CN115650991A - Preparation method of decursinol ester derivative and application of decursinol ester derivative in inhibiting activity of acetylcholinesterase - Google Patents
Preparation method of decursinol ester derivative and application of decursinol ester derivative in inhibiting activity of acetylcholinesterase Download PDFInfo
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- CN115650991A CN115650991A CN202211293121.0A CN202211293121A CN115650991A CN 115650991 A CN115650991 A CN 115650991A CN 202211293121 A CN202211293121 A CN 202211293121A CN 115650991 A CN115650991 A CN 115650991A
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- decursinol
- ester derivative
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- acetylcholinesterase
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- BGXFQDFSVDZUIW-UHFFFAOYSA-N Decursinol Natural products O1C(=O)C=CC2=C1C=C1OC(C)(C)C(O)CC1=C2 BGXFQDFSVDZUIW-UHFFFAOYSA-N 0.000 title claims abstract description 69
- -1 decursinol ester Chemical class 0.000 title claims abstract description 48
- 108010022752 Acetylcholinesterase Proteins 0.000 title claims abstract description 27
- 229940022698 acetylcholinesterase Drugs 0.000 title claims abstract description 27
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 102000012440 Acetylcholinesterase Human genes 0.000 title claims abstract 9
- 230000000694 effects Effects 0.000 claims abstract description 14
- 230000005764 inhibitory process Effects 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 29
- BGXFQDFSVDZUIW-LBPRGKRZSA-N decursinol Chemical compound O1C(=O)C=CC2=C1C=C1OC(C)(C)[C@@H](O)CC1=C2 BGXFQDFSVDZUIW-LBPRGKRZSA-N 0.000 claims description 23
- 239000000243 solution Substances 0.000 claims description 19
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000005303 weighing Methods 0.000 claims description 14
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- 239000002244 precipitate Substances 0.000 claims description 10
- 238000010898 silica gel chromatography Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 239000008055 phosphate buffer solution Substances 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- QOSSAOTZNIDXMA-UHFFFAOYSA-N N,N′-Dicyclohexylcarbodiimide Substances C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 238000000338 in vitro Methods 0.000 claims description 5
- 238000012544 monitoring process Methods 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- VYWYYJYRVSBHJQ-UHFFFAOYSA-N 3,5-dinitrobenzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 VYWYYJYRVSBHJQ-UHFFFAOYSA-N 0.000 claims description 4
- 238000002965 ELISA Methods 0.000 claims description 4
- 241000277305 Electrophorus electricus Species 0.000 claims description 4
- 238000010521 absorption reaction Methods 0.000 claims description 4
- 239000013641 positive control Substances 0.000 claims description 4
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 claims description 4
- 229960001685 tacrine Drugs 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims description 3
- 229960001231 choline Drugs 0.000 claims description 3
- 238000011534 incubation Methods 0.000 claims description 3
- 230000010355 oscillation Effects 0.000 claims description 3
- 230000000202 analgesic effect Effects 0.000 abstract description 2
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 2
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 2
- 230000000259 anti-tumor effect Effects 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 19
- 229910052739 hydrogen Inorganic materials 0.000 description 19
- 239000001257 hydrogen Substances 0.000 description 19
- 102100033639 Acetylcholinesterase Human genes 0.000 description 18
- 239000011734 sodium Substances 0.000 description 18
- 238000001819 mass spectrum Methods 0.000 description 16
- 238000002844 melting Methods 0.000 description 16
- 230000008018 melting Effects 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- 229940125782 compound 2 Drugs 0.000 description 4
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N benzo-alpha-pyrone Natural products C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 2
- 241000244269 Peucedanum Species 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- KIUMMUBSPKGMOY-UHFFFAOYSA-N 3,3'-Dithiobis(6-nitrobenzoic acid) Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(SSC=2C=C(C(=CC=2)[N+]([O-])=O)C(O)=O)=C1 KIUMMUBSPKGMOY-UHFFFAOYSA-N 0.000 description 1
- 241000125175 Angelica Species 0.000 description 1
- 241000213006 Angelica dahurica Species 0.000 description 1
- 241001254604 Angelica pubescens Species 0.000 description 1
- 241000356446 Cnidium monnieri Species 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 235000001287 Guettarda speciosa Nutrition 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 235000019084 Selinum monnieri Nutrition 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- ZCCUUQDIBDJBTK-UHFFFAOYSA-N furocoumarin Natural products C1=C2OC(=O)C=CC2=CC2=C1OC=C2 ZCCUUQDIBDJBTK-UHFFFAOYSA-N 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- OLOOJGVNMBJLLR-UHFFFAOYSA-N imperatorin Chemical compound C1=CC(=O)OC2=C1C=C1C=COC1=C2OCC=C(C)C OLOOJGVNMBJLLR-UHFFFAOYSA-N 0.000 description 1
- XKVWLLRDBHAWBL-UHFFFAOYSA-N imperatorin Natural products CC(=CCOc1c2OCCc2cc3C=CC(=O)Oc13)C XKVWLLRDBHAWBL-UHFFFAOYSA-N 0.000 description 1
- XDROKJSWHURZGO-UHFFFAOYSA-N isopsoralen Natural products C1=C2OC=CC2=C2OC(=O)C=CC2=C1 XDROKJSWHURZGO-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- MLMVLVJMKDPYBM-UHFFFAOYSA-N pseudoisopsoralene Natural products C1=C2C=COC2=C2OC(=O)C=CC2=C1 MLMVLVJMKDPYBM-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 description 1
- 229950005143 sitosterol Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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Abstract
The invention discloses a preparation method of a decursinol ester derivative and application of the decursinol ester derivative in inhibiting the activity of acetylcholinesterase, wherein the decursinol ester derivative 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3l, 3m, 3n and 3o are prepared by a preparation method of the decursinol ester derivative, and the invention shows the inhibition activity to the acetylcholinesterase; has antitumor, antiinflammatory, antibacterial, analgesic, and acetylcholinesterase resisting effects, and has potential medicinal value.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a preparation method of a decursinol ester derivative and application of the decursinol ester derivative in inhibiting activity of acetylcholinesterase.
