CN105566340A - White mulberry root-bark active ingredient Morusin derivative and application and preparation method thereof - Google Patents
White mulberry root-bark active ingredient Morusin derivative and application and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a Morusin derivative and a preparation method. A Morusin total-synthesis route is adopted to achieve a structure modification scheme, in the process of Morusin total synthesis, structure modification is carried out by replacing substituent groups of a reaction substrate, and a series of Morusin derivatives are synthesized. The Morusin total-synthesis route is an important anti-tumor activity lead compound, by means of synthesis of the derivatives, a compound source is provided for anti-tumor activity screening, and the derivative has great significance in finding a novel anti-tumor activity lead compound. The method is easy to operate and implement, the raw materials are low in synthesis cost and easy to obtain, synthesizing can be carried out in various kinds of organic solvent, and the derivative has good air stability, is wide in application range, and has good compatibility with various kinds of substituent groups. The derivatives have certain tumor cell growth inhibiting activity, and can be used as anti-tumor medicine or the anti-tumor medicine lead compound.
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, especially a kind of White Mulberry Root-bark activeconstituents Morusin derivative and applications and preparation method thereof.
Background technology
White Mulberry Root-bark (MoriCortex) is the dry root skin of moraceae plants mulberry MorusalbaL., begin to be loaded in Shennong's Herbal, be classified as middle warp, history tree all records, the relieving cough and asthma Chinese medicine commonly used clinically, taste is sweet cold, and property is fallen, and master enters lung, with purging the lung of pathogenic fire heat, relieving asthma for speciality, energy inducing diuresis to remove edema, regulating fluid apssage, and can respectful lung qi fall.The chemical composition of White Mulberry Root-bark, based on Diels-Alder type adducts and flavonoid compound, also has terpene, coumarins, carbohydrate, sterols, volatile oil etc. in addition.Pharmacological research shows that White Mulberry Root-bark has multiple pharmacologically active, comprises antitumour activity.But detect through document and find not carry out more deep research to the anticancer active constituent of White Mulberry Root-bark.
Find through literature survey, Yean-JangLee seminar [Tetrahedron, 2010,66,1335-1340] reports Morusin and has stronger anti-tumor activity.Applicant team has no Morusin structure modified outcome bibliographical information through SciFinder retrieval.Therefore, structural modification is carried out to Cortex Mori (MoriCortex) activeconstituents Morusin, its structure activity relationship of further research and tumour mechanism thereof, by contributing to the determination of potential antineoplastic new target spot, have important researching value to the discovery of new type antineoplastic medicine.Further, synthesis Morusin derivative may produce series of new anti-tumor activity molecule, and their synthesis can provide compound source for antitumor activity screening, has great importance to the novel anti-tumor activity lead compound of searching.
Summary of the invention
The object of the invention is: a kind of White Mulberry Root-bark activeconstituents Morusin derivative and applications and preparation method thereof are provided, this compound and derivative thereof can as the important anti-tumor activity lead compounds of a class, to drug screening and pharmaceutical industry, there is important using value, and its synthetic method is very economical easy.
The present invention is achieved in that the application of a kind of White Mulberry Root-bark activeconstituents Morusin derivative at preparation control tumor disease medicine, and this compound has the structure as shown in logical formula I;
White Mulberry Root-bark activeconstituents Morusin derivative is in the application of preparation control tumor disease medicine
The preparation method of Morusin derivative, acidylate decarboxylic reaction is first there is with potassium ethyl malonate salt by the Benzoyl chloride 1 of corresponding replacement, generate intermediate 2, then there is Michael addition reaction with methylene acetone again in intermediate 2, obtain intermediate 3, then intermediate 3 and Phloroglucinol generation annulation, generate intermediate 4, intermediate 4 again with isoamyl olefine aldehydr generation annulation, generate Morusin derivative 5, Morusin derivative 5 and generate Morusin derivative 6 by there is Aldol addition reaction with the Grignard reagent of various replacement; Or Morusin derivative 5 obtains Morusin derivative 7 by sodium borohydride reduction carbonyl.
Morusin derivative synthetic route is as follows:
By adopting technique scheme, the present invention synthesizes Morusin derivative, it is the important anti-tumor activity lead compound of a class, and their synthesis can provide compound source for antitumor activity screening, has great importance to the novel anti-tumor activity lead compound of searching.Operation is simple in the present invention, and Material synthesis is cheaply easy to get, and can carry out, also have good air stability in various organic solvent, and suitability is wide, has good compatibility for various substituting group.
Accompanying drawing explanation
Accompanying drawing 1-4 is embodiments of the invention part Morusin derivative
1h-NMR spectrum and
13cNMR spectrogram.
Embodiment
The present embodiment is intended to set forth instead of limit the scope of the invention.Gained compound measures it with Inova400MHz NMR spectrometer with superconducting magnet (TMS is interior mark, Varian company of the U.S.)
1h-NMR spectrum and
13cNMR composes; With HRMS-ESI mass spectrograph (Micro
tMq-TOF) its molecular weight is measured.Agents useful for same is analytical pure or chemical pure.
The Morusin derivative prepared by the present embodiment is in table 1, but it is emphasized that embodiment is intended to set forth instead of limit the scope of the invention.Morusin derivative of the present invention is not limited to the content represented by table 1.
