CN115581689B - Application of urolithin B amide derivatives - Google Patents
Application of urolithin B amide derivatives Download PDFInfo
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- CN115581689B CN115581689B CN202211265773.3A CN202211265773A CN115581689B CN 115581689 B CN115581689 B CN 115581689B CN 202211265773 A CN202211265773 A CN 202211265773A CN 115581689 B CN115581689 B CN 115581689B
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- urolithin
- benzopyran
- acetamide
- oxy
- oxo
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- WXUQMTRHPNOXBV-UHFFFAOYSA-N urolithin-B Natural products C1=CC=C2C3=CC=C(O)C=C3OC(=O)C2=C1 WXUQMTRHPNOXBV-UHFFFAOYSA-N 0.000 title claims abstract description 146
- RIUPLDUFZCXCHM-UHFFFAOYSA-N urolithin-A Natural products OC1=CC=C2C3=CC=C(O)C=C3OC(=O)C2=C1 RIUPLDUFZCXCHM-UHFFFAOYSA-N 0.000 title claims abstract description 81
- -1 urolithin B amide Chemical class 0.000 title claims abstract description 56
- 239000003814 drug Substances 0.000 claims abstract description 20
- 229940079593 drug Drugs 0.000 claims abstract description 14
- 241000244206 Nematoda Species 0.000 claims description 65
- 230000003712 anti-aging effect Effects 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims 1
- 230000009758 senescence Effects 0.000 claims 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 abstract description 70
- 230000000694 effects Effects 0.000 abstract description 18
- 238000012360 testing method Methods 0.000 abstract description 17
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 abstract description 15
- 241000244203 Caenorhabditis elegans Species 0.000 abstract description 13
- 230000032683 aging Effects 0.000 abstract description 8
- 208000015122 neurodegenerative disease Diseases 0.000 abstract description 6
- 230000004770 neurodegeneration Effects 0.000 abstract description 4
- 208000010877 cognitive disease Diseases 0.000 abstract description 3
- 208000012902 Nervous system disease Diseases 0.000 abstract description 2
- 230000003930 cognitive ability Effects 0.000 abstract description 2
- 230000002438 mitochondrial effect Effects 0.000 abstract description 2
- 208000025966 Neurological disease Diseases 0.000 abstract 1
- 230000002708 enhancing effect Effects 0.000 abstract 1
- 150000001408 amides Chemical class 0.000 description 44
- 230000004083 survival effect Effects 0.000 description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 239000002609 medium Substances 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 230000001954 sterilising effect Effects 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
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- 238000002474 experimental method Methods 0.000 description 6
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- 229910001385 heavy metal Inorganic materials 0.000 description 6
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- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- 230000035882 stress Effects 0.000 description 4
- 229930186301 urolithin Natural products 0.000 description 4
- 229920001817 Agar Polymers 0.000 description 3
- 241000238631 Hexapoda Species 0.000 description 3
- 239000007836 KH2PO4 Substances 0.000 description 3
- 239000001888 Peptone Substances 0.000 description 3
- 108010080698 Peptones Proteins 0.000 description 3
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- 235000012000 cholesterol Nutrition 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000033001 locomotion Effects 0.000 description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 3
- FIKAKWIAUPDISJ-UHFFFAOYSA-L paraquat dichloride Chemical compound [Cl-].[Cl-].C1=C[N+](C)=CC=C1C1=CC=[N+](C)C=C1 FIKAKWIAUPDISJ-UHFFFAOYSA-L 0.000 description 3
- 235000019319 peptone Nutrition 0.000 description 3
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 125000006516 2-(benzyloxy)ethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 2
- ZELMDXUEWHBWPN-UHFFFAOYSA-N 3,4,8,9,10-pentahydroxybenzo[c]chromen-6-one Chemical compound OC1=C(O)C(O)=C2C3=CC=C(O)C(O)=C3OC(=O)C2=C1 ZELMDXUEWHBWPN-UHFFFAOYSA-N 0.000 description 2
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 2
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 2
- 229920002079 Ellagic acid Polymers 0.000 description 2
- AFSDNFLWKVMVRB-UHFFFAOYSA-N Ellagic acid Chemical compound OC1=C(O)C(OC2=O)=C3C4=C2C=C(O)C(O)=C4OC(=O)C3=C1 AFSDNFLWKVMVRB-UHFFFAOYSA-N 0.000 description 2
- ATJXMQHAMYVHRX-CPCISQLKSA-N Ellagic acid Natural products OC1=C(O)[C@H]2OC(=O)c3cc(O)c(O)c4OC(=O)C(=C1)[C@H]2c34 ATJXMQHAMYVHRX-CPCISQLKSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229940041514 candida albicans extract Drugs 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000035605 chemotaxis Effects 0.000 description 2
- 239000007799 cork Substances 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 229960002852 ellagic acid Drugs 0.000 description 2
- 235000004132 ellagic acid Nutrition 0.000 description 2
- 229920001968 ellagitannin Polymers 0.000 description 2
- 125000000686 lactone group Chemical group 0.000 description 2