Background
The coumarin compound is a heterocyclic compound with a benzo alpha-pyrone parent nucleus, widely exists in various medicinal plants, has biological activities of cancer resistance, antibiosis, antivirus, anti-inflammation, antioxidation and the like, and is widely concerned by drug research personnel.
The peucedanum lactone, also called imperatorin and angelicin, belongs to the linear furocoumarin compound, and has the structural characteristics of a furan ring, a hexahydric lactone ring and a branched chain ether structure. The decursinol is mainly contained in medicinal plants such as peucedanum root, angelica dahurica, angelica, cnidium monnieri, pubescent angelica root and the like, has various biological activities and has potential medicinal value.
Disclosure of Invention
The invention provides a preparation method of a decursinol ester derivative and application of the decursinol ester derivative in inhibiting activity of acetylcholinesterase, which aim to solve the problems in the prior art.
The scheme of the invention is as follows:
a preparation method of a decursinolide ester derivative comprises the following steps:
1) Dissolving decursinol with 1,4-dioxane, heating to 60 deg.C, adding selenium dioxide under stirring, heating to 80 deg.C, continuing to react, tracking and monitoring by TLC, filtering after the reaction is finished, and removing precipitate in the reaction solution;
2) Washing the precipitate with dichloromethane, mixing organic solvents, drying with anhydrous sodium sulfate, concentrating with rotary evaporator, and separating with thin layer silica gel chromatography to obtain decursinol;
3) Weighing decursinol, adding into a round-bottom flask, dissolving with absolute ethanol, cooling to 0 deg.C in ice bath, adding sodium borohydride, stirring, reacting, adding diluted hydrochloric acid to terminate the reaction, extracting with ethyl acetate, concentrating, and separating by column chromatography;
4) Weighing the compound in the step 3), adding the compound into a round-bottom flask, adding anhydrous dichloromethane for dissolving, then adding the weighed substituted acid, DCC and DMAP, and detecting whether the reaction is complete by TLC; then filtering, concentrating, and separating by thin layer silica gel chromatography to obtain the decursinol ester derivatives 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3l, 3m, 3n and 3o.
As a preferred technical scheme, 1mmol of decursinol is weighed in the step 1); 1.2mmol of selenium dioxide are added.
As a preferable technical scheme, 1mmol of decursinol lactone aldehyde is weighed in the step 3) and added into a round-bottom flask; 2mmol of sodium borohydride was added.
As a preferable technical scheme, the 1mmol de compound obtained in the step 3) is weighed in the step 4) and added into a round-bottom flask.
The invention also discloses application of the decursinol ester derivative in inhibiting the activity of acetylcholinesterase.
The invention also discloses a method for detecting the activity of the decursinol ester derivative on in-vitro acetylcholinesterase, which comprises the following steps:
1) Dissolving a decursinol ester derivative sample in a proper amount of dimethyl sulfoxide, and then adding a 0.1mol/L phosphate buffer solution with the pH of 7.4 to prepare a solution to be detected, wherein the solution to be detected is 1 mg/mL;
2) The positive control adopts tacrine, and the blank control adopts a phosphate buffer solution;
3) In the determination, 10 mu L of a solution sample to be determined is firstly added on a 96-well plate, then 40 mu L of PB, 20 mu L of 2.5 mmol/L5,5-two-flow dinitrobenzoic acid and 10 mu L of electric eel acetylcholinesterase are sequentially added, the oscillation and the mixing are carried out, the incubation is carried out for 10 minutes at 37 ℃, then 20 mu L of 10mmol/L iodinated thioacetyl choline is added, the reaction is carried out for 10 minutes at 37 ℃, 30uL of 1% SDS is added to stop the reaction, and an enzyme-linked immunosorbent assay instrument is used for determining the absorption value at 405nm and calculating the inhibitory activity of the sample on the acetylcholinesterase.
