400 mg/Kg (body weight)/day, and the injection is used once each for 24 hours and 15min before irradiation.
2. The use according to claim 1, wherein the medicament is a pharmaceutical composition comprising the benzylnaphthyl (sulfoxide) compound, a geometric isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a pharmaceutically acceptable carrier or excipient.
3. The use according to claim 1, wherein the medicament is a tablet, pill, granule, capsule, coating, oral liquid, emulsion, powder, injection or suppository.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810146424 | 2018-02-12 | ||
| CN2018101464247 | 2018-02-12 | ||
| CN201810666530.8A CN108653252A (en) | 2018-02-12 | 2018-06-26 | Benzyl naphthalene（It is sub-）Application of the sulfone compound in preparing radioprotector |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810666530.8A Division CN108653252A (en) | 2018-02-12 | 2018-06-26 | Benzyl naphthalene（It is sub-）Application of the sulfone compound in preparing radioprotector |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115364079A true CN115364079A (en) | 2022-11-22 |
Family
ID=63772969
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211074747.2A Pending CN115364079A (en) | 2018-02-12 | 2018-06-26 | Application of benzyl naphthyl (sulfoxide) sulfone compound in preparing radioprotective medicament |
| CN201810666530.8A Pending CN108653252A (en) | 2018-02-12 | 2018-06-26 | Benzyl naphthalene（It is sub-）Application of the sulfone compound in preparing radioprotector |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810666530.8A Pending CN108653252A (en) | 2018-02-12 | 2018-06-26 | Benzyl naphthalene（It is sub-）Application of the sulfone compound in preparing radioprotector |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN115364079A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892471A (en) * | 2015-05-15 | 2015-09-09 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | Substances having protein tyrosine kinase inhibitory activity, and preparation method and use thereof |
-
2018
- 2018-06-26 CN CN202211074747.2A patent/CN115364079A/en active Pending
- 2018-06-26 CN CN201810666530.8A patent/CN108653252A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892471A (en) * | 2015-05-15 | 2015-09-09 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | Substances having protein tyrosine kinase inhibitory activity, and preparation method and use thereof |
Non-Patent Citations (2)
| Title |
|---|
| 井娟;王力彬;冯甜;张书锋;黄海英;刘畅;李想;郝勇;: "抗辐射药Ex-RAD的研究进展", 中国药师, no. 09, pages 1631 * |
| 周玉美;唐林;张首国;彭涛;王刚;温晓雪;刘曙晨;孙云波;王林;: "香豆素苄(亚)砜类化合物的合成及其抗辐射活性评价", 国际药学研究杂志, no. 05, pages 427 - 431 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108653252A (en) | 2018-10-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Pietrofesa et al. | Radiation mitigating properties of the lignan component in flaxseed | |
| WO2021032212A1 (en) | Anti-aging medicine d/a targeting aging cells in tissue microenvironment and use thereof | |
| EP0986378A1 (en) | Phorbol esters as anti-neoplastic agents | |
| Feng et al. | Salidroside, a scavenger of ROS, enhances the radioprotective effect of Ex-RAD® via a p53-dependent apoptotic pathway | |
| WO2017177479A1 (en) | Application of syringaldehyde in preparation of drug for preventing intestinal injuries caused by ionizing radiation | |
| EP3957314A1 (en) | Use of extract from rabbit skin inflamed by vaccinia virus in treating hematopoietic system damage | |
| CN115364079A (en) | Application of benzyl naphthyl (sulfoxide) sulfone compound in preparing radioprotective medicament | |
| EP0680756B1 (en) | Use of a combination of antineoplastons for the manufacture of a medicament for the treatment of neurofibromatosis | |
| RU2516027C2 (en) | Combination of anticancer agents | |
| CN109700808B (en) | Application of SB203580 in preparation of medicine for preventing and/or treating altitude disease caused by acute altitude advance | |
| CA3166741A1 (en) | Combination therapy for treating cancer | |
| CN111728966A (en) | Application of EGCG in preparation of medicine for preventing intestinal injury caused by ionizing radiation | |
| RU2448973C2 (en) | Application of trisubstituted glycerol compounds for treatment of radiolesions | |
| CN108992463A (en) | A kind of composition and pharmaceutical preparation for treating lung cancer | |
| CN111407748B (en) | Application of tyrosol in preparation of medicine for treating brain glioma | |
| US11986541B2 (en) | Method of preventing the development of melanoma | |
| CN111249298B (en) | Anticancer pharmaceutical composition containing maduramicin and cisplatin | |
| CN108403701B (en) | Application of dihydrotripterine in preparing medicine for preventing or treating blood tumor diseases | |
| CN117942345A (en) | Method for treating NUT cancer by using ARV-825 molecular ligand | |
| CN111450104A (en) | Application of vitamin D in preventing and treating intestinal injury caused by radiation | |
| EP4322958A1 (en) | Wee1 compound for treating uterine serous carcinoma | |
| CN117500505A (en) | WEE1 compounds for the treatment of uterine serous carcinoma | |
| Wu | Clinical application of palbociclib as a treatment of cancer | |
| WO2022218958A1 (en) | Combination comprising everolimus and amcenestrant | |
| CN111658634A (en) | Medicine for radically treating vivax malaria |
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 | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20221122 |