(1), the synthesis of Morusin derivative 5a and the preparation of reaction intermediate thereof
Experimental implementation: get potassium ethyl malonate salt 1.00g(and be about 5.47mmol) and Magnesium Chloride Anhydrous 0.65g(be about 6.84mmol) in 25mL round-bottomed flask, add 6mL acetonitrile after instillation 0.55g triethylamine and dissolve, in stirred at ambient temperature 30min.The 0.48g(2.5mmol that instillation is subsequently dissolved with 2mL acetonitrile) 2,4-dimethoxy-benzoyl chlorides, then add triethylamine 0.06mL, stirred overnight at room temperature.Aftertreatment: first add 30mL water dilute reaction solution, then add 30 respectively, 20,20mL extraction into ethyl acetate, collect ethyl acetate layer.With 30mL saturated aqueous common salt cleaning ethyl acetate layer after anhydrous sodium sulfate drying, be spin-dried for, column chromatography (PE:EA=15:1) be separated obtain product 2a, productive rate 90%; HRMS (ESI-TOF) m/z:Calcd.forC
13h
16naO
5[M+Na]
+: 275.0895; Found:275.0899.
Experimental implementation: get 0.452g(2mmol) 2a is in 25mL round-bottomed flask, use 10mL dissolve with ethanol after adding sodium ethylate 0.16g, stirring at room temperature 15 minutes, gets 0.162mL(2mmol subsequently) acrylketone in flask, stirring at room temperature 2h.Aftertreatment: add 5% hydrochloric acid reaction solution, then use 30 respectively, 20,20mL extraction into ethyl acetate aqueous phase, the oil reservoir that saturated common salt water washing has merged, is spin-dried for after anhydrous sodium sulfate drying, and column chromatography (PE:EA=10:1) is separated and obtains product 3a, productive rate 86%; HRMS (ESI-TOF) m/z:Calcd.forC
17h
22naO
6[M+Na]
+: 345.1314; Found:345.1310.
Experimental implementation: get 0.38g(3mmol) 3a is in 25mL round-bottomed flask, add 0.126g (1mmol) Phloroglucinol again, with being placed in household microwave oven, under 640W, heating 8min, taking out subsequently and being down to room temperature, add acetic acid ethyl dissolution, cross leaching ethyl acetate layer, be spin-dried for, column chromatography (PE:EA=5:1) is separated and obtains product 4a, productive rate 45%
1h-NMR (CDCl
3, 100MHz) and δ: 2.09 (s, 3H), 2.21 (t, J=8.1Hz; 2H), 2.69 (t, J=6.0Hz, 2H); (3.67 s, 1H), 3.78 (s, 3H); (5.35 s, 1H), 6.43 (m, 2H); (7.26 d, J=4.2Hz, 2H), 7.885 (d; J=12.1Hz, 1H), 12.95 (s, 1H);
13cNMR (CDCl
3, 100MHz) and δ: 22.6,29.6,42.3,52.1,55.4,93.7,98.1,98.7,105.1,105.7,120.1,131.1,133.5,158.1,160.7,162.7,165.1,171.3,182.2,194.0,208.9; HRMS (ESI-TOF) m/z:Calcd.forC
21h
20naO
7[M+Na]
+: 407.1106; Found:407.1108.
Experimental implementation: take 384mg (1mmol) 4a in 50mL round-bottomed flask, even instillation 85mg (1mmol) 3-methyl butene aldehyde, get anhydrous sodium carbonate system is covered, be placed in microwave oven, under 640W, heating is total to 20min at twice, acetic acid ethyl dissolution, and add water extraction, dry ethyl acetate layer, decompression is spin-dried for.Be separated with silica gel column chromatography under sherwood oil (1:5) system in ethyl acetate, obtain pale yellow oily liquid body 5a, productive rate 23%.
1HNMR(CDCl
3,400MHz)δ:1.45(s,6H),2.09(s,3H),2.57(t,J=7.2Hz,2H),2.69(m,2H),3.78(s,3H),3.87(s,3H),5.48(d,J=10.0Hz,1H),6.26(s,1H),6.55(d,J=2.6Hz,1H,),6.57(s,1H),6.61(d,J=2.4Hz,1H),7.26(s,1H),7.28(s,1H);
13CNMR(CDCl
3,100MHz)δ:20.3,28.2,29.3,29.7,41.9,55.5,55.6,76.8,77.6,98.8,99.7,100.9,104.9,114.4,115.0,120.3,126.7,131.2,152.4,158.2,159.2,160.4,161.7,162.7,182.4,208.3;HRMS(ESI-TOF)m/z:Calcd.forC
26H
26NaO
7[M+Na]
+:473.1576;Found:473.1577.