As a preferred technical solution, the formula used in the calculation in step 3) is as follows:
inhibition rate = [ (OD blank control-OD reaction background) - (OD sample to be detected-OD reaction background) ]/(OD blank control-OD reaction background) × 100%.
The invention discloses a preparation method of a decursinol ester derivative, which comprises the following steps:
1) Dissolving decursinol with 1,4-dioxane, heating to 60 deg.C, adding selenium dioxide under stirring, heating to 80 deg.C for continuous reaction, tracking and monitoring by TLC, filtering after the reaction is finished, and removing precipitate from the reaction solution; 2) Washing the precipitate with dichloromethane, mixing organic solvents, drying with anhydrous sodium sulfate, concentrating with rotary evaporator, and separating with thin layer silica gel chromatography to obtain decursinol; 3) Weighing decursinol, adding into a round-bottom flask, dissolving with absolute ethanol, cooling to 0 deg.C in ice bath, adding sodium borohydride, stirring, reacting, adding diluted hydrochloric acid to terminate the reaction, extracting with ethyl acetate, concentrating, and separating by column chromatography; 4) Weighing the compound in the step 3), adding the compound into a round-bottom flask, adding anhydrous dichloromethane for dissolving, then adding the weighed substituted acid, DCC and DMAP, and detecting whether the reaction is complete by TLC; then filtering, concentrating, and separating by thin layer silica gel chromatography to obtain the decursinol ester derivatives 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3l, 3m, 3n and 3o.
The invention has the advantages that:
the product of the invention has an inhibitory effect on acetylcholinesterase and shows the inhibitory activity on acetylcholinesterase.
Has various biological activities, such as anti-tumor, anti-inflammatory, antibacterial, analgesic, anti-acetylcholinesterase activity and the like, and has potential medicinal value.
Drawings
FIG. 1 is a hydrogen spectrum of a decursinolactone ester derivative 3a in example 1 of the present invention;
FIG. 2 is a hydrogen spectrum of the ester derivative of decursinolactone 3b in example 1 of the present invention;
FIG. 3 is a hydrogen spectrum of the ester derivative of decursinolactone 3c in example 1 of the present invention.
Detailed Description
In order to make up for the above deficiencies, the present invention provides a preparation method of a decursinol ester derivative and an application of the decursinol ester derivative in inhibiting acetylcholinesterase activity so as to solve the problems in the background art.
A preparation method of a decursinolide ester derivative comprises the following steps:
1) Dissolving decursinol with 1,4-dioxane, heating to 60 deg.C, adding selenium dioxide under stirring, heating to 80 deg.C for continuous reaction, tracking and monitoring by TLC, filtering after the reaction is finished, and removing precipitate from the reaction solution;
2) Washing the precipitate with dichloromethane, mixing organic solvents, drying with anhydrous sodium sulfate, concentrating with rotary evaporator, and separating with thin layer silica gel chromatography to obtain decursinol;
3) Weighing decursinol, adding into a round-bottom flask, dissolving with absolute ethanol, cooling to 0 deg.C in ice bath, adding sodium borohydride, stirring, reacting, adding diluted hydrochloric acid to terminate the reaction, extracting with ethyl acetate, concentrating, and separating by column chromatography;
4) Weighing the compound in the step 3), adding the compound into a round-bottom flask, adding anhydrous dichloromethane for dissolving, then adding the weighed substituted acid, DCC and DMAP, and detecting whether the reaction is complete by TLC; then filtering, concentrating, and separating by thin layer silica gel chromatography to obtain the decursinol ester derivatives 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3l, 3m, 3n and 3o.
Weighing 1mmol of decursinol in the step 1); 1.2mmol of selenium dioxide are added.
Weighing 1mmol of decursinol in the step 3), and adding the decursinol into a round-bottom flask; 2mmol of sodium borohydride was added.
Weighing the 1mmol compound obtained in the step 3) in the step 4), and adding the compound into a round-bottom flask.
The invention also discloses application of the decursinol ester derivative in inhibiting the activity of acetylcholinesterase.