- 230000006742 locomotor activity Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- FAARLWTXUUQFSN-UHFFFAOYSA-N methylellagic acid Natural products O1C(=O)C2=CC(O)=C(O)C3=C2C2=C1C(OC)=C(O)C=C2C(=O)O3 FAARLWTXUUQFSN-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
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- 239000012138 yeast extract Substances 0.000 description 2
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 206010007027 Calculus urinary Diseases 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108010017842 Telomerase Proteins 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000003529 anticholesteremic agent Substances 0.000 description 1
- 230000004922 autophagy dysfunction Effects 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000003399 chemotactic effect Effects 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 230000006999 cognitive decline Effects 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 230000002542 deteriorative effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 238000005553 drilling Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 229920001461 hydrolysable tannin Polymers 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- WRUGWIBCXHJTDG-UHFFFAOYSA-L magnesium sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Mg+2].[O-]S([O-])(=O)=O WRUGWIBCXHJTDG-UHFFFAOYSA-L 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000007111 proteostasis Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
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- 239000007787 solid Substances 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
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- 239000002904 solvent Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 239000012137 tryptone Substances 0.000 description 1
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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Hospice & Palliative Care (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides application of urolithin B amide derivatives, and belongs to the field of medicines. The urolithin B amide derivatives can be used for preventing or treating neurological diseases related to mitochondrial activity reduction, including aging and neurodegenerative diseases, and the invention adopts caenorhabditis elegans as a model, and test results show that 20 mu M of urolithin B and N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide and 2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide have the effects of prolonging the service life of the caenorhabditis elegans and enhancing the cognitive ability or relieving cognitive dysfunction. The invention discloses an application of an amide derivative of urolithin B in resisting aging and preventing neurodegenerative diseases.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of a urolithin B amide derivative in preparation of a medicine for preventing organism aging.
Background
Alzheimer's Disease (AD) is the most common neurological disorder associated with cognitive decline, and AD is a neurodegenerative disorder in which the degree of dementia gradually worsens with aging of the human body's age.
The aging of the organism is essentially related to the autophagy dysfunction of mitochondria, the instability of genome, the shortening of telomerase, the imbalance of protein homeostasis and the degradation of cell viability. Since the mechanism of AD formation is unknown, the deposition of senile plaques pushes to aβ (amyloid β), and the formation of amyloid β has numerous possible causes. At most, the current test drugs such as cholesterol inhibitors, cholinesterase inhibitors and the like used for preventing the Alzheimer's disease caused by aging clinically only can prevent the disease from deteriorating, and no drugs and methods for completely treating the disease exist. Because the etiology of AD is not yet clear, research is also lacking in better animal models. The caenorhabditis elegans (Caenorhabditis elegans, C.elegans) is taken as a model organism, only 3 days is needed for the development of the caenorhabditis elegans from eggs to adults under the condition of rich nutrition at 20 ℃, the genes of the caenorhabditis elegans and related genes of human beings have high conservation of 60-80%, and experimental results play an important role in prompting the anti-aging effect of the human beings; because the growth period of the nematodes is short, a large amount of sample amount nematodes can be used for experiments in a short period, and the experimental results are reliable; in the research of neurodegenerative diseases, the nematode can easily obtain an ideal disease defect type system model, has transparent body, is easy to observe and detect phenotypic characteristics, has complete nerves, movements and reproductive systems, and the interaction among cells enables the nematode to form rich movement behaviors such as advancing, retreating, group chemotaxis and the like, so that the nematode can be easily operated in genetics and pharmacology in the model research of related diseases, and has important significance for preventing and exploring pathogenesis and treatment methods of the neurodegenerative diseases.
