CN117820250A - Application of 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative in osteoporosis - Google Patents
Application of 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative in osteoporosis Download PDFInfo
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- 208000001132 Osteoporosis Diseases 0.000 title claims abstract description 23
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- 230000034994 death Effects 0.000 claims abstract description 34
- 239000003814 drug Substances 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- -1 naphthalene-1-ylmethyl Chemical group 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 claims abstract description 5
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims abstract description 4
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims abstract description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 4
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims abstract description 4
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims abstract description 3
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Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative, a method thereof and application thereof in preventing osteoporosis. 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivatives having the structure shown in formula (I):wherein R is one of hydrogen, benzyl, 4-methylbenzyl, 4-methoxybenzyl, 4-cyanophenyl, 4-fluorobenzyl, naphthalene-1-ylmethyl, methyl and 4-nitrobenzyl. The 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative can block the chain reaction of lipid free radicals, reduce the damage effect of the free radicals on cell membranes and prevent the death of cell ironsAnd the cells are protected, so that the treatment effect on diseases related to an iron death mechanism is realized.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative, a preparation method thereof and application thereof in preventing osteoporosis.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Osteoporosis (OP) is a disease characterized by low bone mass and destruction of bone structure, resulting in a decrease in bone strength in patients and an increased risk of fracture. At present, with further intensive researches on the mechanism of osteoporosis, researches prove that the osteoporosis is indistinct from iron death.
Cell iron death (ferrovision) is a novel cell death pattern, different from apoptosis, necrosis, autophagy, etc. A decrease in mitochondrial number, an increase in membrane density, and a disruption of the normal structure of the mitochondrial cristae were observed in human epidermal fibroblasts treated with the iron death inducer, erastin, these morphological features helping to distinguish iron death from other cell death patterns. Expressed in terms of biological properties are reduced cystine uptake, glutathione (GSH) consumption, reduced cystine/glutamate antiporter (cystone/glutamate antiporter, also known as System Xc ∈) activity, and abnormal accumulation of iron ions and ROS. Typical features are: mitochondria become smaller, the density of the bilayer membrane increases, and the membrane also shows increased lipid active oxygen free radicals in the cell membrane.
It was found that iron death can disrupt bone homeostasis by inhibiting osteogenic differentiation and stimulating osteoclast production, resulting in osteoporosis. The key of the osteoporosis mechanism is imbalance of bone steady state, and the pathogenesis is closely related to factors such as abnormal metabolism of the organism, gene polymorphism, microcirculation disturbance and the like. During the onset of osteoporosis, the iron death process of osteoblasts, osteoclasts, is involved, which involves a large accumulation of lipid peroxides. The iron death inhibitor takes osteoblasts, osteoclasts and osteocytes as targets, improves osteoporosis by reducing iron overload in vivo and inhibiting the generation of lipid free radicals, and is expected to be used for elucidating a new mechanism of osteoporosis and developing new technologies and new medicines for treating the osteoporosis.
Ferrosistatin-1 and Liproxstatin-1 are first-generation small molecule iron death inhibitors, and serve as free radical capturing agents to inhibit the propagation of lipid peroxidation and block the occurrence of cell iron death. The inhibitor has definite action mechanism and structure-activity relationship. However, these two compounds have the disadvantages of short half-life, poor metabolic stability and greater toxicity, respectively.
Disclosure of Invention
In order to solve the defects in the prior art, the invention aims to provide a 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative, and preparation and application thereof. On the basis of researching the action mechanism of cell iron death, the invention discovers that a 2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol derivative can be used as an inhibitor for targeting cell iron death through reasonable drug design, and provides the application of the compound in preventing and treating osteoporosis.
In order to achieve the above object, the present invention is realized by the following technical scheme:
in a first aspect, the present invention provides a 2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol derivative having the structure shown in formula (I):
wherein R is one of hydrogen, benzyl, 4-methylbenzyl, 4-methoxybenzyl, 4-cyanophenyl, 4-fluorobenzyl, naphthalene-1-ylmethyl, methyl and 4-nitrobenzyl.
