CN114989151B - Mountain lotus leaf extract 5-substituted triazole derivative and preparation method thereof - Google Patents
Mountain lotus leaf extract 5-substituted triazole derivative and preparation method thereof Download PDFInfo
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- -1 5-substituted triazole Chemical class 0.000 title claims abstract description 46
- 240000002853 Nelumbo nucifera Species 0.000 title claims abstract description 45
- 235000006508 Nelumbo nucifera Nutrition 0.000 title claims abstract description 45
- 235000006510 Nelumbo pentapetala Nutrition 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 30
- YXVXMURDCBMPRH-UHFFFAOYSA-N Lirinidine Natural products C1C2=CC=CC=C2C2=C(O)C(OC)=CC3=C2C1N(C)CC3 YXVXMURDCBMPRH-UHFFFAOYSA-N 0.000 claims abstract description 18
- ORJVQPIHKOARKV-UHFFFAOYSA-N Nuciferine Natural products C1C2=CC=CC=C2C2=C(OC)C(OC)=CC3=C2C1N(C)CC3 ORJVQPIHKOARKV-UHFFFAOYSA-N 0.000 claims abstract description 18
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 14
- 239000004593 Epoxy Substances 0.000 claims abstract description 10
- ORJVQPIHKOARKV-OAHLLOKOSA-N nuciferine Chemical compound C1C2=CC=CC=C2C2=C(OC)C(OC)=CC3=C2[C@@H]1N(C)CC3 ORJVQPIHKOARKV-OAHLLOKOSA-N 0.000 claims abstract description 9
- GKIPXFAANLTWBM-UHFFFAOYSA-N epibromohydrin Chemical compound BrCC1CO1 GKIPXFAANLTWBM-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- 238000004440 column chromatography Methods 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 150000001540 azides Chemical class 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 238000007865 diluting Methods 0.000 claims description 7
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 claims description 6
- 150000001345 alkine derivatives Chemical class 0.000 claims description 6
- 235000019270 ammonium chloride Nutrition 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- QHMOWPJARYQHOB-UHFFFAOYSA-M cyclopenta-1,3-diene;ruthenium(2+);triphenylphosphane;chloride Chemical compound [Ru+]Cl.C=1C=C[CH-]C=1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QHMOWPJARYQHOB-UHFFFAOYSA-M 0.000 claims description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
- LFZJRTMTKGYJRS-UHFFFAOYSA-N 1-chloro-4-ethynylbenzene Chemical group ClC1=CC=C(C#C)C=C1 LFZJRTMTKGYJRS-UHFFFAOYSA-N 0.000 claims description 2
- KBIAVTUACPKPFJ-UHFFFAOYSA-N 1-ethynyl-4-methoxybenzene Chemical group COC1=CC=C(C#C)C=C1 KBIAVTUACPKPFJ-UHFFFAOYSA-N 0.000 claims description 2
- BWIOURVJVDKDOC-UHFFFAOYSA-N 6-bromo-1-(chloromethyl)-2-methoxynaphthalene Chemical compound C1=C(Br)C=CC2=C(CCl)C(OC)=CC=C21 BWIOURVJVDKDOC-UHFFFAOYSA-N 0.000 claims description 2
- QDEOKXOYHYUKMS-UHFFFAOYSA-N but-3-ynylbenzene Chemical compound C#CCCC1=CC=CC=C1 QDEOKXOYHYUKMS-UHFFFAOYSA-N 0.000 claims description 2
- NPTDXPDGUHAFKC-UHFFFAOYSA-N ethynylcyclopropane Chemical group C#CC1CC1 NPTDXPDGUHAFKC-UHFFFAOYSA-N 0.000 claims description 2
- KVNYFPKFSJIPBJ-UHFFFAOYSA-N ortho-diethylbenzene Natural products CCC1=CC=CC=C1CC KVNYFPKFSJIPBJ-UHFFFAOYSA-N 0.000 claims description 2
- 150000002924 oxiranes Chemical class 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 21
- 239000002246 antineoplastic agent Substances 0.000 abstract description 4
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 4
- 230000000259 anti-tumor effect Effects 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 11
- 230000000694 effects Effects 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 6
- 210000004881 tumor cell Anatomy 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 229930012538 Paclitaxel Natural products 0.000 description 5