(2), Morusin derivative 5c, the synthesis of 6c-1,6c-2 and 7c and the preparation of reaction intermediate 2c-4c thereof
Experimental implementation: get potassium ethyl malonate salt 1.00g(and be about 5.47mmol) and Magnesium Chloride Anhydrous 0.65g(be about 6.84mmol) in 25mL round-bottomed flask, add 6mL acetonitrile after instillation 0.55g triethylamine and dissolve, in stirred at ambient temperature 30min.The 0.48g(2.5mmol that instillation is subsequently dissolved with 2mL acetonitrile) o-chlorobenzoyl chloride 1c, then add triethylamine 0.06mL, stirred overnight at room temperature.Aftertreatment: first add 30mL water dilute reaction solution, then add 30 respectively, 20,20mL extraction into ethyl acetate, collect ethyl acetate layer.With 30mL saturated aqueous common salt cleaning ethyl acetate layer after anhydrous sodium sulfate drying, be spin-dried for, column chromatography (PE:EA=15:1) be separated obtain product 2c, productive rate 91%;
1h-NMR (CDCl
3, 400MHz) and δ: 1.24 (t, J=8.0Hz, 3H), 4.04 (s, 2H); 4.19 (m, J=4.2Hz, 2H), 7.31-7.37 (m, 1H); 7.43-7.44 (m, 2H), 7.61 (d, J=8.1Hz, 1H);
13c-NMR (CDCl
3, 100MHz) and δ: 14.0,49.1,61.4,130.0,130.6,130.1,130.7,131.0,132.6,166.9,194.70; HRMS (ESI-TOF) m/z:Calcd.forC
11h
11clNaO
3[M+Na]
+: 249.0294; Found:249.0297.
Experimental implementation: get 0.452g(2mmol) 2c is in 25mL round-bottomed flask, use 10mL dissolve with ethanol after adding sodium ethylate 0.16g, stirring at room temperature 15 minutes, gets 0.162mL(2mmol subsequently) acrylketone in flask, stirring at room temperature 2h.Aftertreatment: add 5% hydrochloric acid reaction solution, use 30 more respectively, 20,20mL extraction into ethyl acetate aqueous phase, the oil reservoir that saturated common salt water washing has merged, be spin-dried for after anhydrous sodium sulfate drying, column chromatography (PE:EA=10:1) is separated and obtains product 3c, productive rate 87%, HRMS (ESI-TOF) m/z:Calcd.forC
15h
17clNaO
4[M+Na]
+: 319.0713; Found:319.0713.
Experimental implementation: get 0.38g(3mmol) 3c is in 25mL round-bottomed flask; add 0.126g (1mmol) Phloroglucinol again; with being placed in household microwave oven; under 640W, heat 8min, take out subsequently and be down to room temperature, add acetic acid ethyl dissolution; cross leaching ethyl acetate layer; be spin-dried for, column chromatography (PE:EA=5:1) is separated and obtains product 4c, productive rate 66%;
1h-NMR (CDCl
3, 400MHz) and δ: 2.12 (s, 3H), 2.56 (s; 2H), 2.70 (s, 2H); 6.28 (d, J=4.0Hz, 2H); 7.26 (s, 1H), 740-7.49 (m; 3H), 7.53 (d, J=8.2Hz; 1H), 12.77 (s, 1H);
13c-NMR (CDCl
3, 100MHz) and δ: 19.9,29.7,41.7,93.9,99.3,105.1,120.1,127.1,130.1,130.6,131.5,131.7,133.3,157.9,160.3,162.3,162.5,182.1,208.7; HRMS (ESI-TOF) m/z:Calcd.forC
19h
15clNaO
5[M+Na]
+: 381.0505; Found:381.0507.
Experimental implementation: get 0.358g(1mmol) 4c and 0.114mL3-Methylacrylaldehyde in 25mL round-bottomed flask, then adds 0.147g anhydrous sodium carbonate and is placed in household microwave oven, under 640W, heat 13min.Take out subsequently and be down to room temperature, add acetic acid ethyl dissolution, cross leaching ethyl acetate layer, be spin-dried for, column chromatography (PE:EA=9:1) is separated and obtains product 5c, weak yellow liquid, productive rate 19%;
1h-NMR (CDCl
3, 400MHz) and δ: 12.81 (s, 1H), 7.56-7.53 (m; 1H), 7.51-7.46 (m, 1H), 7.45-7.40 (m; 2H), 6.59-6.52 (m, 1H), 6.29 (s; 1H), 5.51-5.46 (m, 1H), 2.75-2.65 (m; 2H), 2.62-2.50 (m, 2H), 2.08 (s; 3H), 1.45 (s, 6H);
13c-NMR (CDCl
3, 100MHz) and δ: 207.7,161.7,159.9,159.6,152.1,133.4,131.7,131.5,130.9; 130.7,130.2,128.8,127.1,120.3,114.7,105.0,101.0,100.1,78.1; 77.3,77.0,76.8,41.6,29.7,29.7,28.3,19.8,14.1,13.7; HRMS (ESI-TOF) m/z:Calcd.forC
24h
21clNaO
5[M+Na]
+: 447.0975; Found:447.0973.