The invention also discloses a method for detecting the activity of the decursinol ester derivative on in-vitro acetylcholinesterase, which comprises the following steps:
1) Dissolving a decursinol ester derivative sample in a proper amount of dimethyl sulfoxide, and then adding a 0.1mol/L phosphate buffer solution with the pH of 7.4 to prepare a solution to be detected, wherein the solution to be detected is 1 mg/mL;
2) The positive control adopts tacrine, and the blank control adopts phosphate buffer solution;
3) In the determination, 10 mu L of a solution sample to be determined is firstly added on a 96-well plate, then 40 mu L of PB, 20 mu L of 2.5 mmol/L5,5-two-flow dinitrobenzoic acid and 10 mu L of electric eel acetylcholinesterase are sequentially added, the oscillation and the mixing are carried out, the incubation is carried out for 10 minutes at 37 ℃, then 20 mu L of 10mmol/L iodinated thioacetyl choline is added, the reaction is carried out for 10 minutes at 37 ℃, 30uL of 1% SDS is added to stop the reaction, and an enzyme-linked immunosorbent assay instrument is used for determining the absorption value at 405nm and calculating the inhibitory activity of the sample on the acetylcholinesterase.
The formula used for calculation in the step 3) is as follows:
inhibition rate = [ (OD blank control-OD reaction background) - (OD sample to be detected-OD reaction background) ]/(OD blank control-OD reaction background) × 100%.
In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further described with the specific embodiments.
Example 1
1. The product is as follows: the physicochemical properties of the decursinolide ester derivatives are detailed below;
2. the preparation method comprises the following steps:
the chemical synthetic route for compound 2 is as follows:
dissolving weighed 1mmol of decursinol with 1,4-dioxane, heating to 60 ℃, adding 1.2mmol of selenium dioxide under the condition of continuously stirring, heating to 80 ℃, continuing to react, tracking and monitoring by TLC, filtering after the reaction is finished, and removing the precipitate in the reaction solution. The precipitate was washed with dichloromethane. Mixing organic solvents, drying with anhydrous sodium sulfate, concentrating with rotary evaporator, and separating by thin layer silica gel chromatography to obtain decursinol. Adding weighed decursinol (1 mmol) into a round-bottom flask, dissolving with absolute ethanol, cooling to 0 ℃ in an ice bath, adding 2mmol of sodium borohydride, stirring for reaction, adding diluted hydrochloric acid after the reaction is finished to stop the reaction, extracting with ethyl acetate, concentrating, and separating by column chromatography to obtain compound 2. Yield of
The flower-conditioning properties of compound 2 are as follows:
1) Yield =69%, white solid, melting point 130-132 ℃;
2) Hydrogen nuclear magnetic resonance image characteristics 1 H NMR(600MHz,CDCl 3 )δ:7.76(d,J＝9.6Hz,1H,H-5),7.69(d,J＝2.4Hz,1H,H-2),7.37(s,1H,H-4),6.82(d,J＝2.4Hz,1H,H-3),6.36(d,J＝9.6Hz,1H,H-6),5.89(t,J＝6.6Hz,1H,H-2’),5.06(d,J＝7.2Hz,2H,H-1’),4.04(s,2H,H-4’),1.75(s,3H,H-5’),1.69(s,1H,OH)；
3) ESI-TRAP source mass spectrum MS M/z of the compound is 309.2 ([ M + Na ]] + ,100)。
The following synthetic routes of the decursinolide ester derivatives 3 a-3 o are as follows:
adding weighed compound 2 (1 mmol) into a round-bottom flask, adding anhydrous dichloromethane for dissolving, directly adding weighed substituted acid, DCC (dicyclohexylcarbodiimide) and DMAP (4-dimethylaminopyridine), and detecting whether the reaction is complete by TLC. Then filtering, concentrating, and separating by thin-layer silica gel chromatography to obtain the decursinol ester derivatives 3 a-3 o.
The physicochemical properties of the decursinol ester derivative 3a are as follows:
1) Yield =58%, white solid, melting point 114-116 ℃;
2) Characteristic of hydrogen nuclear magnetic resonance image 1 H NMR(600MHz,CDCl 3 )δ:8.02(d,J＝7.8Hz,2H,H-Ar),7.74(d,J＝10.8Hz,1H,H-5),7.66(d,J＝3.6Hz,1H,H-2),7.55(t,J＝7.8Hz,1H,H-Ar),7.43(t,J＝7.8Hz,2H,H-Ar),7.37(s,1H,H-4),6.80(d,J＝3.0Hz,1H,H-3),6.35(d,J＝9.0Hz,1H,H-6),5.98(t,J＝7.2Hz,1H,H-2’),5.10(d,J＝6.6Hz,2H,H-1’),4.72(s,2H,H-4’),1.82(s,3H,H-5’)；
3) The ESI-TRAP source mass spectrum MS M/z of the compound is 413.1 ([ M + Na)] + ,100)。
The physicochemical properties of the decursinol ester derivative 3b are as follows:
1) Yield =64%, white solid, melting point 46-48 ℃;
2) Characteristic of hydrogen nuclear magnetic resonance image 1 H NMR(600MHz,CDCl 3 )δ:7.77(d,J＝9.6Hz,1H,H-5),7.69(d,J＝2.4Hz,1H,H-2),7.37(s,1H,H-4),6.82(d,J＝2.4Hz,1H,H-3),6.36(d,J＝9.6Hz,1H,H-6),5.87(td,J＝6.6,1.2Hz,1H,H-2’),5.07(d,J＝7.2Hz,2H,H-1’),4.48(s,2H,H-4’),2.29(t,J＝7.2Hz,2H,CH 2 CH 2 CH 3 ),1.73(s,3H,H-5’),1.61-1.68(m,2H,CH 2 CH 2 CH 3 ),0.93(t,J＝7.2Hz,3H,CH 2 CH 2 CH 3 )；
3) The ESI-TRAP source mass spectrum MS M/z of the compound is 379.2 ([ M + Na)] + ,100)。
The physicochemical properties of the decursinol ester derivative 3c are as follows:
1) Yield =69%, white solid, melting point 83-85 ℃;
2) Characteristic of hydrogen nuclear magnetic resonance image 1 H NMR(600MHz,CDCl 3 )δ:7.76(d,J＝9.6Hz,1H,H-5),7.69(d,J＝2.4Hz,1H,H-2),7.38(s,1H,H-4),6.82(d,J＝2.4Hz,1H,H-3),6.36(d,J＝9.0Hz,1H,H-6),5.88(td,J＝6.6,1.2Hz,1H,H-2’),5.06(d,J＝7.8Hz,2H,H-1’),4.48(s,2H,H-4’),2.33(q,J＝7.8Hz,2H,CH 2 CH 3 ),1.73(s,3H,H-5’),1.12(t,J＝7.8Hz,3H,CH 2 CH 3 )；
3) ESI-TRAP source mass spectrum MS M/z 365.1 ([ M + Na ] of the compound] + ,100)。
The physicochemical properties of the decursinol ester derivative 3d are as follows:
1) Yield =89%, white solid, melting point 88-90 ℃;
2) Hydrogen nuclear magnetic resonance image characteristics 1 H NMR(600MHz,CDCl 3 )δ:8.78(d,J＝6.0Hz,2H,H-Ar),8.69(d,J＝6.0Hz,2H,H-Ar),7.75(d,J＝9.6Hz,1H,H-5),7.67(d,J＝2.4Hz,1H,H-2),7.38(s,1H,H-4),6.81(d,J＝2.4Hz,1H,H-3),6.36(d,J＝9.6Hz,1H,H-6),5.99(td,J＝6.6,1.2Hz,1H,H-2’),5.10(d,J＝6.6Hz,2H,H-1’),4.76(s,2H,H-4’),1.83(s,3H,H-5’)；
3) The ESI-TRAP source mass spectrum MS M/z of the compound is 414.2 ([ M + Na)] + ,100)。
The physicochemical properties of the decursinol ester derivative 3e are as follows:
1) Yield =51%, white solid, melting point 126-128 ℃;
2) Characteristic of hydrogen nuclear magnetic resonance image 1 H NMR(600MHz,CDCl 3 )δ:8.29(d,J＝8.4Hz,2H,H-Ar),8.21(d,J＝8.4Hz,2H,H-Ar),7.76(d,J＝9.6Hz,1H,H-5),7.68(s,1H,H-2),7.38(s,1H,H-4),6.82(s,1H,H-3),6.36(dd,J＝9.6,2.4Hz,1H,H-6),6.01(t,J＝6.6Hz,1H,H-2’),5.10(d,J＝7.2Hz,2H,H-1’),4.78(s,2H,H-4’),1.84(s,3H,H-5’)；
3) ESI-TRAP source mass spectrum MS M/z of the compound is 458.1 ([ M + Na)] + ,100)。
The physicochemical properties of the decursinol ester derivative 3f are as follows:
1) Yield =53%, white solid, melting point 110-112 ℃;
2) Characteristic of hydrogen nuclear magnetic resonance image 1 H NMR(600MHz,CDCl 3 )δ:7.98(d,J＝8.0Hz,2H,H-Ar),7.74(d,J＝9.6Hz,1H,H-5),7.66(s,1H,H-2),7.37(s,1H,H-4),6.91(d,J＝8.4Hz,2H,H-Ar),6.80(s,1H,H-3),6.35(d,J＝9.6Hz,1H,H-6),5.97(t,J＝6.6Hz,1H,H-2’),5.09(d,J＝6.6Hz,2H,H-1’),4.69(s,2H,H-4’),3.86(s,3H,OCH 3 ),1.80(s,3H,H-5’)；