Ellagitannins (ELLAGITANNIN) are polyhydric phenolic compounds currently found in certain fruits, nuts and plants, and belong to the class of hydrolysable tannins which are metabolized by the human intestinal flora into more readily absorbable uroliths, a process in which ellagic acid loses a lactone ring and gradually removes hydroxyl groups. The ellagic acid loses lactone ring to obtain urolithin M5, and the urolithin M5 is dehydroxylated at different positions to obtain monohydroxy urolithin B. Patent number CN 113387916 discloses a process for the preparation of urolithin B and amidated derivatives. If a novel urolithin inhibitor is found to be effective in improving cognitive function, or improving cognitive ability, or even treating cognitive impairment, it would make a valuable contribution to the anti-aging field.
The name and chemical structure of urolithin B and amide derivatives are as follows:
UB：
Urolithin B
1a：
N-hexyl-2- (6-oxo-6H-benzo [ c ] benzopyran-3-y 1) oxy) acetamide
1b：
N-butyl-2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide
1c：
2- ((6-Oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) -N- ((tetrahydrofuran-2-yl) methyl) acetamide
1d：
2- ((6-Oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) -N- (2- (thiophen-2-yl) ethyl) acetamide
1e：
N- (furan-2-ylmethyl) -2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide
1f：
N-benzyl-2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide
1g：
N- (cyclohexylmethyl) -2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide
1h：
N- ((5-methylfuran-2-yl) methyl) -2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide
1i：
N- (3-chloro-5-fluorobenzyl) -2- (6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide
1j：
N- (2- (benzyloxy) ethyl) -2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide
1k：
2- ((6-Oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide
1l：
2- ((6-Oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) -N- (2- (pyridin-2-yl) ethyl) acetamide
1m：
2- ((6-Oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) -N- (2- (piperidin-1-yl) ethyl) acetamide
Disclosure of Invention
Under the background, the invention discloses an anti-aging application of a urolithin B amide derivative, and aims to provide a new application of the urolithin B amide derivative in anti-aging medicines.
In order to achieve the above object, the present invention adopts the following technical scheme.
The application of the urolithin B amide derivatives comprises the following two compounds:
the two compounds are used for preparing anti-aging medicines.
Use of amide derivatives of urolithin B in the manufacture of a medicament for the treatment or prophylaxis of neurodegenerative disorders associated with reduced mitochondrial activity.
Use of amide derivatives of urolithin B for the preparation of a medicament for prolonging nematode life.
Further, the nematode is caenorhabditis elegans.
Further, the two compounds have obvious anti-aging effect at 20 mu M.
The technical scheme of the invention has the following advantages:
1. Under the condition of lower dosage and concentration, the urolithin B amide derivative has obvious effect of prolonging the service life of the caenorhabditis elegans compared with the urolithin B, and can delay the aging process of the caenorhabditis elegans; the method is simple to operate and has the advantage of effect.
2. The exercise behavior and the stress capability of the caenorhabditis elegans again indicate that the urea Dan Su B amide derivative has obvious effect of prolonging the service life, further delays the aging, and has good application value and significance for far-reaching medical application.
3. The invention provides a certain theoretical basis for the application of urolithin B and amide derivatives thereof in anti-aging medicaments, and lays a good foundation for the development of medicaments in the future.
Drawings
Figure 1 shows the effect on the healthy life of the insects with different concentrations of urolithin B. Wherein, (a) is the survival curve of the urolithin-B nematodes with different concentrations, and (B) is the average life span of the urolithin-B nematodes with different concentrations.