Experimental implementation: take 424mg (1mmol) 5c in 25mLTHF, ice bath is down to sub-zero zero to system, adds excess methyl iodate magnesium (3.5eq), stir 2h under keeping ice bath, the cancellation that adds water is reacted, and adds extraction into ethyl acetate, dry ethyl acetate layer, is spin-dried for.Be separated with silica gel column chromatography under sherwood oil (1:5) system in ethyl acetate, obtain pale yellow oily liquid body 6c, productive rate 77%;
1h-NMR (CDCl
3, 400MHz) and δ: 12.82 (s, 1H); (7.59-7.54 m, 1H), 7.51-7.46 (m; 1H), 7.44-7.42 (m, 1H); (7.26 s, 1H), 6.64-6.49 (m; 1H), 6.28 (s, 1H); (5.55-5.43 m, 1H), 2.51-2.27 (m; 2H), 1.79 (s, 1H); 1.72-1.68 (m; 2H), 1.45 (s, 6H); 1.12 (s, 6H);
13c-NMR (CDCl
3, 100MHz) and δ: 182.3,161.8,159.7,159.6,152.2; 133.5,132.3,131.7,131.6,130.9,130.7; 130.2,128.8,127.0,126.9,122.0; 114.8,105.1,101.0,100.1,78.1; 77.3,77.0,76.8,70.5,42.1; 30.6,29.7,28.9,28.2,13.7; HRMS (ESI-TOF) m/z:Calcd.forC
25h
25clNaO
5[M+Na]
+: 463.1288; Found:463.1291.
Experimental implementation: take 424mg (1.0mmol) 5c in 25mLTHF, ice bath is down to sub-zero zero to system, it is excessive in fluorobenzenemagnesium bromide (3.5eq) to add, stir 3h under keeping ice bath, the cancellation that adds water is reacted, and adds extraction into ethyl acetate, dry ethyl acetate layer, is spin-dried for.Be separated with silica gel column chromatography under sherwood oil (1:5) system in ethyl acetate, obtain pale yellow oily liquid body 6c-2, productive rate 68%;
1h-NMR (CDCl
3, 400MHz) and δ: 12.71 (s, 1H), 7.52-7.44 (m, 2H); (7.34-7.26 m, 3H), 6.94-6.82 (m, 2H); (6.58-6.49 m, 1H), 6.27 (s, 1H); (5.53-5.42 m, 1H), 4.13-4.11 (m, 1H); (2.04 s, 2H), 1.97 (s, 2H); (1.76 s, 1H), 1.44 (s, 9H);
13c-NMR (CDCl
3, 100MHz) and δ: 182.3,161.6,159.7,152.2,143.0,142.9,131.6,131.4,130.6; 127.1,126.9,126.5,126.4,121.6,114.7,114.5,105.0,101.0,100.1; 78.1,77.3,77.0,76.8,73.9,42.2,29.7,28.3,14.2; HRMS (ESI-TOF) m/z:Calcd.forC
30h
26clFNaO
5[M+Na]
+: 543.1350; Found:543.1352.
Experimental implementation: take 424mg (1.0mmol) 5c in 25mL methyl alcohol, ice bath adds excess sodium borohydrate (3.0eq) under stirring, stirring at room temperature 3h, with in rare HCl and superfluous sodium borohydride, adds extraction into ethyl acetate, dry ethyl acetate layer, is spin-dried for.Be separated with silica gel column chromatography under sherwood oil (1:4) system in ethyl acetate, obtain pale yellow oily liquid body 7c, productive rate 88%;
1h-NMR (CDCl
3, 400MHz) and δ: 12.93 (s, 1H); (7.56-7.52 m, 1H), 7.51-7.45 (m; 1H), 7.43-7.39 (m, 2H); (6.78-6.69 m, 1H), 6.28 (s; 1H), 5.65-5.58 (m, 1H); (3.70-3.60 m, 1H), 3.10 (s; 1H), 2.67-2.58 (m, 1H); 2.29-2.21 (m; 1H), 1.46 (s, 8H); 1.11-1.07 (m, 3H);
13c-NMR (CDCl
3, 100MHz) and δ: 182.7,160.6,159.8,157.3,156.3,133.4,131.7,131.6,130.5; 130.2,128.8,128.1,127.0,121.2,115.4,105.5,104.9,94.8; 78.0,77.3,77.0,76.8,65.9,65.5,44.9,38.3,28.3; HRMS (ESI-TOF) m/z:Calcd.forC
24h
23clNaO
5[M+Na]
+: 449.1131; Found:449.1133.
(3), Morusin derivative 5e, the synthesis of 6e-1,6e-2,6e-3 and 7e and the preparation of reaction intermediate 2e-4e thereof
Experimental implementation: get potassium ethyl malonate salt 1.00g(and be about 5.47mmol) and Magnesium Chloride Anhydrous 0.65g(be about 6.84mmol) in 25mL round-bottomed flask, add 6mL acetonitrile after instillation 0.55g triethylamine and dissolve, in stirred at ambient temperature 30min.The 0.48g(2.5mmol of instillation 2mL acetonitrile dissolving subsequently) adjacent bromo-benzoyl chloride 1e, then add triethylamine 0.06mL, stirred overnight at room temperature.Aftertreatment: first add 30mL water dilute reaction solution, then add 30 respectively, 20,20mL extraction into ethyl acetate, collect ethyl acetate layer.With 30mL saturated aqueous common salt cleaning ethyl acetate layer after anhydrous sodium sulfate drying, be spin-dried for, column chromatography (PE:EA=15:1) be separated obtain product 2e, productive rate 92%;
1h-NMR (CDCl
3, 400MHz) and δ: 1.26 (t, J=8.1Hz, 3H), 4.03 (s; 2H), 4.19 (m, J=12.0Hz, 2H), 7.32-7.42 (m; 2H), 7.49-7.54 (m, 1H), 7.63-7.65 (m, 1H);
13c-NMR (CDCl
3, 100MHz) and δ: 14.0,48.7,61.5,119.1,127.4,129.4,132.3,133.8,139.9,166.7,196.6; HRMS (ESI-TOF) m/z:Calcd.forC
11h
11brNaO
3[M+Na]
+: 292.9789; Found:292.9786.