3) The ESI-TRAP source mass spectrum MS M/z of the compound is 443.2 ([ M + Na ]] + ,100)。
The physicochemical properties of 3g of the decursinol ester derivative are as follows:
1) Yield =52%, white solid, melting point 109-111 ℃;
2) Hydrogen nuclear magnetic resonance image characteristics 1 H NMR(600MHz,CDCl 3 )δ:7.96(d,J＝8.4Hz,2H,H-Ar),7.76(d,J＝9.6Hz,1H,H-5),7.66(d,J＝2.4Hz,1H,H-2),7.41(d,J＝8.4Hz,2H,H-Ar),7.37(s,1H,H-4),6.81(d,J＝1.8Hz,1H,H-3),6.36(d,J＝9.6Hz,1H,H-6),5.97(td,J＝7.2,1.8Hz,1H,H-2),5.09(d,J＝6.6Hz,2H,H-1’),4.72(s,2H,H-4’),1.81(d,J＝1.2Hz,3H,H-5’)；
3) ESI-TRAP source mass spectrum MS M/z 447.1 ([ M + Na ] of the compound] + ,100)。
The physicochemical properties of the decursinol ester derivative in 3h are as follows:
1) Yield =60%, white solid, melting point 76-78 ℃;
2) Characteristic of hydrogen nuclear magnetic resonance image 1 H NMR(600MHz,CDCl 3 )δ:8.04-8.06(m,2H,H-Ar),7.75(d,J＝9.6Hz,1H,H-5),7.66(d,J＝1.8Hz,1H,H-2),7.37(s,1H,H-4),7.10(t,J＝9.0Hz,2H,H-Ar),6.81(d,J＝1.8Hz,1H,H-3),6.36(d,J＝9.0Hz,1H,H-6),5.98(td,J＝6.6,1.2Hz,1H,H-2’),5.09(d,J＝6.6Hz,2H,H-1’),4.71(s,2H,H-4’),1.81(s,3H,H-5’)；
3) ESI of the compound431.1 ([ M + Na) ] from the TRAP source mass spectrum MS M/z] + ,100)。
The physicochemical properties of the decursinol ester derivative 3i are as follows:
1) Yield =58%, white solid, melting point 116-118 ℃;
2) Characteristic of hydrogen nuclear magnetic resonance image 1 H NMR(600MHz,CDCl 3 )δ:7.76(d,J＝9.6Hz,1H,H-5),7.68(d,J＝2.4Hz,1H,H-2),7.43(d,J＝8.4Hz,2H,H-Ar),7.38(s,1H,H-4),7.14(d,J＝8.4Hz,2H,H-Ar),6.82(d,J＝2.4Hz,1H,H-3),6.36(d,J＝9.6Hz,1H,H-6),5.85(td,J＝6.6,1.8Hz,1H,H-2’),5.04(d,J＝6.6Hz,2H,H-1’),4.49(s,2H,H-4’),3.59(s,2H,CH 2 ),1.69(s,3H,H-5’)；
3) The ESI-TRAP source mass spectrum MS M/z of the compound is 405.1 ([ M + Na ]] + ,75),507.1([M+Na] + ,100)。
The physicochemical properties of the decursinol ester derivative 3j are as follows:
1) Yield =86%, white solid, melting point 96-98 ℃;
2) Characteristic of hydrogen nuclear magnetic resonance image 1 H NMR(600MHz,CDCl 3 )δ:7.98(d,J＝8.4Hz,1H,H-Ar),7.84(d,J＝8.4Hz,1H,H-Ar),7.77(dd,J＝7.2,1.8Hz,1H,H-Ar),7.73(d,J＝9.6Hz,1H,H-5),7.65(d,J＝1.8Hz,1H,H-2),7.51-7.54(m,1H,H-Ar),7.46-7.49(m,1H,H-Ar),7.40-7.40(m,2H,H-Ar),7.35(s,1H,H-4),6.80(d,J＝1.8Hz,1H,H-3),6.35(d,J＝9.6Hz,1H,H-6),5.82(td,J＝6.6,1.2Hz,1H,H-2’),5.00(d,J＝7.2Hz,2H,H-1’),4.48(s,2H,H-4’),4.09(s,2H,CH 2 ),1.60(s,3H,H-5’)；
3) ESI-TRAP source mass spectrum MS M/z:477.2 ([ M + Na ]) of the compound] + ,100)。
The physicochemical properties of the decursinol ester derivative 3k are as follows:
1) Yield =58%, white solid, melting point 116-118 ℃;
2) Characteristic of hydrogen nuclear magnetic resonance image 1 H NMR(600MHz,CDCl 3 )δ:9.20(s,1H,H-Ar),8.78(dd,J＝4.8,1.8Hz,1H,H-Ar),8.29(dt,J＝7.8,1.8Hz,1H,H-Ar),7.75(d,J＝9.6Hz,1H,H-5),7.67(d,J＝2.4Hz,1H,H-2),7.40-7.42(m,1H,H-Ar),7.38(s,1H,H-4),6.81(d,J＝2.4Hz,1H,H-3),6.35(d,J＝9.6Hz,1H,H-6),5.99(td,J＝6.6,1.8Hz,1H,H-2’),5.10(d,J＝6.6Hz,2H,H-1’),4.76(s,2H,H-4’),1.82(s,3H,H-5’)；
3) The ESI-TRAP source mass spectrum MS M/z of the compound is 414.1 ([ M + Na ]] + ,100)。
The physicochemical properties of the decursinol ester derivative 3l are as follows:
1) Yield =76%, white solid, melting point 113-115 ℃;