- 230000001472 cytotoxic effect Effects 0.000 description 5
- 229930182470 glycoside Natural products 0.000 description 5
- 229960001592 paclitaxel Drugs 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 206010009944 Colon cancer Diseases 0.000 description 4
- 208000029742 colonic neoplasm Diseases 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 201000007270 liver cancer Diseases 0.000 description 3
- 208000014018 liver neoplasm Diseases 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000004973 liquid crystal related substance Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000005744 Glycoside Hydrolases Human genes 0.000 description 1
- 108010031186 Glycoside Hydrolases Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 150000002338 glycosides Chemical group 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229930013686 lignan Natural products 0.000 description 1
- 150000005692 lignans Chemical class 0.000 description 1
- 235000009408 lignans Nutrition 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application belongs to the technical fields of pharmaceutical chemistry and pharmacology, and discloses a mountain lotus leaf extract 5-substituted triazoleThe derivative has a chemical structural formula shown in a formula (I), and is prepared by reacting mountain nuciferine with anhydrous potassium carbonate and epoxybromopropane in N, N-dimethylformamide to obtain a mountain nuciferine epoxy intermediate 1, then reacting the mountain nuciferine epoxy intermediate 1 with sodium azide in N, N-dimethylformamide to obtain a mountain nuciferine azide intermediate 2, and then reacting the mountain nuciferine azide intermediate 2 with acetylenic compounds and cyclopentadiene bis (triphenylphosphine) ruthenium chloride in dioxane to obtain a mountain nuciferine 5-substituted triazole derivative 3. The obtained mountain lotus leaf element 5-substituted triazole derivative has stronger anti-tumor activity and can be used for preparing anti-tumor drugs.
Description
Technical Field
The application belongs to the technical fields of pharmaceutical chemistry and pharmacology, and particularly relates to a mountain lotus leaf element 5-substituted triazole derivative and a preparation method thereof.
Background
With the advancement of medicine, general infectious diseases are gradually controlled, and malignant tumor-cancer is one of the main diseases that are common and seriously threatening human life and quality of life. Antitumor drugs derived from plants are important in clinical treatment. In recent years, researches show that natural lignan mountain nuciferine glycoside such as Cleistantin-A and PatentiflorinA has strong anti-tumor activity. However, the natural shan nuciferine glycoside is not abundant in nature, chemical synthesis is complex, and the metabolic stability of the glycosidic bond in human body is poor, so that the natural shan nuciferine glycoside is easy to hydrolyze and inactivate by endogenous glycosidase.
Disclosure of Invention
In view of the above, the present application aims to provide a non-glycoside structure mountain lotus leaf element 5-substituted triazole derivative, wherein the structure of the compound does not contain a glycosidic bond which is easy to hydrolyze in vivo, the metabolic stability is superior to that of glycoside compounds, and the compound has strong tumor cell proliferation inhibition activity.
The application provides a mountain lotus leaf essence 5-substituted triazole derivative, which has a structure shown in a formula (I):
wherein R represents phenyl, p-methylphenyl, p-methoxyphenyl, p-chlorophenyl, phenethyl, phenoxymethyl or cyclopropyl.