The 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative can block the chain reaction of lipid free radicals, reduce the damage effect of the free radicals on cell membranes, prevent the occurrence of cell iron death and protect cells, thereby realizing the treatment effect on iron death related diseases.
In a second aspect, the present invention provides a process for the preparation of a 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative according to the first aspect, comprising the steps of, when R is other than hydrogen:
s1, dissolving 2-amino-3-hydroxybenzoyl hydrazine, carbon disulfide and alkali into methanol for reaction, removing a solvent after the reaction is finished, and purifying a product to obtain 2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol;
s2, when R is not hydrogen, dissolving R-X, 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol and alkali into a solvent for reaction, removing the solvent after the reaction is finished, and purifying the product to obtain a 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative;
r in R-X is the same as R in formula (I) and is not H, X is Br or I.
Preferably, in the step S1, the molar ratio of the 2-amino-3-hydroxybenzohydrazide to the carbon disulfide to the alkali is 1:2.9-3.1:0.9-1.1, the reaction temperature is 65-75 ℃ and the time is 7-9h.
Preferably, in step S2, the molar ratio of R-X, 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol and base is 0.9-1.1:1:0.9-1.1, the reaction temperature is room temperature, and the reaction time is 3-5h.
Preferably, the base comprises potassium hydroxide or sodium hydroxide and the solvent comprises methanol.
In a third aspect, the present invention provides the use of a 2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol derivative as described in the first aspect as an iron death inhibitor.
Preferably, the application includes any one of the following:
(1) For use in the prevention, amelioration or treatment of a disease associated with the iron death pathway;
(2) Is applied to the preparation of medicaments for preventing, improving or treating diseases related to the iron death pathway;
(3) The method is applied to the preparation of the iron death pathway inhibition model.
In a fourth aspect, the present invention provides the use of a 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative as described in the first aspect for the preparation of an osteoporosis prevention product.
In a fifth aspect, the present invention provides a medicament comprising a 2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol derivative as described in the first aspect.
Preferably, the medicament further comprises pharmaceutically acceptable additives or auxiliary materials; the dosage form of the medicine is selected from tablet, pill, powder, suspension, gel, emulsion, cream, granule, nanoparticle, capsule, suppository, injection, spray or injection.
The beneficial effects obtained by one or more of the technical schemes of the invention are as follows:
the series of 2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol derivatives prepared by the invention can effectively inhibit cell iron death, promote the expression of osteoblast osteogenesis indexes, have the effect of treating and relieving osteoporosis, provide theoretical support for taking the death of the osteoblast iron as a target point, improve bone homeostasis and treat osteoporosis, and particularly provide guidance for clinically developing novel medicines, thereby improving the quality of life of patients suffering from osteoporosis and reducing the risk of related fracture.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 is a graph showing comparison of cell viability in different treatment groups in an iron cell death assay, wherein Control represents addition of DMSO, erastin represents addition of Erastin (10. Mu.M), E+Compoun3 represents addition of Erastin (10. Mu.M) +2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol derivative 3 (1. Mu.M), E+Fer-1 represents Erastin (10. Mu.M) +Ferrosin-1 (0.1. Mu.M);
FIG. 2 is a graph of lipid peroxidation fluorescence staining of different treatment groups in an iron cell death assay, wherein Control represents addition of DMSO, erastin represents addition of Erastin (10. Mu.M), E+Compound3 represents addition of Erastin (10. Mu.M) +2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol derivative 3 (1. Mu.M), E+Fer-1 represents Erastin (10. Mu.M) +Ferrositin-1 (0.1. Mu.M);