Experimental implementation: get 0.452g(2mmol) 2e in 25mL round-bottomed flask, use 10mL dissolve with ethanol after adding sodium ethylate 0.16g, stirring at room temperature 15 minutes, get 0.162mL (2mmol) acrylketone subsequently in flask, stirring at room temperature 2h.Aftertreatment: add 5% hydrochloric acid reaction solution, then use 30 respectively, 20,20mL extraction into ethyl acetate aqueous phase, the oil reservoir that saturated common salt water washing has merged, is spin-dried for after anhydrous sodium sulfate drying, and column chromatography (PE:EA=10:1) is separated and obtains product 3e, productive rate 85%; HRMS (ESI-TOF) m/z:Calcd.forC
15h
17brNaO
4[M+Na]
+: 363.0207; Found:363.0204.
Experimental implementation: get 0.38g(3mmol) 3e is in 25mL round-bottomed flask; add 0.126g (1mmol) Phloroglucinol again; with being placed in household microwave oven; under 640W, heat 8min, take out subsequently and be down to room temperature, add acetic acid ethyl dissolution; cross leaching ethyl acetate layer; be spin-dried for, be separated through silicagel column column chromatography (PE:EA=5:1) and obtain product 4e, productive rate 57%;
1h-NMR (CDCl
3, 400MHz) and δ: 2.11 (s, 3H), 2.57 (d; J=8.1Hz, 2H), 2.70 (d; J=8.2Hz, 2H), 6.30 (s; 2H), 7.27 (s, 1H); 7.37-7.47 (m, 3H), 7.72 (m; 1H), 12.77 (s, 1H);
13c-NMR (CDCl
3, 100MHz) and δ: 19.8,29.6,41.7,93.9,99.3,105.1,119.8,122.6,127.6,130.64,131.8,133.2,133.5,157.9,161.4,162.2,162.5,182.1,208.2; HRMS (ESI-TOF) m/z:Calcd.forC
19h
15brNaO
5[M+Na]
+: 425.0001; Found:425.0001.
Experimental implementation: get 0.358g(1mmol) 4e and 0.114mL3-Methylacrylaldehyde in 25mL round-bottomed flask, then adds 0.147g anhydrous sodium carbonate and is placed in microwave oven, under 640W, heat 13min.Take out subsequently and be down to room temperature, add acetic acid ethyl dissolution, cross leaching ethyl acetate layer, be spin-dried for, column chromatography (PE:EA=9:1) is separated and obtains product 5e, weak yellow liquid, productive rate 15%;
1h-NMR (CDCl
3, 400MHz) and δ: 12.81 (s, 1H), 7.74-7.71 (m; 1H), 7.47-7.44 (m, 1H), 7.43-7.39 (m; 2H), 6.59-6.53 (m, 1H), 6.29 (s; 1H), 5.51-5.45 (m, 1H), 2.75-2.65 (m; 2H), 2.59-2.52 (m, 2H), 2.08 (s; 3H), 1.26 (s, 6H);
13c-NMR (CDCl
3, 100MHz) and δ: 207.7,182.3,161.7,161.1,159.6; 152.1,133.6,133.3,132.3,131.8,130.9; 130.8,128.8,127.6,127.1,122.7,120.0; 114.7,105.1,101.0,100.1,94.8,78.1; 77.3,77.0,76.8,41.6,30.6; 29.7,29.7,28.4,28.1,13.7; HRMS (ESI-TOF) m/z:Calcd.forC
24h
21brNaO
5[M+Na]
+: 491.0470; Found:491.0470.
Experimental implementation: take 468mg (1mmol) 5e in 25mLTHF, ice bath is down to sub-zero zero to system, adds excess methyl iodate magnesium (3.5eq), stir 2h under keeping ice bath, the cancellation that adds water is reacted, and adds extraction into ethyl acetate, dry ethyl acetate layer, is spin-dried for.Be separated with silica gel column chromatography under sherwood oil (1:5) system in ethyl acetate, obtain pale yellow oily liquid body 6e-1, productive rate 75%;
1h-NMR (CDCl
3, 400MHz) and δ: 12.83 (s, 1H), 7.74 (d; J=8.2Hz, 1H), 7.50-7.45 (m, 1H); (7.44-7.40 m, 2H), 6.58 (d, J=10.0Hz; 1H), 6.29 (s, 1H), 5.49 (d; J=10.0Hz, 1H), 2.52-2.42 (m; 1H), 2.34-2.25 (m, 1H); (1.74-1.63 m, 2H), 1.58 (dd; J=11.2,5.3Hz, 1H); (1.45 d, J=13.7Hz, 6H); (1.12 d, J=4.9Hz, 6H);
13c-NMR (CDCl
3, 100MHz) and δ: 182.3,161.7,160.8,159.6,133.7; 133.3,131.7,130.9,130.7,128.8; 127.5,127.0,122.7,121.6,114.7; 105.1,101.0,100.0,78.1,77.3; 77.0,76.7,70.4,42.1,30.5; 28.9,28.8,28.4,28.1,13.7; HRMS (ESI-TOF) m/z:Calcd.forC
25h
25brNaO
5[M+Na]
+: 507.0783; Found:507.0785.