2) Characteristic of hydrogen nuclear magnetic resonance image 1 H NMR(600MHz,CDCl 3 )δ:7.76(d,J＝9.6Hz,1H,H-5),7.68(d,J＝2.4Hz,1H,H-2),7.38(s,1H,H-4),7.13(s,1H,H-Ar),6.81(s,1H,H-3),6.46(s,1H,H-Ar),6.36(d,J＝9.6Hz,1H,H-6),5.94(t,J＝7.2Hz,1H,H-2’),5.08(d,J＝6.6Hz,2H,H-1’),4.69(s,2H,H-4’),1.78(s,3H,H-5’)；
3) The ESI-TRAP source mass spectrum MS M/z of the compound is 481.0 ([ M + Na ]] + ,100),483.0([M+Na] + ,80)。
The physicochemical properties of the decursinol ester derivative 3m are as follows:
1) Yield =84%, white solid, melting point 88-90 ℃;
2) Hydrogen nuclear magnetic resonance image characteristics 1 H NMR(600MHz,CDCl 3 )δ:8.02(s,1H,H-Ar),7.77(d,J＝9.6Hz,1H,H-5),7.68(d,J＝2.2Hz,1H,H-2),7.43(t,J＝1.8Hz,1H,H-Ar),7.38(s,1H,H-4),6.82(d,J＝2.2Hz,1H,H-3),6.74(d,J＝1.8Hz,1H,H-Ar),6.37(d,J＝9.6Hz,1H,H-6),5.95(td,J＝6.8,1.4Hz,1H,H-2’),5.09(d,J＝6.8Hz,2H,H-1’),4.66(s,2H,H-4’),1.78(d,J＝1.3Hz,3H,H-5’)；
3) The ESI-TRAP source mass spectrum MS M/z of the compound is 403.3 ([ M + Na ]] + ,100)。
The physicochemical properties of the decursinol ester derivative 3n are as follows:
1) Yield =64%, white solid, melting point 109-111 ℃;
2) Characteristic of hydrogen nuclear magnetic resonance image 1 H NMR(600MHz,CDCl 3 )δ:7.80(d,J＝3.6Hz,1H,H-Ar),7.76(d,J＝9.3Hz,1H,H-5),7.67(s,1H,H-2),7.56(d,J＝5.0Hz,1H,H-Ar),7.37(s,1H,H-4),7.11(t,J＝4.4Hz,1H,H-Ar),6.81(s,1H,H-3),6.37(d,J＝9.5Hz,1H,H-6),5.98(t,J＝7.2Hz,1H,H-2’),5.10(d,J＝6.8Hz,2H,H-1’),4.70(s,2H,H-4’),1.80(s,3H,H-5’)；
3) ESI-TRAP source mass spectrum MS M/z 419.2 ([ M + Na) of the compound] + ,100)。
The physicochemical properties of the decursinol ester derivative 3o are as follows:
1) Yield =57%, white solid, melting point 65-67 ℃;
2) Characteristic of hydrogen nuclear magnetic resonance image 1 H NMR(600MHz,CDCl 3 )δ:9.11(s,1H,NH),7.75(d,J＝9.5Hz,1H,H-5),7.70(d,J＝8.1Hz,1H,H-Indole),7.66(d,J＝2.1Hz,1H,H-2),7.48(d,J＝8.4Hz,1H,H-Indole),7.37(s,1H,H-4),7.34(t,J＝7.8Hz,1H,H-Indole),7.25(s,1H,H-Indole),7.16(t,J＝7.5Hz,1H,H-Indole),6.80(d,J＝2.2Hz,1H,H-3),6.36(d,J＝9.6Hz,1H,H-6),6.03(t,J＝7.1Hz,1H,H-2’),5.09(d,J＝7.0Hz,2H,H-1’),4.74(s,2H,H-4’),1.80(s,3H,H-5’)；
3) The ESI-TRAP source mass spectrum MS M/z of the compound is 452.1 ([ M + Na)] + ,100)。
Examples 2,
Activity assay
AChE in vitro inhibitory activity was tested using the Ellman method. And adding a proper amount of dimethyl sulfoxide into the weighed sample, dissolving the sample, and adding a 0.1mol/L Phosphate Buffer Solution (PBS) solution with the pH value of 7.4 to prepare a solution to be detected, wherein the solution to be detected is 1 mg/mL. Tacrine was used as a positive control, and a Phosphate Buffered Saline (PBS) solution was used as a blank control. During the determination, firstly, 10 mu L of a sample to be determined is added on a 96-well plate, then 40 mu LPB, 20 mu L of 2.5 mmol/L5,5-two-flow dinitrobenzoic acid (DTNB) and 10 mu L of electric eel acetylcholinesterase are sequentially added, the mixture is uniformly stirred and incubated for 10 minutes at 37 ℃, then 20 mu L of 10mmol/L iodinated thioacetylcholine is added, the reaction is carried out for 10 minutes at 37 ℃, 30uL of 1% SDS is added to stop the reaction, an enzyme-linked immunosorbent assay instrument is used for determining the absorption value at 405nm and calculating the inhibitory activity of the sample to the acetylcholinesterase, and the calculation formula is as follows:
inhibition rate = [ (OD blank control-OD reaction background) - (OD sample to be detected-OD reaction background) ]/(OD blank control-OD reaction background) × 100%.