FIG. 3 is a graph showing comparison of GPX4 and Runx-2 protein levels in different treatment groups in a cell iron death assay, wherein Control represents addition of DMSO, erastin represents addition of Erastin (10. Mu.M), E+Compound3 represents addition of Erastin (10. Mu.M) +2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol derivative 3 (1. Mu.M), E+Fer-1 represents Erastin (10. Mu.M) +Ferrositin-1 (0.1. Mu.M);
FIG. 4 is a graph showing the comparison of the mRNA levels of GPX4 and Runx-2 in different treatment groups in a cell iron death assay, wherein Control represents the addition of DMSO, erastin represents the addition of Erastin (10. Mu.M), E+Compound3 represents the addition of Erastin (10. Mu.M) +2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol derivative 3 (1. Mu.M), E+Fer-1 represents Erastin (10. Mu.M) +Ferrosin-1 (0.1. Mu.M);
FIG. 5 is a graph showing a comparison of bone conditions in a rat osteoporosis alleviation test, wherein BLANK represents an untreated control group, DMSO under GIOP model represents a GIOP model group, compound 3 under GIOP model represents a GIOP model+2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative 3 group;
FIG. 6 is a comparative image of immunohistochemical staining of GPX4 expression in bone in a rat osteoporosis mitigation experiment, wherein BLANK represents untreated control group, DMSO under GIOP model represents GIOP model group, compound 3 under GIOP model represents GIOP model+2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol derivative 3 group.
Detailed Description
In order to enable those skilled in the art to more clearly understand the technical scheme of the present invention, the technical scheme of the present invention will be described in detail below with reference to specific examples and comparative examples.
Ferrosistatin-1, erastin and RSL3 were purchased from sigma, and were all dissolved in sterile dimethyl sulfoxide DMSO to make the desired concentration. The preparation of 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivatives is shown in examples 1-9 of the present invention.
MC3T3 cell line culture conditions: alpha-MEM Medium (GIBCO) containing 10% FBS (GIBCO), 37℃and 5% CO 2 Saturated humidity incubator.
Statistics used in the present invention were analyzed using R software and experimental data were expressed as mean±sem. The comparison between the groups of cells and animals was tested using Tukey's test (ANOVA), the comparison between the two groups was tested using Student's t-test, and was considered statistically significant by P <0.05, with the letter differences representing P <0.05.
Example 1
Synthesis of 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol (as shown in formula (II):
2-amino-3-hydroxybenzohydrazine (1.67 g,10 mmol), KOH (0.56 g,10 mmol) and carbon disulphide (CS 2 ) (1.80 mL,30 mmol). The mixture was heated at 70℃for 8 hours. After removal of the solvent, the crude product was purified by column chromatography to give 1.15 g (yield 55.0%) of a white powder. 1 HNMR(400MHz,DMSO)δ14.72(s,1H),9.88(s,1H),7.08(dd,J＝8.1,1.2Hz,1H),6.85(dd,J＝7.7,1.2Hz,1H),6.56(t,J＝7.9Hz,1H),5.80(s,2H).HRMS(ESI)m/z:calcd for C8H7N3O2S:[M+H]210.0337；found:210.0322.HPLC purity＝97.1％.
Example 2
Synthesis of 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative wherein R is benzyl 2, 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative 2 is represented by formula (III):
benzyl bromide (171 mg,1 mmol) was added to a solution of 2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol (structure shown in formula (II), 209mg,1 mmol) and potassium hydroxide (56 mg,1 mmol) in methanol (5 mL) at room temperature, and stirred at room temperature for 4h. After removal of the solvent, the crude product was purified by column chromatography to give 261mg (yield 87.3%) of pure product as a white solid. 1 H NMR(400MHz,DMSO)δ9.81(s,1H),7.50-7.44(m,2H),7.37-7.26(m,3H),7.11(dd,J＝8.1,1.3Hz,1H),6.83(dd,J＝7.7,1.2Hz,1H),6.54(t,J＝7.9Hz,1H),6.10(s,2H),4.57(s,2H).HPLC purity＝96.3％。
Example 3
Synthesis of 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative 3, R being 4-methylbenzyl, is shown in formula (IV):
4-methylbenzyl bromide (185 mg,1 mmol) was added to a solution of 2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol (209 mg,1 mmol) and potassium hydroxide (56 mg,1 mmol) in methanol (5 mL) at room temperature, and stirred at room temperature for 4h. After removal of the solvent, the crude product was purified by column chromatography to give 247mg (yield 78.9%) of pure product as a white solid. 1 HNMR(400MHz,DMSO)δ9.82(s,1H),7.35(d,J＝8.0Hz,2H),7.17-7.09(m,3H),6.83(dd,J＝7.6,1.2Hz,1H),6.54(t,J＝7.9Hz,1H),6.11(s,2H),4.53(s,2H),2.27(s,3H).HPLC purity＝96.7％.
