CN102127046B - 4', 5-dyhydroxyl-7-(4-(N, N-diethylamino group) butoxy) isoflavone, preparation method and application of 4', 5-dyhydroxyl-7-(4-(N, N-diethylamino group) butoxy) isoflavone - Google Patents
4', 5-dyhydroxyl-7-(4-(N, N-diethylamino group) butoxy) isoflavone, preparation method and application of 4', 5-dyhydroxyl-7-(4-(N, N-diethylamino group) butoxy) isoflavone Download PDFInfo
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- butoxy
- genistein
- novasoy
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- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 title abstract description 7
- 235000008696 isoflavones Nutrition 0.000 title abstract description 7
- GOMNOOKGLZYEJT-UHFFFAOYSA-N isoflavone Chemical compound C=1OC2=CC=CC=C2C(=O)C=1C1=CC=CC=C1 GOMNOOKGLZYEJT-UHFFFAOYSA-N 0.000 title abstract 6
- 230000000694 effects Effects 0.000 claims abstract description 22
- 239000003814 drug Substances 0.000 claims abstract description 21
- 108010022752 Acetylcholinesterase Proteins 0.000 claims abstract description 18
- 229940022698 acetylcholinesterase Drugs 0.000 claims abstract description 16
- 229940011871 estrogen Drugs 0.000 claims abstract description 11
- 239000000262 estrogen Substances 0.000 claims abstract description 11
- 102000012440 Acetylcholinesterase Human genes 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 52
- 229940045109 genistein Drugs 0.000 claims description 38
- TZBJGXHYKVUXJN-UHFFFAOYSA-N genistein Natural products C1=CC(O)=CC=C1C1=COC2=CC(O)=CC(O)=C2C1=O TZBJGXHYKVUXJN-UHFFFAOYSA-N 0.000 claims description 38
- 235000006539 genistein Nutrition 0.000 claims description 38
- ZCOLJUOHXJRHDI-CMWLGVBASA-N genistein 7-O-beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C2C(=O)C(C=3C=CC(O)=CC=3)=COC2=C1 ZCOLJUOHXJRHDI-CMWLGVBASA-N 0.000 claims description 38
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 230000002401 inhibitory effect Effects 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 5
- 239000013067 intermediate product Substances 0.000 claims description 4
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical class CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 claims description 2
- 208000024827 Alzheimer disease Diseases 0.000 abstract description 19
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- 210000002569 neuron Anatomy 0.000 abstract description 3
- 229920005610 lignin Polymers 0.000 abstract 2
- 230000001681 protective effect Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 22
- 102100033639 Acetylcholinesterase Human genes 0.000 description 16
- 230000004083 survival effect Effects 0.000 description 11
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 10
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 10
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- 230000000994 depressogenic effect Effects 0.000 description 4
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- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 238000003032 molecular docking Methods 0.000 description 4
- 208000037259 Amyloid Plaque Diseases 0.000 description 3
- 241000277305 Electrophorus electricus Species 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 3
- 229960004373 acetylcholine Drugs 0.000 description 3
- 230000007131 anti Alzheimer effect Effects 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 239000002329 esterase inhibitor Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
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- 238000012360 testing method Methods 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- GGRLKHMFMUXIOG-UHFFFAOYSA-M 2-acetyloxyethyl(trimethyl)azanium;hydroxide Chemical compound [OH-].CC(=O)OCC[N+](C)(C)C GGRLKHMFMUXIOG-UHFFFAOYSA-M 0.000 description 2
- 206010029350 Neurotoxicity Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 206010044221 Toxic encephalopathy Diseases 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
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- 230000030833 cell death Effects 0.000 description 2
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- 210000002932 cholinergic neuron Anatomy 0.000 description 2
- 239000000544 cholinesterase inhibitor Substances 0.000 description 2
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- 238000012827 research and development Methods 0.000 description 2
- 150000004508 retinoic acid derivatives Chemical class 0.000 description 2
- 230000001568 sexual effect Effects 0.000 description 2
- NTBLZMAMTZXLBP-UHFFFAOYSA-M 2-acetylsulfanylethyl(trimethyl)azanium;iodide Chemical compound [I-].CC(=O)SCC[N+](C)(C)C NTBLZMAMTZXLBP-UHFFFAOYSA-M 0.000 description 1
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 description 1
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 description 1