FIG. 2 shows the effect of 20. Mu.M urolithin B and amide derivatives on the longevity of insects. Wherein (a) a 20. Mu.M urolithin B nematode survival curve (B) a 20. Mu.M N-butyl-2- ((6-oxo-6H-benzopyran-3-yl) oxy) acetamide nematode survival curve (c) a 20. Mu.M N-butyl-2- ((6-oxo-6H-benzopyran-3-yl) oxy) acetamide nematode survival curve (d) a 20. Mu.M 2- ((6-oxo-6H-benzopyran-3-yl) oxy) -N- ((tetrahydrofuran-2-yl) methyl) acetamide nematode survival curve (e) a 20. Mu.M 2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) -N- (2- (thiophen-2-yl) ethyl) acetamide nematode survival curve (f) a 20. Mu.52- (furan-2-ylmethyl) -2- (6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide nematode survival curve (d) a 20. Mu.M 2- ((6-oxo-6H-benzopyran-3-yl) oxy) methyl) acetamide nematode survival curve (e) a 20. Mu.M 2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide nematode survival curve (e) a 20. Mu.M 2-benzopyran-6H-yl) benzopyran-3-yl) nematode survival curve (f) is 20. Mu.6 g h) 20 mu M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide nematode survival curve (i) 20 mu M N- ((5-methylfuran-2-yl) methyl) -2- (6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide nematode survival curve (j) 20 mu M N- (3-chloro-5-fluorobenzyl) -2- (6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide nematode survival curve (k) 20. Mu. M N- (2- (benzyloxy) ethyl) -2- (6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide nematode survival curve (l) 20. Mu.M 2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide nematode survival curve (M) 20. Mu.M 2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) -N- (2- (pyridine-2 ] Radical) ethyl) acetamide nematode survival curve (N) 20. Mu.M 2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) -N- (2- (piperidin-1-yl) ethyl) acetamide nematode survival curve (o) 20. Mu.M urolithin B mean life (p) 20. Mu.M urolithin B and amide derivative nematode mean life.
FIG. 3 shows the effect of 20. Mu.M urolithin B and 71g,71k amide derivatives on nematode locomotor activity on days 4,8, 12. Wherein (a) 20. Mu.M urolithin B body curve (B) 4 days 20. Mu. M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide and 2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide body curve (c) 4 days 20. Mu.M urolithin B head swing (d) 4 days 20. Mu. M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide and 2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide head swing (e) 8 days 20. Mu.M urolithin B body curve (f) 8 days 20. Mu. M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide and 2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide Body curve (g) 20 mu M urolithin B head swing on day 8 (H) 20 mu M urolithin B head swing on day 12 mu M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide and 2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide head swing (i) 20 mu M urolithin B head swing on day 12 mu M M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide and 2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide body curve (k) 12 mu M urolithin B head swing (i) 20 mu M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide and 2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide The amide head swings.
FIG. 4 shows the effect of 20. Mu.M urolithin B and 71g,71k amide derivatives on nematode oxidative stress capacity. Wherein (a) is 20 μM urolithin B oxidative stress survival (B) is 20 μ M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide oxidative stress survival (c) is 20 μM 2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide oxidative stress survival (d) is 20 μM urolithin B oxidative stress average lifetime (e) is 20 μ M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide and 2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide oxidative average lifetime.
FIG. 5 is a graph showing the effect of 20. Mu.M urolithin B and 71g,71k amide derivatives on nematode heavy metal capacity assessment. Wherein (a) 20. Mu.M urolithin B heavy metal survival curve (B) 20. Mu.M urolithin B average lifetime (e) 20. Mu. M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide heavy metal survival curve (c) 20. Mu.M 2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide heavy metal survival curve (d) 20. Mu.M urolithin B average lifetime (e) 20. Mu. M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide and 2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide average lifetime.