Active results
TABLE 1 inhibitory Activity of the object Compounds on acetylcholinesterase (1. Mu. Mol/L)
a This test was performed in parallel 3 times and 2 times.
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (7)
1. A preparation method of the decursinol ester derivative is characterized by comprising the following steps:
1) Dissolving decursinol with 1,4-dioxane, heating to 60 deg.C, adding selenium dioxide under stirring, heating to 80 deg.C, continuing to react, tracking and monitoring by TLC, filtering after the reaction is finished, and removing precipitate in the reaction solution;
2) Washing the precipitate with dichloromethane, mixing organic solvents, drying with anhydrous sodium sulfate, concentrating with rotary evaporator, and separating with thin layer silica gel chromatography to obtain decursinol;
3) Weighing decursinol, adding into a round-bottom flask, dissolving with absolute ethanol, cooling to 0 deg.C in ice bath, adding sodium borohydride, stirring, reacting, adding diluted hydrochloric acid to terminate the reaction, extracting with ethyl acetate, concentrating, and separating by column chromatography;
4) Weighing the compound in the step 3), adding the compound into a round-bottom flask, adding anhydrous dichloromethane for dissolving, then adding the weighed substituted acid, DCC and DMAP, and detecting whether the reaction is complete by TLC; then filtering, concentrating, and separating by thin layer silica gel chromatography to obtain the decursinol ester derivatives 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3l, 3m, 3n and 3o.
2. A method for preparing a decursinolactone ester derivative as defined in claim 1, wherein: weighing 1mmol of decursinol in the step 1); 1.2mmol of selenium dioxide are added.
3. A method for preparing a decursinolactone ester derivative as defined in claim 1, wherein: weighing 1mmol of decursinol in the step 3), and adding the decursinol into a round-bottom flask; 2mmol of sodium borohydride was added.
4. A method for preparing a decursinolactone ester derivative as defined in claim 1, wherein: weighing the 1mmol compound obtained in the step 3) in the step 4), and adding the compound into a round-bottom flask.
5. Use of a decursinolactone ester derivative prepared according to claim 1 for inhibiting acetylcholinesterase activity.
6. A method for detecting in vitro acetylcholinesterase activity of the decursinol ester derivative as claimed in claim 1, comprising the steps of:
1) Dissolving a decursinol ester derivative sample in a proper amount of dimethyl sulfoxide, and then adding a 0.1mol/L phosphate buffer solution with the pH of 7.4 to prepare a solution to be detected, wherein the solution to be detected is 1 mg/mL;
2) The positive control adopts tacrine, and the blank control adopts a phosphate buffer solution;
3) In the determination, 10 mu L of a solution sample to be determined is firstly added on a 96-well plate, then 40 mu L of PB, 20 mu L of 2.5 mmol/L5,5-two-flow dinitrobenzoic acid and 10 mu L of electric eel acetylcholinesterase are sequentially added, the oscillation and the mixing are carried out, the incubation is carried out for 10 minutes at 37 ℃, then 20 mu L of 10mmol/L iodinated thioacetyl choline is added, the reaction is carried out for 10 minutes at 37 ℃, 30uL of 1% SDS is added to stop the reaction, and an enzyme-linked immunosorbent assay instrument is used for determining the absorption value at 405nm and calculating the inhibitory activity of the sample on the acetylcholinesterase.
7. The method for detecting the in vitro acetylcholinesterase activity of the decursinol ester derivative as claimed in claim 6, wherein the formula used in the calculation in step 3) is as follows:
inhibition rate = [ (OD blank control-OD reaction background) - (OD sample to be detected-OD reaction background) ]/(OD blank control-OD reaction background) × 100%.
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| Title |
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| HILAL OZBEK，等: "In vitro anticholinesterase activity and molecular docking studies of coumarin derivatives isolated from roots of Heptaptera cilicica", MED CHEM RES, vol. 27, pages 538 - 545, XP036415620, DOI: 10.1007/s00044-017-2080-x * |
| 於祥，等: "前胡内酯肟酯衍生物的合成及其抑制乙酰胆碱酯酶活性评价", 化学通报, vol. 84, no. 7, pages 738 - 742 * |
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