- 239000004261 Ascorbyl stearate Substances 0.000 description 1
- 108010058699 Choline O-acetyltransferase Proteins 0.000 description 1
- 102100023460 Choline O-acetyltransferase Human genes 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102100029951 Estrogen receptor beta Human genes 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 101001010910 Homo sapiens Estrogen receptor beta Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010056677 Nerve degeneration Diseases 0.000 description 1
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000006933 amyloid-beta aggregation Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 210000004227 basal ganglia Anatomy 0.000 description 1
- 229940088623 biologically active substance Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000006949 cholinergic function Effects 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 210000003792 cranial nerve Anatomy 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 210000005168 endometrial cell Anatomy 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002515 isoflavone derivatives Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 210000004129 prosencephalon Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
- C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Hospice & Palliative Care (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses 4', 5-dyhydroxyl-7-(4-(N, N-diethylamino group) butoxy) isoflavone of dye lignin derivative, a preparation method and an application of the 4', 5-dyhydroxyl-7-(4-(N, N-diethylamino group) butoxy) isoflavone. The 4', 5-dyhydroxyl-7-(4-(N, N-diethylamino group) butoxy) isoflavone obtained by chemically modifying the dye lignin derivative has the acetylcholinesterase inhibition activity, the estrogen activity and the nerve cell protective action; and the 4', 5-dyhydroxyl-7-(4-(N, N-diethylamino group) butoxy) isoflavone which is taken as a multi-function target spot can be used for preparing the alzheimer disease-resistant medicament.
Description
Technical field
The present invention relates to a kind of genistein verivate, specifically, relate to 4 ', 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400.
Background technology
Alzheimer's disease is a kind of common senile cranial nerve degeneration, and sickness rate is higher, has become one of disease of modern society serious threat the elderly life and health.The typical pathological change of this disease comprises
βAmyloid beta deposition forms senile plaque; Neurofibrillary tangles; The change of neuron loss and cynapse form widely of basal forebrain cholinergic function obstacle and cortex, hippocampus (referring to: Roberson ED, Mucke L. 100 years and counting:prospects for defeating Alzheimer's disease. Science 2006; 314 (5800): 781-4).
The pathology of discovering patients with Alzheimer disease brain endodermis and hippocampus is apparent in view, and former basal ganglia cholinergic neuron destroys at most.Therefore, through the content of increase vagusstoff, or act on cholinocepter; The function of central cholinergic system be can strengthen and improve, thereby purpose (Baskin DS, Browning JL that short intelligence is cured the disease reached; Pirozzolo FJ; Korporaal S, Baskin JA, Appel SH. Brain choline acetyltransferase and mental function in Alzheimer disease. Archives of Neurology 1999; 56 (9): 1121-3).Acetylcholinesterase depressant is exactly to be based upon the most sophisticated the earliest one type of medicine that is used for treatment of alzheimer clinically (the Taylor P. Development of acetylcholinesterase inhibitors in the therapy of Alzheimer's disease. Neurology 1998 that develops on this theoretical basis; 51 (Supplement 1), S30 – S35), such medicine can make its cognitive function and other symptom obtain part and improve light, moderate Alzheimer's disease patient's determined curative effect.Present multiple acetylcholinesterase depressant has been used for the treatment of alzheimer's disease.
But E.C. 3.1.1.7 suppresses the integrated degree that the curative effect of type medicine depends on cholinergic neuron, is inappropriate for the severe patient.Simultaneously; Such medicine can only improve the content of vagusstoff, and what can not stop cholinergic nerve of centrum unit carries out sexual involution death, along with the development of the state of an illness; Cholinergic nerve of centrum unit carries out sexual involution death, and the drug effect of acetylcholinesterase depressant also can reduce gradually.Therefore, searching can stop the dead novel acetylcholinesterase depressant of cholinergic nerve of centrum unit degeneration to become the key of seeking therapeutic agent for alzheimer's disease again by acetylcholine esterase inhibition activity.