Experimental implementation: take 468mg (1.0mmol) 5e in 25mLTHF, ice bath is down to sub-zero zero to system, it is excessive in fluorobenzenemagnesium bromide (3.5eq) to add, stir 3h under keeping ice bath, the cancellation that adds water is reacted, and adds extraction into ethyl acetate, dry ethyl acetate layer, is spin-dried for.Be separated with silica gel column chromatography under sherwood oil (1:5) system in ethyl acetate, obtain pale yellow oily liquid body 6e-2, productive rate 71%;
1h-NMR (CDCl
3, 400MHz) and δ: 12.88-12.56 (m, 1H); (7.72-7.66 m, 1H), 7.44-7.36 (m; 2H), 7.33-7.28 (m, 1H); (7.27-7.22 m, 2H), 6.94-6.81 (m; 2H), 6.60-6.52 (m, 1H); (6.28 s, 1H), 5.54-5.44 (m; 1H), 2.05 (s, 2H); 2.01-1.93 (m; 2H), 1.78 (s, 1H); 1.49-1.41 (m, 9H);
13c-NMR (CDCl
3, 100MHz) and δ: 182.4,162.4,162.3,161.6,160.9; 160.8,160.4,160.3,159.7,152.1; 142.9,133.5,133.4,133.3,131.6; 130.6,127.5,127.4,127.1,126.5; 126.5,126.4,126.3,122.7,122.6; 121.4,121.3,114.7,114.7,114.7; 114.6,114.5,105.0,101.0,100.1; 78.1,77.3,77.0,76.8,73.9; 73.8,42.4,42.1,31.1,30.7; 29.7,28.3,28.1,28.0,14.2; HRMS (ESI-TOF) m/z:Calcd.forC
30h
26brFNaO
5[M+Na]
+: 587.0845; Found:587.0845.
Experimental implementation: take 468mg (1.0mmol) 5e in 25mLTHF, ice bath is down to sub-zero zero to system, it is excessive in fluorobenzenemagnesium bromide (3.5eq) to add, stir 3h under keeping ice bath, the cancellation that adds water is reacted, and adds extraction into ethyl acetate, dry ethyl acetate layer, is spin-dried for.Be separated with silica gel column chromatography under sherwood oil (1:5) system in ethyl acetate, obtain pale yellow oily liquid body 6e-3, productive rate 67%;
1h-NMR (CDCl
3, 400MHz) and δ: 12.86-12.53 (m, 1H), 7.72-7.65 (m; 1H), 7.42-7.17 (m, 7H), 7.16-7.09 (m; 1H), 6.60-6.52 (m, 1H), 6.27 (s; 1H), 5.51-5.45 (m, 1H), 2.99 (s; 1H), 2.42-2.13 (m, 2H), 2.08-1.98 (m; 2H), 1.47-1.42 (m, 9H);
13c-NMR (CDCl
3, 100MHz) and δ: 182.4,161.6,160.8,159.6,152.1,147.3,133.5; 133.4,133.3,132.3,131.6,130.9,130.6,128.8,128.0; 127.9,127.5,127.4,127.0,126.3,126.2,124.7,124.6; 122.6,121.5,121.4,114.7,105.0,101.0,100.0; 78.1,77.3,77.0,76.8,74.1,42.2,41.9; 30.9,30.7,30.5,29.7,28.3,28.1,13.7; HRMS (ESI-TOF) m/z:Calcd.forC
30h
27brNaO
5[M+Na]
+: 569.0939; Found:569.0941.
Experimental implementation: take 468mg (1.0mmol) 5e in 25mL methyl alcohol, ice bath adds excess sodium borohydrate (3.0eq) under stirring, stirring at room temperature 3h, with in rare HCl and superfluous sodium borohydride, adds extraction into ethyl acetate, dry ethyl acetate layer, is spin-dried for.Be separated with silica gel column chromatography under sherwood oil (1:4) system in ethyl acetate, obtain pale yellow oily liquid body 7e, productive rate 83%;
1h-NMR (CDCl
3, 400MHz) and δ: 12.78-12.60 (m, 1H), 7.78-7.68 (m; 1H), 7.50-7.45 (m, 1H); (7.44-7.38 m, 2H), 6.64-6.52 (m; 1H), 6.30 (s, 1H); (5.53-5.46 m, 1H), 3.70-3.59 (m; 1H), 3.11-2.98 (m, 1H); (2.71-2.58 m, 1H), 2.40-2.29 (m; 1H), 2.26-2.13 (m, 1H); (1.75-1.66 m, 1H), 1.48-1.44 (m; 6H), 1.14-1.07 (m, 3H);
13c-NMR (CDCl
3, 100MHz) and δ: 182.9,161.7,161.6,159.9,152.2; 133.7,133.4,133.4,131.8,130.9,130.7; 130.6,128.8,127.6,127.5,127.1,122.9; 122.6,121.2,120.9,114.7,104.9,101.0; 100.2,78.2,77.3,77.0,76.8,38.6; 37.9,30.6,29.7,28.4,28.2,13.7; HRMS (ESI-TOF) m/z:Calcd.forC
24h
23brNaO
5[M+Na]
+: 493.0626; Found:493.0628.