Further, the mountain lotus leaf essence 5-substituted triazole derivative has a structure as shown in any one of formulas 3a to 3d:
wherein, the liquid crystal display device comprises a liquid crystal display device,
when R is phenyl, the mountain lotus leaf essence 5-substituted triazole derivative is a compound with a structure shown in a formula 3 a;
when R is p-methylphenyl, the mountain lotus leaf essence 5-substituted triazole derivative is a compound with a structure shown in a formula 3 b;
when R is phenoxymethyl, the mountain lotus leaf essence 5-substituted triazole derivative is a compound with a structure shown in a formula 3 c;
when R is cyclopropyl, the mountain lotus leaf essence 5-substituted triazole derivative is a compound with a structure shown in a formula 3 d;
the application also provides a preparation method of the mountain lotus leaf essence 5-substituted triazole derivative, which comprises the following steps:
the method comprises the steps of reacting mountain lotus leaf essence with anhydrous potassium carbonate and epoxybromopropane in N, N-dimethylformamide to obtain a mountain lotus leaf essence epoxy intermediate 1, then reacting mountain lotus leaf essence epoxy intermediate 1 with sodium azide and ammonium chloride in N, N-dimethylformamide to obtain a mountain lotus leaf essence azide intermediate 2, and then reacting mountain lotus leaf essence azide intermediate 2 with alkyne compounds and cyclopentadienyl bis (triphenylphosphine) ruthenium chloride in dioxane to obtain a mountain lotus leaf essence 5-substituted triazole derivative 3.
The reaction formula of the preparation method is as follows:
wherein R represents phenyl, p-methylphenyl, p-methoxyphenyl, p-chlorophenyl, phenethyl, phenoxymethyl or cyclopropyl. Specifically, the preparation method comprises the following steps:
(1) Dissolving mountain lotus leaf essence in N, N-dimethylformamide, adding epoxy bromopropane and anhydrous potassium carbonate for reaction to obtain a first reaction solution, cooling the first reaction solution, concentrating under reduced pressure, diluting with organic solvent, washing with water, saturated salt water, and MgSO 4 Drying under reduced pressure, and performing column chromatography to obtain a white solid, wherein the white solid is a shan lotus leaf element epoxy intermediate 1, and the molar ratio of shan lotus leaf element to epoxy bromopropane to anhydrous potassium carbonate is 1:5:6;
(2) Dissolving the shan nuciferine epoxy intermediate 1 in N, N-dimethylformamide, adding sodium azide and ammonium chloride for reaction to obtain a second reaction solution, cooling the second reaction solution, concentrating under reduced pressure, diluting with an organic solvent, washing with water, washing with saturated salt water, and MgSO 4 Drying under reduced pressure, and performing column chromatography to obtain a white solid, wherein the white solid is a shan lotus leaf element azide intermediate 2, and the molar ratio of the shan lotus leaf element epoxide intermediate 1 to sodium azide to ammonium chloride is 1:3:2;
(3) Dissolving a shan lotus leaf element azide intermediate 2 in dioxane, adding cyclopentadiene bis (triphenylphosphine) ruthenium chloride and alkyne for reaction to obtain a third reaction solution, concentrating the third reaction solution under reduced pressure, diluting with an organic solvent, washing with water, washing with saturated salt water and MgSO (MgSO) 4 Drying under reduced pressure, and performing column chromatography to obtain a white solid, wherein the white solid is mountain lotus leaf essence 5-substituted triazole 3, and the molar ratio of mountain lotus leaf essence azide intermediate 2 to cyclopentadiene bis (triphenylphosphine) ruthenium chloride to alkyne is 1:0.05:2;
wherein the alkyne is one of phenylacetylene, p-tolylene, p-methoxy phenylacetylene, p-chlorophenylacetylene, 4-phenyl-1-butyne, phenyl propargyl ether and cyclopropylacetylene.
Further, in the step (1) of the preparation method, the reaction temperature is 60 ℃ and the reaction time is 2 hours.
Further, in the step (2) of the preparation method, the reaction temperature is 70 ℃ and the reaction time is 12 hours.
Further, in the step (3) of the preparation method, the reaction temperature is 70 ℃ and the reaction time is 36 hours.
Further, in the above preparation method, the organic solvent is at least one of ethyl acetate, diethyl ether and benzene.
Compared with the prior art, the application provides a new compound, namely the mountain nuciferine 5-substituted triazole derivative and a preparation method thereof, wherein the structure of the compound does not contain glycosidic bonds which are easy to hydrolyze in vivo, the metabolic stability is superior to that of the glycoside compound, and the compound has stronger tumor cell proliferation inhibition activity.