βAmyloid is piled up the formation that has caused senile plaque; The neurotoxicity approach that promoted the inflammatory reaction activation has caused the dysfunction and the death of neurocyte, is to form senile plaque; Cause one of the main reasons (the Riviere C of neurocyte degeneration; Richard T, Vitrac X, Merillon JM; Valls J, Monti JP. New polyphenols active on beta-amyloid aggregation. Bioorganic and Medicinal Chemistry Letters 2008; 18 (2): 828-31).Research shows that oestrogenic hormon can suppress
βAmyloid inductive nerve cell death has good neurocyte protection effect.But oestrogenic hormon causes the non-neurocyte that oestrogenic hormon is relevant such as the hyperplasia and the canceration of mammary gland cell and endometrial cell during alzheimer's disease in treatment; Therefore in clinical application, be restricted (Bang OY, Hong HS, Kim DH; Kim H; Boo JH, Huh K, et al. Neuroprotective effect of genistein against beta amyloid-induced neurotoxicity. Neurobiology of Disease 2004; 16 (1): 21-8).
Genistein (4 ', 5, the 7-trihydroxy-isoflavone) is the main biologically active substance of soybean isoflavones, and this compound has stronger estrogen activity.Research shows that genistein can either suppress
βAmyloid inductive nerve cell death can not cause Normocellular canceration again as oestrogenic hormon, in the treatment of alzheimer's disease, have good application prospects.But this compound does not have inhibiting activity of acetylcholinesterase,, and its application receives certain restriction.
The incidence and development of considering alzheimer's disease is caused by a plurality of factors; " multi-target-directed drug design strategy " (i.e. design concept that compound molecule can act on a plurality of targets in the development of Alzheimer's disease mutually) is introduced into (Bolognesi ML in the research and development of therapeutic agent for alzheimer's disease; Cavalli A; Valgimigli L; Bartolini M; Rosini M, Andrisano V, et al. Multi-target-directed drug design strategy:from a dual binding site acetylcholinesterase inhibitor to a trifunctional compound against Alzheimer's disease. Journal of Medicinal Chemistry 2007; 50 (26): 6446-9).The therapeutic agent for alzheimer's disease that can act on a plurality of target spots has simultaneously become the trend of alzheimer's disease medicament research and development.Genistein is carried out chemically modified, and the multiple acting target spot compound that is had estrogen activity and inhibiting activity of acetylcholinesterase, simultaneously will have good application prospects in treatment of alzheimer.
Summary of the invention
The object of the present invention is to provide a kind of genistein verivate that has inhibiting activity of acetylcholinesterase, and estrogen activity simultaneously; Be specially 4 '; 5-dihydroxyl-7-[4-(N; The N-diethylin) butoxy] NOVASOY 400, and the preparation method of this compound and the application that is used to prepare treatment Alzheimer medicine.
The present invention adopts following technical scheme: a kind of genistein verivate has the structure shown in the formula I:
Described genistein verivate 4 '; 5-dihydroxyl-7-[4-(N; The N-diethylin) butoxy] NOVASOY 400 can synthesize as follows, with genistein and 1, the reaction of 4-dibrominated butane make intermediate product 4 '; 5-dihydroxyl-7-(4-bromine butoxy) NOVASOY 400, resulting intermediate product and diethylamine reaction make object genistein verivate.
Described method specifically may further comprise the steps:
1) 4 ', the preparation of 5-dihydroxyl-7-(4-bromine butoxy) NOVASOY 400
Genistein (0.27 g, 1 mmol), 1,4-dibromobutane (5.4 g, 25 mmol), K
2CO
3(0.07 g, 0.5 mmol) is dissolved in the dry DMF of 60 mL, 40 ℃-50 ℃ of following ultrasonic reaction 1-2 hours.After reaction is accomplished, the reaction mixture cool to room temperature, behind the filtering insolubles, the filtrate decompression distillation obtains faint yellow solid, and recrystallization obtains light yellow needle-like crystal in the acetone.
2) 4 ', the preparation of 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400
With compound 4 ', 5-dihydroxyl-7-(4-bromine butoxy) NOVASOY 400 (0.40 g, 1 mmol) is dissolved in the 5 mL dry DMF; Slowly drip diethylamine (0.37 g, 5 mmol), 80 ℃-90 ℃ were stirred 1-2 hour down; Reaction product is slowly in the impouring 100mL mixture of ice and water; Hold over night leaches solid, acetone recrystallization.