Formula of the present invention (1) Morusin derivative has important anti-tumor activity, external to human lung carcinoma cell (A549), human leukemia cell (K562), the cell toxicity test of human prostate (PC-3) totally three strain tumour cells shows: the Morusin derivative of the structure shown in this type of formula (1) is inhibited to growth of tumour cell, likely develops into new control tumour medicine or control tumour medicine lead compound.Mandatory declaration, Pharmacological Examples of the present invention is for illustration of the present invention instead of limitation of the present invention.Essence according to the present invention all belongs to application claims protection to the simple modifications that the present invention carries out and denies scope.
Pharmacological Examples 1:Morusin derivative 5a, 5c, 5e, 6c-1,6c-2,6e-1,6e-2,6e-3,7c or 7e are to the cytotoxicity of A549 cell
A549(Non-small cell lung carcinoma lung cancer) use DMEM culture medium culturing, containing the foetal calf serum of 10% in substratum, the penicillin of 100U/mL and 100U/mL Streptomycin sulphate.Cell joins in 96 holes with the concentration of 4000 cells in every hole, at 37 DEG C containing 5%CO
2cultivate 24 hours in the incubator of damp atmosphere.
The mensuration improvement mtt assay of cell survival rate.Cell after 24 hours hatch, the compound Morusin derivative 5a will newly joined respectively, 5c, 5e, 6c-1,6c-2,6e-1, the dimethyl sulphoxide solution of 6e-2,6e-3,7c or 7e joins in each hole with concentration gradient, compound ultimate density in hole is made to be respectively 5 μm of ol/L, 10 μm of ol/L, 20 μm of ol/L, 40 μm of ol/L and 80 μm ol/L.After 48 hours, every hole adds 10 μ LMTT(5mg/mL) phosphate buffered saline buffer, then to continue 37
oafter C cultivates 4 hours, within centrifugal 5 minutes, remove unconverted MTT, in every hole, add 150 μ L dimethyl sulfoxide (DMSO).With the MTT crystal formazan (formazan) of dissolving and reducing, measure OD value by microplate reader at 490nm wavelength.Wherein Morusin derivative 5a, 5c, 5e, 6c-1,6c-2,6e-1,6e-2,6e-3,7c or 7e are to A549 cell 503nhibiting concentration IC
50obtained by spss software (19 version) analysis.Compound 5a is to the IC of A549 tumour cell
50be 28.3 μm of ol/L; Compound 5c is to the IC of A549 tumour cell
50be 19.4 μm of ol/L; Compound 5e is to the IC of A549 tumour cell
50be 28.7 μm of ol/L; Compound 6c-1 is to the IC of A549 tumour cell
50be 8.9 μm of ol/L; Compound 6c-2 is to the IC of A549 tumour cell
50be 3.5 μm of ol/L; Compound 6e-1 is to the IC of A549 tumour cell
50be 7.8 μm of ol/L; Compound 6e-2 is to the IC of A549 tumour cell
50be 8.7 μm of ol/L; Compound 6e-3 is to the IC of A549 tumour cell
50be 2.7 μm of ol/L; Compound 7c is to the IC of A549 tumour cell
50be 12.3 μm of ol/L; Compound 7e is to the IC of A549 tumour cell
50be 15.6 μm of ol/L; And positive control cis-platinum is to the IC of A549 tumour cell
50be 25.7 μm of ol/L.
Experiment conclusion: A549 cell is that test compounds is to the Cytotoxic effective tool of tumour cell and evaluation index.This experiment shows that the Morusin derivative shown in this type of formula (1) has stronger cytotoxicity to A549 cell, better with the oncotherapy one line same order of magnitude of medication cis-platinum or specific activity cis-platinum, likely develop into the new medicine with antitumor action or lead compound.
Pharmacological Examples 2:Morusin derivative 5a, 5c, 5e, 6c-1,6c-2,6e-1,6e-2,6e-3,7c or 7e are to the cytotoxicity of K562 cell
K562(people's chronic myelogenous leukemia cell) use RPMI-1640 culture medium culturing, containing the foetal calf serum of 10% in substratum, the penicillin of 100U/mL and 100U/mL Streptomycin sulphate.Cell joins in 96 holes with the concentration of 5000 cells in every hole, at 37 DEG C containing 5%CO
2cultivate 24 hours in the incubator of damp atmosphere.
The mensuration improvement mtt assay of cell survival rate.Concrete grammar is as Pharmacological Examples 1.Compound 5a is to the IC of K562 tumour cell
50be 26.8 μm of ol/L; Compound 5c is to the IC of K562 tumour cell
50be 13.4 μm of ol/L; Compound 5e is to the IC of K562 tumour cell
50be 23.1 μm of ol/L; Compound 6c-1 is to the IC of K562 tumour cell
50be 5.8 μm of ol/L; Compound 6c-2 is to the IC of K562 tumour cell
50be 9.1 μm of ol/L; Compound 6e-1 is to the IC of K562 tumour cell
50be 8.5 μm of ol/L; Compound 6e-2 is to the IC of K562 tumour cell
50be 7.2 μm of ol/L; Compound 6e-3 is to the IC of K562 tumour cell
50be 2.3 μm of ol/L; Compound 7c is to the IC of K562 tumour cell
50be 42.3 μm of ol/L; Compound 7e is to the IC of K562 tumour cell
50be 32.5 μm of ol/L; And positive control cis-platinum is to the IC of K562 tumour cell
50be 24.6 μm of ol/L.