FIG. 6 shows the effect of 20. Mu.M urolithin B and 71g,71k amide derivatives on nematode learning and memory. Wherein (a) is 20 μM urolithin B learning memory (B) is 20 μ M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide and 2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide learning memory.
FIG. 7 shows the effect of 20. Mu.M urolithin B and 71g,71k amide derivatives on E.coli growth status. Wherein (a) is the effect of urolithin B on E.coli growth (B) is the effect of N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide on E.coli growth (c) is the effect of 2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide on E.coli growth status.
Fig. 8 is a schematic diagram of a test plate.
Detailed Description
The present invention will be described in further detail with reference to examples. It will be apparent to those skilled in the art that several simple deductions or substitutions may be made without departing from the spirit of the invention, and these should be considered to be within the scope of the invention.
1. Experimental materials and reagents
Both the C.elegans strain to which the test belongs and the E.coli op50 strain are purchased from Caenorha bd ITIS GENETICS CENTER (CGC);
caenorhabditis elegans strain: wild type N2
Urolithin B and its amide derivatives: synthesized at Changzhou university
Paraquat was purchased from Sigma Aldrich trade Co., ltd, and other reagents were purchased from Shanghai Biotechnology Co., ltd
NGM medium: 3g of NaCl,2.5g of tryptone, 17g of agar, 25ml of phosphate buffer solution and 975ml of distilled water, sterilizing at 121 ℃ for 20min, cooling to about 50-70 ℃, sterilizing by passing through a membrane, adding 1ml of 5mol/L cholesterol solution, 1ml of 1mol/L anhydrous MgSO 4 solution and 1ml of 1mol/L CaCl 2 ml into a culture medium, adding the culture medium into a flat plate, cooling and solidifying, and pouring the culture medium into a refrigerator at 4 ℃.
100MMNaCl:NaCl 5.85g, peptone 2.5g, agar 17g, distilled water 1L.
Preparing an LB culture medium:
① Liquid medium: respectively weighing peptone, yeast extract and 10g, 5g and 10g of NaCl, adding distilled water to a constant volume of 1L,121 ℃, sterilizing for 20min, and refrigerating at 4 ℃ for later use.
② Solid medium: respectively weighing 10g, 5g, 10g and 17g of peptone, yeast extract, naCl and agar powder, adding distilled water to a constant volume of 1L,121 ℃, sterilizing for 20min, pouring into a flat plate, and standing in a refrigerator at 4 ℃ after solidification.
M9 buffer ：Na2HPO4 6g,KH2PO4 3g,NaCl5g,MgSO4.7H2O 0.25g,H2O 1L.
1Mol/L phosphate buffer: k 2HPO4 3.56g,KH2PO4 10.83g,H2 O100 ml.
1Mg/mLMgSO 4 solution: 120.3g of MgSO4 powder is taken, distilled water is added, the volume is fixed to 1L, the temperature is 121 ℃, and the sterilization is carried out for 20min for standby.
1Mg/mLCaCl 2 solution: 110.9g of CaCl2 powder is taken, distilled water is added, the volume is fixed to 1L, the temperature is 121 ℃, and the sterilization is carried out for 20min for standby.
5Mol/L cholesterol solution: 0.25g of cholesterol was dissolved in 50mL of absolute ethanol and sterile filtered using a needle filter.
50% Glycerol: sterilizing 100% glycerol 5mL in 5mL distilled water at 121deg.C for 20min, cooling, and placing in a refrigerator at 4deg.C for use.
Nematode frozen stock solution: 0.3g of NaCl, 0.3g of KH 2PO4 0.055g,KH2PO4, 21.5mL of glycerol, 50mL of distilled water and sterilization at 121 ℃ for 20 min.
2. Method of
EXAMPLE 1 urolithin B amide derivatives extend the longevity of caenorhabditis elegans
Test drug:
negative controls were formulated with 0.1% dmso.
The positive control urolithin B and its amide derivatives were dissolved in 0.1% dmso to prepare stock solutions.