BA through to this compound is studied, and finds that this compound has stronger acetylcholinesteraseinhibition inhibition, the estrogen activity suitable with the parent compound genistein and right
βThe provide protection of-amyloid inductive neural cell injury.Therefore, this compound can be used as the anti-Alzheimer disease compound of many target spots, is used to prevent and treat the preparation of Alzheimer medicine.
The invention still further relates to the application of described genistein verivate in preparation treatment Alzheimer medicine.
4 '; 5-dihydroxyl-7-[4-(N; The N-diethylin) butoxy] NOVASOY 400 is as a kind of compound of novel anti alzheimer's disease of multiple acting target spot; Can have inhibiting activity of acetylcholinesterase,, estrogen activity and neurocyte protection effect simultaneously, be used for preparing the medicine of treating alzheimer's disease, alzheimer's disease is had good therapeutic action.
The genistein verivate 4 of the present invention through genistein being carried out chemically modified and obtain ', 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 has inhibiting activity of acetylcholinesterase, and estrogen activity simultaneously, for
β-amyloid inductive neural cell injury has provide protection, can be used as a kind of compound of novel anti alzheimer's disease of multiple acting target spot, is used for preparation treatment Alzheimer medicine.
Below through embodiment the present invention is done further detailed explanation, but protection scope of the present invention does not receive any restriction of specific embodiment, but is limited claim.
Embodiment
Embodiment 1:4 ', 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400) and preparation
Preparation genistein verivate 4 ', 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 may further comprise the steps:
1,4 ', the preparation of 5-dihydroxyl-7-(4-bromine butoxy) NOVASOY 400
Genistein (0.27 g, 1 mmol), 1,4-dibromobutane (5.4 g, 25 mmol), K
2CO
3(0.07 g, 0.5 mmol) is dissolved in the dry DMF of 60 mL, 40 ℃ of following ultrasonic reactions 1.5 hours.After reaction is accomplished, the reaction mixture cool to room temperature, behind the filtering insolubles, the filtrate decompression distillation obtains faint yellow solid, and recrystallization obtains light yellow needle-like crystal in the acetone, productive rate 86 %, fusing point 130-131 ℃.
1?H?NMR?(DMSO-d
6):?1.83?(m,?2H),?1.94?(m,?2H),?3.60?(t,?J?=?6.2?Hz,?2H),?4.12?(t,?J?=?6.4?Hz,?2H),?6.40?(d,?J?=?2.0?Hz,?1H),?6.65?(d,?J?=?2.0?Hz,?1H),?6.80?(d,?J?=?8.5?Hz,?2H),?7.38?(d,?J?=?8.5?Hz,?2H),?8.40?(s,?1H),?9.65?(s,?1H),?12.95?(s,?1H).?ESI-MS?C
19H
17BrO
5?[M+H]
+?405.?Anal.?Calcd?for?C
19H
17?BrO
5:?C,?56.31;?H,?4.23.?Found:?C,?56.28;?H,?4.27。
2,4 ', the preparation of 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400
With compound 4 ', 5-dihydroxyl-7-(4-bromine butoxy) NOVASOY 400 (0.40 g, 1 mmol) is dissolved in the 5 mL dry DMF; Slowly drip diethylamine (0.37 g, 5 mmol), 80 ℃-90 ℃ were stirred 1 hour down; Slowly in the impouring 100mL mixture of ice and water, hold over night leaches solid to reaction product; Acetone recrystallization, productive rate 82 %, fusing point 170-171 ℃.