Example 4
Synthesis of 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative 4, R being 4-methoxybenzyl, is shown in formula (V):
4-methoxybenzyl bromide (201 mg,1 mmol) was added to a solution of 2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol (209 mg,1 mmol) and potassium hydroxide (56 mg,1 mmol) in methanol (5 mL) at room temperature and stirred for 4h at room temperature. After removal of the solvent, the crude product was purified by column chromatography to give 147mg (yield 44.7%) of pure product as an orange solid. 1 HNMR(400MHz,DMSO)δ9.82(s,1H),7.39(d,J＝8.6Hz,2H),7.13(dd,J＝8.1,1.2Hz,1H),6.90(d,J＝8.6Hz,2H),6.84(dd,J＝7.6,1.2Hz,1H),6.55(t,J＝7.9Hz,1H),6.11(s,2H),4.52(s,2H),3.73(s,3H).HPLC purity＝95.1％.
Example 5
Synthesis of 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative 5, R being 4-cyanobenzyl, is shown in formula (VI):
4-cyanobenzyl bromide (196 mg,1 mmol) was added to a solution of 2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol (209 mg,1 mmol) and potassium hydroxide (56 mg,1 mmol) in methanol (5 mL) at room temperature, and stirred for 4h at room temperature. After removal of the solvent, the crude product was purified by column chromatography to give (280 mg (86.4% yield) pure product as a yellow solid. 1 HNMR(400MHz,DMSO)δ9.81(s,1H),7.82(d,J＝8.3Hz,,2H),7.69(d,J＝8.3Hz,2H),7.08(dd,J＝8.1,1.2Hz,1H),6.83(dd,J＝7.6,1.2Hz,1H),6.54(t,J＝7.9Hz,1H),6.09(s,2H),4.64(s,2H).HPLC purity＝98.2％.
Example 6
Synthesis of 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative 6, R being 4-fluorobenzyl group, is shown in formula (VII):
4-Fluorobenzyl bromide (189 mg,1 mmol) was added to a solution of 2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol (209 mg,1 mmol) and potassium hydroxide (56 mg,1 mmol) in methanol (5 mL) at room temperature and stirred for 4h at room temperature. After removal of the solvent, the crude product was purified by column chromatography to give 224mg (yield 70.7%) of pure product as a yellow solid. 1 HNMR(400MHz,DMSO)δ9.82(s,1H),7.55-7.50(m,2H),7.20-7.15(m,2H),7.11(dd,J＝8.1,1.2Hz,1H),6.83(dd,J＝7.6,1.1Hz,1H),6.54(t,J＝7.9Hz,1H),6.11(s,2H),4.57(s,2H).HPLC purity＝94.8％.