Drawings
In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
FIG. 1 shows nuclear magnetic resonance of a 5-substituted triazole derivative (3 a) of mountain lotus leaf extract provided in example 3 of the present application 1 H spectrogram;
FIG. 2 shows nuclear magnetic resonance of a 5-substituted triazole derivative (3 a) of mountain lotus leaf extract as provided in example 3 of the present application 13 C, spectrogram;
FIG. 3 shows the nuclear magnetic resonance of the 5-substituted triazole derivative (3 d) of mountain lotus leaf extract provided in example 4 of the present application 1 H spectrogram;
FIG. 4 shows the nuclear magnetic resonance of the 5-substituted triazole derivative (3 d) of mountain lotus leaf extract provided in example 4 of the present application 13 C, spectrogram;
Detailed Description
The following description of the technical solutions in the embodiments of the present application will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present application, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
Example 1
190mg (0.5 mmol) of mountain lotus leaf essence, 343mg of epoxybromopropane (2.5 mmol) and 414mg of anhydrous potassium carbonate (3 mmol) are dissolved in N, N-dimethylformamide (5 ml), and reacted at 60℃for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate (15 ml), washed with water, saturated brine, and MgSO 4 Drying, drying under reduced pressure, and column chromatography (petroleum ether: ethyl acetate=1:1) gave 174mg of a white solid, i.e., shan nuciferine epoxy intermediate 1 (yield=80%).
1 H NMR(400MHz,CDCl 3 )δ:7.62(s,1H,ArH),7.07(s,1H,ArH),6.95(d,J＝7.8Hz,1H,ArH),6.76(m,2H,ArH),6.07(dd,J＝18.6,1.2Hz,2H,OCH 2 O),5.47(s,2H,ArCH2O),4.55(dd,J＝11.2,1H,OCH 2 ),4.09(s,3H,OCH 3 ),4.03(dd,J＝11.2,6.4Hz,1H,OCH 2 ),3.81(s,3H,OCH 3 ),3.47–3.45(m,1H,CH),2.98(t,J＝4.5Hz,1H,OCH 2 ),2.83(dd,J＝4.8,2.6Hz,1H,OCH 2 )； 13 C NMR(100MHz,CDCl 3 )δ:169.6,151.8,150.3,147.5,147.5,146.5,135.5,130.8,128.3,127.4,126.8,123.6,119.1,110.7,108.2,106.3,101.3,100.5,73.7,66.4,56.2,55.9,50.5,44.4；HRMS(ESI):m/z calcd for C 24 H 20 O 8 :437.1192；found:437.1186[M+H] +
Example 2
750mg (1.72 mmol) of shan lotus leaf element epoxy intermediate 1 was dissolved in a mixed solution of N, N-dimethylformamide (20 ml) and water (5 ml), followed by addition of 335mg (5.16 mmol) of sodium azide and 182mg (3.44 mmol) of ammonium chloride to react at 70℃for 12 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate (15 ml), washed with water, saturated brine, and MgSO 4 Drying, drying under reduced pressure, column chromatography (petroleum ether: ethyl acetate=1:1) gave 600mg of white solid, i.e. shan lotus leaf extract azide intermediate 2 (73%)
1 H NMR(400MHz,CDCl 3 )δ7.58(s,1H,ArH),7.06(s,1H,ArH),6.93(d,J＝7.8Hz,1H,ArH),6.81-6.71(m,2H,ArH),6.05(dd,J＝19.6,1.4Hz,2H,OCH 2 O),5.44(s,2H,COOCH 2 ),4.28(p,J＝5.2Hz,1H,HOCH),4.21(d,J＝4.6Hz,2H,OCH 2 ),4.06(s,3H,OCH 3 ),3.80(s,3H,OCH 3 ),3.64(qd,J＝12.6,5.3Hz,2H,N 3 CH 2 ). 13 C NMR(100MHz,CDCl 3 )δ169.8,151.9,150.4,147.5,146.3,135.5,130.8,128.2,127.1,126.6,123.6,119.1,110.7,108.2,106.3,101.3,100.3,73.7,69.7,66.4,56.2,55.9,53.3.HRMS(ESI):m/z calcd for C 24 H 21 N 3 O 8 :480.1407；found:480.1411[M+H] + .