1?H?NMR?(DMSO-d
6?):?0.94?(t,?J?=?7.2?Hz,?6H),1.52?(m,?2H),?1.72?(m,?2H),?2.40(m,?2H),?3.33?(t,?J?=?7.0?Hz,?4H),?4.10?(t,?J?=?6.5?Hz,?2H),?6.39?(d,?J?=?2.0?Hz,?1H),?6.64?(d,?J?=?2.0?Hz,?1H),?6.82(d,?J?=?8.5?Hz,?2H),?7.39(d,?J?=?8.5?Hz,?2H),?8.40?(s,?1H),?9.60?(s,?1H),?12.93?(s,?1H).?ESI-MS?C
23H
27NO
5?[M+H]
+398.?Anal.?calc.?for?C
23H
27?NO
5?:?C,?69.50;?H,6.85;?N,?3.52.?Found:?C,?69.60;?H,?6.79;?N,?3.58。
Embodiment 2: genistein verivate 4 ' and, the inhibiting activity of acetylcholinesterase, of 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400
1,4 ', 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 is to the electric eel inhibiting activity of acetylcholinesterase,
Enzyme reaction is 25
oC carries out in the phosphoric acid buffer of 0.1 M pH8.0, and total reaction volume is 200 μ L; Include 3.33 mM 5,5 '-two sulphur-Lian (2-nitrobenzoic acid), 20 μ L, 0.35 U/mL E.C. 3.1.1.7 solution, 20 μ L and 5.3 mM acetylthiocholine iodide solution, 20 μ L; Test this compound solution 10 μ L; (Sunrise, Tecan Austria) detect 5 min with ELIASA at 412 nm.The sample triplicate.As 100%, the optical density(OD) in compound determination hole compares with it with the OD value that do not add the compound hole, and the percentage of reduction is enzyme inhibition rate.It is active to the inhibition of E.C. 3.1.1.7 that this compound is surveyed 5 concentration gradients at least, through the compound concentration logarithm inhibiting rate mapped and ask IC
50Value (compound concentrations when suppressing 50% enzymic activity).
The present invention tested 4 ', the inhibiting activity of acetylcholinesterase, of 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400.This compound has significant inhibiting activity of acetylcholinesterase,, the IC of its acetylcholine esterase inhibition
50Value is 0.17 μ M, suitable (IC with the positive control tacrine
50Be worth 0.17 μ M), and its parent compound genistein no obvious inhibiting activity of acetylcholinesterase, under this 100 μ M concentration.
2,4 ', 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 suppresses electric eel E.C. 3.1.1.7 kinetics
When 25 ° of C, measure this compound respectively at 0 μ M, 10 μ M, 20 μ M and 40 μ M, concentration of substrate are 50 μ M, 100 μ M, 200 μ M, the activity of AChE when 300 μ M and 400 μ M.The data that record are observed the inhibition type of enzyme with Lineweaver – Burk method double-reciprocal plot.Lineweaver-Burk figure slope is asked K to this compound concentrations secondary mapping
iValue (compound and enzyme bonded dissociation constant).Double-reciprocal plot shows that this compound is the noncompetitive inhibitor of E.C. 3.1.1.7.The Ki value that this compound acetylcholine esterase inhibition is tried to achieve in the secondary mapping is 0.23 ± 0.01
μM (n=6).
3, computer simulation 4 ', the interaction of 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 and E.C. 3.1.1.7
The crystalline structure of electric eel AChE is downloaded (the PDB numbering is respectively 1C2B) from the PDB DB, and carries out energy-optimised with Amber9 software to it.The three-dimensional structure of compound is with Chemoffice 3D software building and optimization.Carry out molecular docking with AUTODOCK 4.0 softwares.Molecular docking shows that this compound can combine 4 of this compound with the far-end negatively charged ion binding site of E.C. 3.1.1.7
ˊThe S289 of-OH and far-end negatively charged ion binding site forms hydrogen bond, and other parts can interact through hydrophobic interaction and E.C. 3.1.1.7 far-end negatively charged ion binding site and near W82, Y120, W282, R292, Y333, F334, Y337, H443 residue thereof.
Embodiment 3: genistein verivate 4 ' and, the estrogen activity of 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400
1,4 ', 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 promotes the effect of the MCF-7 cell proliferation that oestrogenic hormon relies on
The MCF-7 cell is with 1.5 * 10
4The concentration kind is in 96 orifice plates.Cell cultures 24 h inhale adherent back and remove original substratum, change and contain 1640 substratum that 5% gac/VISOSE is handled foetal calf serum.Continuing to cultivate 48 h runs out the oestrogenic hormon in the cell.Test is divided into blank group, drug-treated group, positive controls.Blank control group is changed and is contained 1640 substratum that 5% gac/VISOSE is handled foetal calf serum; It is 100 μ M that the replacing of drug-treated group contains concentration, 50 μ M, 10 μ M; 1 μ M, 0.1 μ M, 0.01 μ M; 0.001 μ M; 0.0001 μ M and 0.00001 μ M 4 ', 1640 substratum of 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 (contain 5% gac/VISOSE and handle foetal calf serum); It is 100 μ M that the positive controls replacing contains concentration, 50 μ M, 10 μ M, 1 μ M, 0.1 μ M, 0.01 μ M, 0.001 μ M, 1640 substratum of 0.0001 μ M and 0.00001 μ M genistein (contain 5% gac/VISOSE and handle foetal calf serum).After cultivating 96 h, MTT detects cell survival rate.Cell proliferation rate (%)=Δ OD drug-treated/Δ OD blank * 100.Experimental result is seen table 1.