Example 7
Synthesis of 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative 7, R being naphthalen-1-ylmethyl, is shown in formula (VIII):
2-bromomethylnaphthalene (221 mg,1 mmol) was added to a solution of 2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol (209 mg,1 mmol) and potassium hydroxide (56 mg,1 mmol) in methanol (5 mL) at room temperature, and stirred at room temperature for 4h. After removal of the solvent, the crude product was purified by column chromatography to give 256mg (73.4% yield) of pure product as a yellow solid. 1 HNMR(400MHz,DMSO)δ9.81(s,1H),8.00(s,1H),7.95-7.84(m,3H),7.63(dd,J＝8.5,1.5Hz,1H),7.55-7.48(m,2H),7.10(d,J＝8.1Hz,1H),6.83(d,J＝7.6Hz,1H),6.52(t,J＝7.9Hz,1H),6.10(s,2H),4.75(s,2H).HPLC purity＝95.7％.
Example 8
Synthesis of 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative 8, R being methyl, is shown in formula (IX):
methyl iodide (142 mg,1 mmol) was added to a solution of 2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol (209 mg,1 mmol) and potassium hydroxide (56 mg,1 mmol) in methanol (5 mL) at room temperature, and stirred at room temperature for 4h. After removal of the solvent, the crude product was purified by column chromatography to give 97mg (yield 43.5%) of pure product as a white solid. 1 HNMR(400MHz,DMSO)δ9.80(s,1H),7.13(dd,J＝8.1,1.3Hz,1H),6.83(dd,J＝7.7,1.2Hz,1H),6.54(t,J＝7.9Hz,1H),6.11(s,2H),2.76(s,3H).HPLC purity＝96.1％.
Example 9
Synthesis of 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative 9, R being 4-nitrobenzyl group, is shown in formula (X):
4-nitrobenzyl bromide (216 mg,1 mmol) was added to 2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol (209 mg,1 mmol) and potassium hydroxide (56 mg, 1) at room temperatureIn a solution of mmol) in methanol (5 mL) was stirred at room temperature for 4h. After removal of the solvent, the crude product was purified by column chromatography to give 301mg (yield 87.5%) of pure product as a yellow solid. 1 HNMR(400MHz,DMSO)δ9.83(s,1H),8.22(d,J＝8.7Hz,,2H),7.77(d,J＝8.7Hz,2H),7.09(dd,J＝8.1,1.1Hz,1H),6.84(dd,J＝7.6,1.0Hz,1H),6.54(t,J＝7.9Hz,1H),6.11(s,2H),4.70(s,2H).HPLC purity＝97.9％.
Example 10
Inhibiting Erastin-induced iron death by 2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol derivatives
After the cultured MC3T3 osteoblasts were allowed to adhere to the cells, DMSO, erastin (10. Mu.M) +2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol derivatives, erastin (10. Mu.M) +Ferrosin-1 (0.1. Mu.M) were added to the medium, respectively. Cell viability was detected by MTT colorimetric method, MTT kit was purchased from Beijing Soy Bao technology Co., ltd, and the results were as shown in Table 1 (data were obtained after 3-time repetition of the experiment), and 2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol derivative was effective in inhibiting cell iron death, and 2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol derivative 3 having an optimal effect when the R group was 4-methylbenzyl.
Table 12 EC of amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol derivatives for inhibition of cell iron death 50
After the cultured MC3T3 osteoblasts were allowed to adhere to the cell wall, DMSO, erastin (10. Mu.M) +2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol derivative 3 (1. Mu.M), erastin (10. Mu.M) +Ferrostatin-1 (0.1. Mu.M) were added to the medium, respectively, the cell viability was examined after 24 hours of treatment, and the cell membrane lipid peroxidation levels (MC 3T3 cells after 12 hours of drug addition were digested into single cell suspensions with pancreatin. 10. Mu. M C11-BODIPY were added for 60 minutes at room temperature, washed 3 times with PBS, photographed with a fluorescent microscope) and protein and mRNA levels were examined for GPX4 and Runx-2.
As shown in fig. 1, compared with the control group, the iron death inducer Erastin stimulation can significantly kill cells; and the 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative 3 can obviously inhibit cell death induced by Erastin, and the activity is equivalent to that of positive control Fer-1, which shows that the 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative has the effect of inhibiting cell iron death induced by Erastin.