Experiment conclusion: K562 cell is that test compounds is to the Cytotoxic effective tool of tumour cell and evaluation index.This experiment shows that the Morusin derivative shown in this type of formula (1) has stronger cytotoxicity to K562 cell, better with the oncotherapy one line same order of magnitude of medication cis-platinum or specific activity cis-platinum, likely develop into the new medicine with antitumor action or lead compound.
Pharmacological Examples 3:Morusin derivative 5a, 5c, 5e, 6c-1,6c-2,6e-1,6e-2,6e-3,7c or 7e are to the cytotoxicity of PC-3 cell
PC-3(human prostata cancer) cell RPMI-1640 culture medium culturing, containing the foetal calf serum of 10% in substratum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL.Cell joins in 96 holes, 37 with the concentration of 5000 cells in every hole
oc is containing 5%CO
2cultivate 24 hours in the incubator of damp atmosphere.
The mensuration improvement mtt assay of cell survival rate.Concrete grammar is as Pharmacological Examples 1.Compound 5a is to the IC of PC-3 tumour cell
50be 47.54 μm of ol/L; Compound 5c is to the IC of PC-3 tumour cell
50be 25.32 μm of ol/L; Compound 5e is to the IC of PC-3 tumour cell
50be 28.19 μm of ol/L; Compound 6c-1 is to the IC of PC-3 tumour cell
50be 10.64 μm of ol/L; Compound 6c-2 is to the IC of PC-3 tumour cell
50be 11.80 μm of ol/L; Compound 6e-1 is to the IC of PC-3 tumour cell
50be 19.54 μm of ol/L; Compound 6e-2 is to the IC of PC-3 tumour cell
50be 8.97 μm of ol/L; Compound 6e-3 is to the IC of PC-3 tumour cell
50be 9.05 μm of ol/L; Compound 7c is to the IC of PC-3 tumour cell
50be 32.61 μm of ol/L; Compound 7e is to the IC of PC-3 tumour cell
50be 34.67 μm of ol/L; And positive control cis-platinum is to the IC of PC-3 tumour cell
50be 26.2 μm of ol/L.
Experiment conclusion: PC-3 cell is that test compounds is to the Cytotoxic effective tool of tumour cell and evaluation index.This experiment shows that the Morusin derivative shown in this type of formula (1) has stronger cytotoxicity to PC-3 cell, better with the oncotherapy one line same order of magnitude of medication cis-platinum or specific activity cis-platinum, likely develop into the new medicine with antitumor action or lead compound.
From above Pharmacological Examples, we can find out that these Morusin derivatives all show certain cytotoxicity to this three strains tumour cell.These compounds visible have the potentiality that exploitation becomes antitumor drug or lead compound, are worth continuing further investigation and go down.
Claims (3)
1. a White Mulberry Root-bark activeconstituents Morusin derivative, is characterized in that: this compound has the structure as shown in logical formula I:
。
2. a White Mulberry Root-bark activeconstituents Morusin derivative according to claim 1 is in the application preparing control tumor disease medicine.
3. the preparation method of a Morusin derivative as claimed in claim 1, it is characterized in that: by Benzoyl chloride 1 and the potassium ethyl malonate salt of corresponding replacement, acidylate decarboxylic reaction first occurs, generate intermediate 2, then there is Michael addition reaction with methylene acetone again in intermediate 2, obtain intermediate 3, then intermediate 3 and Phloroglucinol generation annulation, generate intermediate 4, intermediate 4 again with isoamyl olefine aldehydr generation annulation, generate Morusin derivative 5, Morusin derivative 5 generates Morusin derivative 6 by there is Aldol addition reaction with the Grignard reagent of various replacement, or Morusin derivative 5 obtains Morusin derivative 7 by sodium borohydride reduction carbonyl,
Morusin derivative synthetic route is as follows:
。
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CN110483543A (en) * | 2019-09-17 | 2019-11-22 | 西北大学 | One breeder mulberry root extract, extraction separation method and its application |
CN115212199A (en) * | 2022-05-24 | 2022-10-21 | 核工业总医院 | Application of small molecular compound in preparation of medicine for treating diffuse large B cell lymphoma |
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CN106117234A (en) * | 2016-06-28 | 2016-11-16 | 贵州大学 | Morusin skeleton splicing convolutamydine A skeleton compounds and preparation method and application |
CN106117234B (en) * | 2016-06-28 | 2019-05-10 | 贵州大学 | Morusin skeleton splices convolutamydine A skeleton class compound and preparation method and application |
CN110483543A (en) * | 2019-09-17 | 2019-11-22 | 西北大学 | One breeder mulberry root extract, extraction separation method and its application |
CN115212199A (en) * | 2022-05-24 | 2022-10-21 | 核工业总医院 | Application of small molecular compound in preparation of medicine for treating diffuse large B cell lymphoma |
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