Table 14 ', 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 is to the promoter action (n=6) of MCF-7 cell proliferation, cell survival rate (%)
| Concentration (μ M) | 4 ', 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 | Genistein |
| 100 | 1.02±1.36 | 48.73±7.27 |
| 50 | 0.87±1.43 | 84.23±8.83 |
| 10 | 35.44±4.99 | 121.51±9.92 |
| 1 | 136.74±0.74 | 136.42±5.40 |
| 0.1 | 135.83±6.68 | 136.54±8.97 |
| 0.01 | 134.87±9.85 | 129.32±13.64 |
| 0.001 | 137.19±4.75 | 131.84±13.59 |
| 0.0001 | 127.61±10.23 | 126.52±18.73 |
| 0.00001 | 121.02±6.08 | 131.67±7.48 |
Can find out that by table 1 when compound concentration was lower than 1 μ M, this compound and genistein can both promote the MCF-7 cell proliferation that oestrogenic hormon relies on, and promptly have estrogen activity.When 1 μ M, this compound and genistein are stronger to MCF-7 cell growth-promoting effect, and these two compounds are suitable basically to the proliferation function of MCF-7 cell.But when being higher than this concentration since this compound and genistein to the CDCC of MCF-7 cell, viable cell number minimizing.When compound concentration was 0.01 and 0.001 μ M, the cell survival rate that the survival rate of the MCF-7 cell of this compound treatment is handled than genistein was slightly high, infers that the estrogen activity of this compound is better than its parent compound genistein.
2, computer simulation 4 ', the interaction of 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 and ERs
ER
αAnd ER
βCrystalline structure from the PDB DB, download (PDB numbering be respectively 2I0J and 2I0G), and carry out energy-optimised to it with Amber9 software.4 ', the three-dimensional structure of 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 is with Chemoffice 3D software building and optimization.Carry out molecular docking with AUTODOCK 4.0 softwares.Molecular docking shows, this compound and ER
αAnd ER
βInteraction is all arranged.This compound and ER
αBound energy be-8.18 kcal/mol far above itself and ER
βBound energy (11.66 kcal/mol).This compound and ER
αAnd ER
βDissociation constant K
iBe respectively 1.01 μ M and 2.86 nM.So this compound and ER
βBinding ability compare ER
αStrong about 350 times, to ER
βHas high selectivity (table 2).
Table 24 ', 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 and ER
αWith ER
βInteractional bound energy and K
iValue
| Parameter | ER α | ER β |
| Binding Energy | -8.18 kcal/mol | -11.66 kcal/mol |
| K i | 1.01 μM | 2.86 nM |
4 ' of this compound-OH and ER
βThe N483 of acceptor forms hydrogen bond, N nuclear power and ER on the 7-O substituting group
βThe E305 of acceptor forms hydrogen bond.The aliphatic chain that is connected on the A of this compound ring and the 7-O has inserted by M340 through hydrophobic interaction, L339, and L343 is in the lipophilic pocket of F356 and L298 formation.The phenyl ring of B ring combines with L476 and M295 through hydrophobic interaction.
This compound and ER
αInteraction than and ER
βInteraction want a little less than.This compound embeds ER α by M343 through hydrophobic interaction, L346, and F404, M421, I424 in the hydrophobic pocket that L523 forms, but does not have stronger interaction of hydrogen bond.