(1) Life test
The synchronized L4-phase nematodes were incubated at 20 ℃. The solvent control group was 0.1% DMSO and the positive control group was 10-100. Mu.M urolithin B. Counts were taken from the time of transfer, and the day of the life test was counted. The number of nematode survival, death and loss was recorded daily, the average life span of each group was obtained, and the data was subjected to survival analysis.
(2) Life test of urolithin B and its amide derivatives
Urolithin B as a control, compared with its amide derivatives at optimal concentrations, was recorded daily for nematode survival, mortality and loss number, and the mean life of each group was obtained and the data was subjected to survival analysis.
Analysis of results
The results are shown in FIG. 1 as the effect of 0.1. Mu.M-100. Mu.M urolithin B on the longevity of the insects. Life tests were performed with 0.1 μm, 1 μm, 10 μm, 20 μm, 50 μm, 100 μm as dosing groups of different concentrations, while with 0.1% dmso as control group. The results showed that 20. Mu.M urolithin B prolonged the average life span of wild type nematodes, allowing the survival curve to shift to the right. Wherein the average life span of 20. Mu.M N2 nematodes is 17.42% as seen in FIG. 1, 71g,71k amide derivatives are 9.06% and 9.96% higher than those of urolithin B in FIG. 2, and 71g,71k amide derivatives are longer than urolithin B in life span, which demonstrates that urolithin B can prolong the life span of caenorhabditis elegans, and that urolithin B has significantly improved nematode life span at a dose of 20. Mu.M, but to a lesser extent than 71g,71k amide derivatives.
Example 2: urolithin B and amide derivatives improve nematode locomotion
Test drug: negative controls were formulated with 0.1% dmso.
The positive control urolithin B and its amide derivatives were dissolved in 0.1% dmso to prepare stock solutions.
Experimental method
Exercise capacity determination
Nematode dosing with synchronized cultures to stage L4 was used to intervene on days four, eight and twelfth. 10 nematodes were placed on a blank NGM medium with M9 buffer, and after 1min recovery, the number of head swings in 1min and the number of body bends in 20s were recorded.
Analysis of results
The number of body curves and head swings in 1min for nematodes 20s on the fourth, eighth and twelfth days of the dosing intervention are shown in fig. 3. 20. Mu.M of urolithin B showed a better increase in the number of body bends and head swings of nematodes on the fourth, eighth and twelfth days, respectively, than the control group, and a remarkable increase in the comparison of 71g,71k amide derivatives with urolithin B as shown in FIG. 3. This example demonstrates that 71g,71k amide derivatives are able to increase the locomotor activity of nematodes over urolithin B, leading to improved health status, side reactions that have anti-aging effects.
Example 3: urolithin B and amide derivatives improve the stress capacity of nematodes
Test drug: negative controls were formulated with 0.1% dmso.
The positive control urolithin B and its amide derivatives were dissolved in 0.1% dmso to prepare stock solutions.
Experimental method
Paraquat oxidative stress: after 48h of administration of the synchronized medium to the nematodes in stage L4, they were transferred to liquid medium of 160mM paraquat concentration, and the number of deaths and survival of the nematodes were recorded every 1 h.
Analysis of results
The results of nematode oxidative stress at 48h of dosing intervention are shown in figure 4. The results showed that 20. Mu.M of urolithin B administration group had a 25.46% increase in nematode oxidative stress over the control group. Compared with urolithin B, the 71g and 71k amide derivatives are respectively 25.92 percent and 29.32 percent higher than the negative control, meanwhile, the 71g and 71k amide derivatives can be seen from the figure to improve the survival time of the nematode stress capability, and the results of the example show that the 71g and 71k amide derivatives improve the nematode stress capability compared with the urolithin B and have anti-aging effect.
Example 4: urolithin B and amide derivatives to improve nematode resistance to heavy metals
Test drug: negative controls were formulated with 0.1% dmso.
The positive control urolithin B and its amide derivatives were dissolved in 0.1% dmso to prepare stock solutions.
Experimental method
The nematode was dosed for 48h,48h with synchronized L4 phase, and a final concentration of 180 μm in copper chloride solution was added, after which the number of nematodes surviving was recorded once a day until all the nematodes died.