As shown in FIG. 2, the degree of lipid peroxidation in cells of the 2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol derivative 3 treated group was greatly reduced compared to Erastin, and thus had a alleviating effect on iron death of osteoblasts.
As shown in FIG. 3 and FIG. 4, the content of GPX4, runx-2 proteins and mRNA in cells of the group treated with 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative 3 is significantly increased compared with Erastin, which indicates that the 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative can inhibit the death of osteoblast iron and promote the expression of osteoblast bone formation index.
Example 11
Alleviation of osteoporosis in rats by compounds
Grouping animals: 30 SD rats of 12 weeks of age were selected, and 30 rats were randomly divided into 3 groups, which were a control group (untreated), a GIOP model group, and a GIOP model+2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol 3 derivative group, respectively.
Treatment of animals: GIOP model+2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative 3 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative 3 was dissolved in DMSO and injected intramuscularly or intravenously in an amount of 5mg/kg. GIOP model groups were injected with equivalent DMSO. After 1 week of drug injection (5 mg drug/kg rat body weight), rats were sacrificed and immediately required specimens were removed and subjected to Micro CT (as shown in FIG. 5) and IHC staining (as shown in FIG. 6).
As shown in fig. 5, the compound-treated group significantly improved joint bone density, bone trabecular thickness, and bone trabecular separation compared to the normal GIOP model group; as shown in fig. 6, GPX4 expression was significantly increased in the joints of rats in the compound-treated group compared to the general GIOP model group, indicating that the compound has therapeutic relief effect on osteoporosis.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative having a structure represented by the formula (I):
wherein R is one of hydrogen, benzyl, 4-methylbenzyl, 4-methoxybenzyl, 4-cyanophenyl, 4-fluorobenzyl, naphthalene-1-ylmethyl, methyl and 4-nitrobenzyl.
2. A process for the preparation of a 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative according to claim 1, comprising the steps of:
s1, dissolving 2-amino-3-hydroxybenzoyl hydrazine, carbon disulfide and alkali into methanol for reaction, removing a solvent after the reaction is finished, and purifying a product to obtain 2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol;
s2, when R is not hydrogen, dissolving R-X, 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol and alkali into a solvent for reaction, removing the solvent after the reaction is finished, and purifying the product to obtain a 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative;
r in R-X is the same as R in formula (I) and is not H, X is Br or I.
3. The process according to claim 2, wherein in step S1, the molar ratio of 2-amino-3-hydroxybenzohydrazide, carbon disulfide to base is 1:2.9-3.1:0.9-1.1, the reaction temperature is 65-75℃and the time is 7-9h.
4. The process according to claim 2, wherein in step S2, the molar ratio of R-X, 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol to base is 0.9-1.1:1:0.9-1.1, the reaction temperature is room temperature, and the reaction time is 3-5 hours.
5. The method of claim 2, wherein the base comprises potassium hydroxide or sodium hydroxide and the solvent comprises methanol.
6. Use of a 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative according to claim 1 as an iron death inhibitor.
7. The application of claim 6, wherein the application comprises any one of:
(1) For use in the prevention, amelioration or treatment of a disease associated with the iron death pathway;
(2) Is applied to the preparation of medicaments for preventing, improving or treating diseases related to the iron death pathway;
(3) The method is applied to the preparation of the iron death pathway inhibition model.
8. Use of a 2-amino-3- (5-mercapto-1, 3, 4-oxadiazole) phenol derivative according to claim 1 for the preparation of an osteoporosis-control product.
9. A medicament comprising a 2-amino-3- (5 mercapto-1, 3,4 oxadiazole) phenol derivative according to claim 1.
10. The medicament of claim 9, further comprising pharmaceutically acceptable additives or adjuvants; the dosage form of the medicine is selected from tablet, pill, powder, suspension, gel, emulsion, cream, granule, nanoparticle, capsule, suppository, injection, spray or injection.
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