Embodiment 4: 4 ', 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 is right
βThe provide protection of-amyloid inductive SH-SY5Y cell injury
The SH-SY5Y cell is with 1 * 10
4Individual/mL is inoculated in porous plate, cultivates the adherent back of 24 h and changes the DMEM substratum that contains 10 μ M vitamin A acids (RA).Changed a subculture in per two days, handled 7 days, the inducing cell differentiation.Induce the cell of differentiation, use D-Hank ' s liquid to wash gently 2 times, test is divided into blank group, model group, drug-treated group, positive controls.The blank group is changed and is contained no phenol red 1640 substratum that 10% gac/VISOSE is handled foetal calf serum; It is 15 μ M's that model group adds final concentration
β-amyloid; The drug-treated group add 4 of different concns ', 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 adds 15 μ M after incubating 3 h in advance
β-amyloid; Positive controls adds after adding oestrogenic hormon 2 nM or genistein 1 nM 3 h
β-amyloid.Detect cell survival rate with mtt assay behind each treatment group cell cultures 72 h.Experimental result is seen table 3.
Table 34 ', 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 is to the provide protection of amyloid-beta inductive SH-SY5Y cell injury
| Group | Cell survival rate (%) |
| Blank | 100±5.89 |
| Model group | 7.64±3.85 |
| 4 ', 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 (1000 nM) | 90.98±4.48 |
| 4 ', 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 (100 nM) | 82.97±6.52 |
| 4 ', 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 (10 nM) | 82.42±6.01 |
| 4 ', 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 (1nM) | 94.21±8.59 |
| 4 ', 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 (0.1 nM) | 85.74±4.19 |
| 4 ', 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 (0.01 nM) | 85.31±3.20 |
| Genistein (0.001 nM) | 85.50±2.92 |
| Oestrogenic hormon (1 nM) | 93.85±4.21 |
Can find out 15 μ M by table 3
βAfter-amyloid was handled SH-SY5Y cell 72 h of differentiation, cell survival rate dropped to 75.6% of blank.1000 nM, this compound treatment cell of 1 nM and 0.1 nM can both obviously improve the survival rate of cell, and the survival rate of this compound treatment group of all the other concentration SH-SY5Y cell also increases, but compares there was no significant difference with model group.1 this compound of nM concentration has the strongest cytoprotection (cell survival rate 94.2%), is superior to the parent compound genistein (cell survival rate is respectively 93.9% and 85.5%) of 2 nM oestrogenic hormon and same concentrations.
Claims (5)
- Genistein verivate 4 with structure shown in the formula I ', 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400,（Ⅰ）。
- 2. the preparation method of the described genistein verivate of claim 1; It is characterized in that genistein and 1; 4-dibrominated butane reaction make intermediate product 4 ', 5-dihydroxyl-7-(4-bromine butoxy) NOVASOY 400, resulting intermediate product and diethylamine react make 4 '; 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400.
- 3. the preparation method of genistein verivate according to claim 2 is characterized in that may further comprise the steps:1) 4 ', the preparation of 5-dihydroxyl-7-(4-bromine butoxy) NOVASOY 400Genistein 0.27 g, 1,4-dibromobutane 5.4 g, K 2CO 30.07 g is dissolved in the dry DMF of 60 mL, 40 ℃-50 ℃ of following ultrasonic reaction 1-2 hours; After reaction is accomplished, the reaction mixture cool to room temperature, behind the filtering insolubles, the filtrate decompression distillation obtains faint yellow solid, and recrystallization obtains light yellow needle-like crystal in the acetone;2) 4 ', the preparation of 5-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400The compound 4 that step 1) is obtained '; 5-dihydroxyl-7-(4-bromine butoxy) NOVASOY 400 0.40 g is dissolved in the 5 mL dry DMF, slowly drips diethylamine 0.37 g, and 80 ℃-90 ℃ were stirred 1-2 hour down; Reaction product is slowly in the impouring 100mL mixture of ice and water; Hold over night leaches solid, acetone recrystallization.
- 4. the application of the described genistein verivate of claim 1 in preparation treatment Alzheimer medicine.
- 5. the application of genistein verivate according to claim 4 in preparation treatment Alzheimer medicine is characterized in that described genistein verivate has inhibiting activity of acetylcholinesterase,, estrogen activity and neurocyte protection effect.
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| PCT/CN2011/080037 WO2012075849A1 (en) | 2010-12-06 | 2011-09-22 | 4',5-dihydroxy-7-[4-(n, n-diethylamino) butoxy] isoflavones, and preparation method and application thereof |
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