Experimental results
The heavy-duty resistance of the nematodes after 48h of administration is shown in figure 5. The results showed that the average lifetime of 20. Mu.M of urolithin B was improved by 9.43% compared to the control group and 71g,71k amide derivative was higher than that of negative control 11.54%,13.63%, respectively. The results of this example demonstrate the effect of 71g,71k amide derivatives having better resistance to heavy metals than urolithin B.
Example 5: urolithin B and amide derivatives improve learning ability of nematodes
Test drug: negative controls were formulated with 0.1% dmso.
The positive control urolithin B and its amide derivatives were dissolved in 0.1% dmso to prepare stock solutions.
Experimental method
Chemical trend ability measurement
The synchronized L4-phase nematodes are respectively exposed to an experimental group and a control group for 72 hours, 100mM NaCl culture medium is prepared for high-temperature and high-pressure sterilization, and the nematodes M9 are washed for 2-3 times to be starved and cultured in a new culture medium for 4 hours. Blank medium and culture with 100mM NaCl were drilled separately with a cork driller and based on overnight 14h in the test plate, chemotactic plates were formed and nematodes to be tested were transferred to the test plate, which is shown in FIG. 8 below: and drilling blank NGM and 100mM NaCl blank NGM at the position 0.5cm away from the two ends of the flat plate by using a cork driller to respectively make sample marks and comparison marks, so that the two-point marks and the center point form a straight line. Drawing two straight lines at the positions 2cm away from the center of the circle. 0.5mol/L NaN 3 was added before the test to turn the nematodes to a starting point, and after 1h the trend index (chemotaxis index) = (N A-NC)/N;NA =number of Nacl group nematodes, N C =number of control group nematodes, n=total number of nematodes) was determined.
Analysis of results
The learning ability of urolithin B and 71g,71k amide derivatives is shown in FIG. 6. As a result, the learning ability of the control group was 0.052, the learning ability of 20. Mu.M urolithin B was 0.32, and the learning ability of 71g,71k amide derivatives was 0.35,0.41. The results show that 20 mu M urolithin B and 71g,71k amide derivatives can significantly improve the learning ability of adult nematodes in the fourth day.
Example 6: influence of 20 mu M urolithin amide derivatives on growth status of E.coli
Test drug: negative controls were formulated with 0.1% dmso.
The positive control urolithin B and its amide derivatives were dissolved in 0.1% dmso to prepare stock solutions.
Experimental method
LB liquid medium after autoclaving was prepared as follows: 1. blank 2, addition of op50 3, addition of methoxy urolithin a and its 6, 7 amide derivatives 4, addition of op50 and methoxy urolithin a and its 6, 7 amide derivatives. Taking blank group as control, firstly measuring and adding oxyurolithin A and 6, 7 amide derivatives thereof, then placing the other two groups into a shaking table at 37 ℃ for 390min, measuring absorbance at OD595 of the other two groups every 30min, and recording and drawing an E.coli OD value growth curve.
Analysis of results
FIG. 7 shows the effect of 20. Mu.M methoxy urolithin A and 71g,71k amide derivatives on E.coli growth status. As shown in FIG. 7, the OP50 growth curve in LB liquid medium supplemented with 20. Mu.M urolithin B and 71g,71k amide derivatives thereof was similar to the OP50 growth curve in LB liquid medium not supplemented with the administration group, and the results of this example demonstrate that the life-prolonging effect of 20. Mu.M urolithin B and 71g,71k amide derivatives thereof was independent of the antimicrobial effect and the usability of foods.
Claims (2)
1. The application of the urolithin B amide derivatives as the only active ingredients in the preparation of the anti-caenorhabditis elegans senescence medicaments is characterized in that the urolithin B amide derivatives are one of the following two compounds:
1g：
Or (b)
1K：
；
The two compounds are used for preparing anti-aging medicines; the concentration of the two urolithin B amide derivatives is 20 mu M/L.
2. The use according to claim 1, characterized in that: the two urolithin B amide derivatives are used for preparing medicines for prolonging the service life of nematodes.
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