Example 3
95mg (0.2 mmol) of shan lotus leaf azide intermediate 2 is dissolved in 2ml dioxane, 7mg (0.01 mmol) of cyclopentadienyl bis (triphenylphosphine) ruthenium chloride and 40mg (0.4 mmol) of phenylacetylene are added in sequence and reacted for 36 hours at 70 ℃. The reaction solution was concentrated under reduced pressure, and column chromatography (dichloromethane: ethyl acetate=5:1) gave 64mg of a white solid, namely, 5-substituted triazole derivative 3a of mountain lotus leaf extract (yield 55%).
1 H NMR(400MHz,CDCl 3 )δ7.71(s,1H,C＝CH),7.56(s,1H,ArH),7.49(s,5H,ArH),7.05(s,1H,ArH),6.94(d,J＝7.8Hz,1H,ArH),6.82-6.75(m,2H,ArH),6.06(d,J＝20.1Hz,2H,OCH 2 O),5.41(m,2H,COOCH 2 ),4.72(m,1H,NCH 2 ),4.70-4.58(m,2H),4.30(m,2H),4.15(s,1H,OH),3.98(s,3H,OCH 3 ),3.80(s,3H,OCH 3 ). 13 C NMR(100MHz,CDCl 3 )δ169.6,151.8,150.3,147.5,146.3,139.3,135.3,132.9,130.7,129.9,129.3,129.1,128.2,126.5,126.4,123.6,119.1,110.7,108.2,106.2,101.3,100.4,76.7,73.7,69.6,66.4,56.2,55.8,50.6.HRMS(ESI):m/z calcd for C 32 H 27 N 3 O 8 :582.7816；found:582.7819[M+H] + .
Examples 4 to 6
The example compounds were prepared according to the procedure of example 3 above.
The physicochemical data for each of the compounds 3b-3d are listed below:
3b, 58% of yield, 1 H NMR(400MHz,CDCl 3 )δ7.67(s,1H,C＝CH),7.56(s,1H,ArH),7.36(d,J＝8.1Hz,2H,ArH),7.29(m,1H,ArH),7.06(s,1H,ArH),6.94(d,J＝7.8Hz,1H,ArH),6.83-6.74(m,3H,ArH),6.07(d,J＝19.3Hz,2H,OCH 2 O),5.40(m,2H,COOCH 2 ),4.76-4.68(m,1H,CHOH),4.66(m,2H,NCH 2 ),4.34-4.23(m,2H,CH 2 OAr),4.15(s,1H,OH),3.98(s,3H,OCH 3 ),3.80(s,3H,OCH 3 ),2.40(s,3H,ArCH 3 ). 13 C NMR(100MHz,CDCl 3 )δ169.6,151.8,150.3,147.5,147.5,146.3,140.1,139.2,135.3,132.8,130.7,129.9,128.9,128.3,126.4,126.4,123.6,123.4,119.1,110.7,108.2,106.2,101.3,100.4,73.6,69.6,66.4,56.1,55.8,50.5,21.4.HRMS(ESI):m/z calcd for C 33 H 29 N 3 O 8 :596.2033；found:596.2037[M+H] + .
3c, the yield is 55 percent, 1 H NMR(400MHz,CDCl 3 )δ7.69(s,1H,C＝CH),7.63(s,1H,ArH),7.29(t,J＝8.0Hz,2H,ArH),7.03(d,J＝8.2Hz,2H,ArH),6.92(t,J＝8.3Hz,3H,ArH),6.78-6.71(m,2H,ArH),6.04(d,J＝23.1Hz,2H,OCH 2 O),5.40(s,2H,COOCH 2 ),5.28-5.17(m,2H,ArOCH 2 ),4.86-4.76(m,1H,CHOH),4.69(dd,J＝12.3,5.1Hz,2H,NCH 2 ),4.27(qd,J＝9.8,4.4Hz,2H,CH 2 OAr),4.11(d,J＝3.8Hz,1H,OH),4.00(s,3H,OCH 3 ),3.79(s,3H,OCH 3 ).HRMS(ESI):m/z calcd for C 33 H 29 N 3 O 9 :612.1982；found:612.1985[M+H] + .
3d, the yield is 52 percent, 1 H NMR(400MHz,CDCl 3 )δ7.68(s,1H,ArH),7.21(s,1H,C＝CH),7.04(s,1H,ArH),6.91(d,J＝7.8Hz,1H,ArH),6.78-6.73(m,2H,ArH),6.04(d,J＝22.0Hz,2H,OCH 2 O),5.46(m,2H,COOCH 2 ),4.76-4.58(m,3H,CHOH,NCH 2 ),4.43(s,1H,OH),4.31(dt,J＝9.8,5.8Hz,2H,ArOCH 2 ),4.05(s,3H,OCH 3 ),3.79(s,3H,OCH 3 ),1.89(tt,J＝8.5,5.2Hz,1H,CHC＝C),1.07(d,J＝8.5Hz,2H,CH 2 CH 2 CHC＝C),0.73(dd,J＝14.3,5.0Hz,2H,CH 2 CH 2 CHC＝C).HRMS(ESI):m/z calcd for C 29 H 27 N 3 O 8 :546.1876；found:546.1872[M+H] + .
in order to better understand the essence of the application, the pharmacological experimental results of the inhibition effect of the mountain lotus leaf element 5-substituted triazole derivative provided by the application on the growth of three tumor cell lines are used for explaining the new application of the mountain lotus leaf element 5-substituted triazole derivative in the field of anti-tumor drug research. Pharmacological examples give partial activity data for representative compounds. It must be noted that the pharmacological examples of the application are intended to illustrate the application and not to limit it. Simple modifications of the application in accordance with the essence of the application are all within the scope of the application as claimed.
Drug experiment example 1: test of cytotoxic Activity of Compounds 3a-3d and paclitaxel against human colon cancer (HT-29)
Human colon cancer cells HT-29 were cultured in DMEM medium. Cells at 5X 10 per well 3 Is added to a 96-well plate and contains 5% CO at 37 DEG C 2 Is cultured in a humid air incubator for 24 hours.
Compounds 3a-3d were dissolved in DMSO to prepare 1X 10 -2 Diluting mother liquor with mol/L mother liquor to corresponding concentration with complete culture medium, inoculating logarithmic growth phase cells into 96-well plate, adhering to wall for 24 hr, adding compound solutions with different concentrations, setting 4 parallel holes for each concentration, culturing for 68 hr, adding tetramethyl azoazole (MTT) solution, culturing for 4 hr, discarding culture solution, adding dimethyl sulfoxide 150 μl, oscillating for 10min, measuring 570nm absorbance (A) value with enzyme-labeled instrument, and calculating half inhibition concentration (IC 50 ) As shown in table 1. As can be seen from Table 1, IC of Compound 3a 50 821nM, whereas the positive control paclitaxel was IC on HT-29 cells 50 11nM.
Pharmaceutical Experimental examples 2-3: test of cytotoxic Activity of Compounds 3a-3d and paclitaxel against human breast cancer cells (MCF-7), human liver cancer cells (HepG 2).
Pharmacological experiments were performed on the growth inhibition effect of human colon cancer (HT-29), human breast cancer cells (MCF-7), human liver cancer cells (HepG 2) by the method shown in pharmaceutical Experimental example 1, and half Inhibition Concentration (IC) 50 ) As shown in table 1.
Table 1 results of the cytotoxic Activity test of Compounds 3a to 3d and paclitaxel (IC 50 ,nM)
| Compounds of formula (I) | HT-29 | MCF-7 | HepG2 |
| 3a | 821 | 13 | 656 |
| 3b | 248 | 31 | 717 |
| 3c | 170 | 125 | 300 |
| 3d | 288 | 332 | 535 |
| Paclitaxel (Taxol) | 11 | 1 | 23 |
According to Table 1, the mountain lotus leaf extract 5-substituted triazole derivative provided by the application has important biological activity, and in vitro cytotoxicity activity tests on three tumor cells of human colon cancer cells (HT-29), human breast cancer cells (MCF-7) and human liver cancer cells (HepG 2) show that: the mountain lotus leaf element 5-substituted triazole derivative with the structure shown in the formula (1) has an inhibition effect on the growth of tumor cells, and can be possibly developed into a novel tumor prevention and treatment drug. From the pharmacological examples, the compounds show strong cytotoxic activity on all three tumor cells, and the cytotoxic activity is close to that of positive control taxol, so that the compounds have potential for developing antitumor drugs.
The foregoing is merely a preferred embodiment of the present application and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present application, which are intended to be comprehended within the scope of the present application.
Claims (7)
1. A shan lotus leaf essence 5-substituted triazole derivative, characterized in that the shan lotus leaf essence 5-substituted triazole derivative has a structure represented by the following formula:
wherein R represents one of phenyl, p-methylphenyl, p-methoxyphenyl, p-chlorophenyl, phenethyl, phenoxymethyl and cyclopropyl.
2. The mountain bikino 5-substituted triazole derivative according to claim 1, wherein the mountain bikino 5-substituted triazole derivative has a structure as shown in any one of formulae 3a to 3d:
3. a process for the preparation of a 5-substituted triazole derivative of mountain nuciferine as claimed in claim 1, wherein the reaction formula of the process is as follows:
the preparation method comprises the following steps:
(1) Dissolving mountain lotus leaf essence in N, N-dimethylformamide, adding epoxybromopropane and anhydrous potassium carbonate, reacting to obtain first reaction solution, cooling the first reaction solution, concentrating under reduced pressure, diluting with organic solvent, washing with water, saturated salt water, and MgSO 4 Drying under reduced pressure, and performing column chromatography to obtain a white solid mountain nuciferine epoxy intermediate 1, wherein the molar ratio of mountain nuciferine, epoxy bromopropane and anhydrous potassium carbonate is 1:5:6;
(2) Dissolving the shan nuciferine epoxy intermediate 1 in N, N-dimethylformamide, adding sodium azide and ammonium chloride for reaction to obtain a second reaction solution, cooling the second reaction solution, concentrating under reduced pressure, diluting with organic solvent, washing with water, saturated salt water, and MgSO 4 Drying under reduced pressure, and performing column chromatography to obtain a white solid shan lotus leaf element azide intermediate 2, wherein the molar ratio of the shan lotus leaf element epoxide intermediate 1 to sodium azide to ammonium chloride is 1:3:2;
(3) Dissolving the intermediate 2 in dioxane, adding cyclopentadienyl bis (triphenylphosphine) ruthenium chloride and alkyne to react to obtain a third reaction solution, concentrating the third reaction solution under reduced pressure, diluting with organic solvent, washing with water, saturated salt water, and MgSO 4 Drying under reduced pressure, and performing column chromatography to obtain white solid mountain nuciferine 5-substituted triazole 3, wherein the molar ratio of mountain nuciferine azide intermediate 2 to cyclopentadiene bis (triphenylphosphine) ruthenium chloride to alkyne is 1:0.05:2; wherein the alkyne is one of phenylacetylene, p-tolylene, p-methoxy phenylacetylene, p-chlorophenylacetylene, 4-phenyl-1-butyne, phenyl propargyl ether and cyclopropylacetylene.
4. The method according to claim 3, wherein in the step (1), the reaction temperature is 60℃and the reaction time is 2 hours.
5. The method according to claim 3, wherein in the step (2), the reaction temperature is 70℃and the reaction time is 12 hours.
6. The method according to claim 3, wherein in the step (3), the reaction temperature is 70℃and the reaction time is 36 hours.
7. The method according to claim 3, wherein the organic solvent is at least one of ethyl acetate, diethyl ether and benzene.
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