CN101108840A - Chirality anona squamosa L. lactone compound with conformation limitation structure and synthesizing method and use thereof - Google Patents
Chirality anona squamosa L. lactone compound with conformation limitation structure and synthesizing method and use thereof Download PDFInfo
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Abstract
The invention relates to the chemical compound of the chiral annonaceous acetogenins of the comformational restriction structure, the synthetic method and the purpose. The compound has the optical activity compound as the above formula. The compound of the invention has high anti-cancer activity and selectivity and has the IC50 (MuM) of the human breast duct cancer reaching less than 0.04, and the suppressive activity on the cancer cell is about 100 times that of the normal cell and has better selectivity. The compound of the invention can also be used as the anti-cancer drug and has simple preparation method, which is a method suitable for the industrial production.
Description
Technical field
The present invention relates to a kind of lactone compound, specifically a kind of chiral anonace-lactone analogue and synthetic method and purposes.
Background technology
Current, cancer has become the biggest threat of human health, and its sickness rate is the trend that rises year by year.Have every year the death above 20% to be caused by cancer, this numeral surpasses because of acquired immune deficiency syndrome (AIDS), the summation of pulmonary tuberculosis and malaria death toll.The traditional treatment method for cancer as excision, radiotherapy and chemotherapy etc., all has certain defective, is not that to treat thoroughly be not exactly that toxic side effect is big.Development along with organic isolation identification of modern times and synthetic technology, many chemists are devoted to from natural product to separate and evaluation has optionally natural compounds of high resistance tumor promotion and tool, and obtain the lower compound of this natural content, and then with the natural compounds lead compound simplification of carrying out structure and modify the compound that obtains the various biological activity excellence of more structures by the means of organic synthesis.
Annona lactone (Annonaceous acetogenin) is to separate a class natural product that obtains from the annonaceae plant.Because they generally have strong anti-tumor activity, the people that cause pay close attention to (A.Cave etc. widely, Progress in the Chemistry of Organic Natural Products:Acetogenins fromAnnonaceae.New York, Springer-Verlag, 1997,70,81-288), people such as Wu Yulin, Yao Zhujun had once reported the Annona lactone analogue (CN97106368.0) with antitumour activity, had following molecular formula:
Wherein R1, R2, R3, R4 are H or chirality OH; L=1-6; M=8-12; N=0-5; O=3-12.And provide the Preparation method and use of this compounds.Such series of compounds is by the synthetic epoxy intermediate that contains the gamma-butyrolactone that is substituted or resets of chiral hydroxyl group acid starting material, reacts through coupling, catalytic hydrogenation, elimination with polyoxyethylene glycol compounds and epoxy intermediate to obtain the product Annona lactone analogue but this method does not obtain chiral product.This compounds is to the Lethal Dose 50 LC of cancer cells
50Be 3-6E-05.People such as Wu Yu woods, Yao Zhujun have reported a class chiral anonace-lactone analogue (CN99125750.2) again subsequently, have following molecular formula:
Y=C wherein
6-20Alkyl, n=1-3, m=7-19.Product ester cpds and chiral aldehydes reaction that this series of compounds by chirality haloalkane and chirality dihydroxyl alkyl carboxylic acid ester coupling and hydroxyl protection takes place obtain the aldol condensation product, obtain through acid lactone cyclisation, elimination hydrolysis again.The more last compounds of this compounds has the Lethal Dose 50 EC of better biological activity to cancer cells
50Be 0.03-0.09 μ gmL
-1Expect to utilize new synthetic method and approach this contriver, in the flexible molecule structure of Annonaceousacetogenicompounds compounds, introduce the rigid structure of conformation restriction, further improve the antitumour activity of compound, meanwhile make it between normal cell and cancer cells, certain selectivity can also be arranged, and prepare for finally being developed to the new cancer therapy drug of a class.
Summary of the invention
The problem to be solved in the present invention provides a kind of chiral anonace-lactone analogue, has optical activity and conformation restriction rigid structure.
The problem that the present invention also will solve provides a kind of preparation method of above-claimed cpd.
The problem that the present invention also will solve provides the purposes of above-claimed cpd.
Chiral anonace-lactone analogue of the present invention is the optically active compound with following molecular formula:
In other words, this compound is:
Refer in particular to
Refer in particular to
Refer in particular to
Refer in particular to
Deng compound, wherein, X=O, S, n=0-5, m=7-19, Y=C
6-20Alkyl, R
1, R
2Be (CH
2)
LR
3, L=0-5 wherein, R
3Be H, OR4, SR
4Or NR
4R
5, when n=0 or 1, R
1And R
2Be (CH
2)
LR
3Or link to each other forming the heterogeneous ring compound of ring texture, ring texture can be five, six or seven-membered ring; R
1, R
2It is identical or different group;
And when X is O and L when being 0, R
3Only be OR
4, SR
4Or NR
4R
5R
5, R
4Be H, alkyl, acyl group or heterogeneous ring compound, R
5, R
4It is identical or different group; Recommend R
5, R
4Be H, C
1～C
10Alkyl, C
1～C
10Acyl group or contain five to seven yuan of saturated or heteroaromatic compounds of N, O, S.
Chiral anonace-lactone compound of the present invention can be with molecular formula
With molecular formula be
Linked reaction takes place in epoxy unsaturated lactone compound in the presence of n-Butyl Lithium and boron trifluoride diethyl etherate; Protect hydroxyl with methylsulfonyl again; Handle with the organic amine compound that lone-pair electron are arranged on the nitrogen-atoms then and obtain to contain two keys and three key compounds; Then with two keys of p-toluene sulfonyl hydrazide reduction and triple bond, acid catalysis removes blocking group.Can represent with following reaction formula:
Wherein, X=O or S, n=0-5, m=7-19, Y=C
6-20Alkyl, R
1, R
2Be (CH
2)
LR
3, L=0-5 wherein, R
3Be H, OR
4, SR
4Or NR
4R
5(R
5, R
4Be H, alkyl, acyl group or heterogeneous ring compound, R
5, R
4Be identical or different group), when n=0 or 1, R
1And R
2Be (CH
2)
LR
3Or link to each other forming the ring texture that contains oxygen, sulphur or nitrogen-atoms, ring texture can be five, six or seven-membered ring.R
1, R
2It is identical or different group;
Unless otherwise indicated, alkyl of the present invention, acyl group are recommended as C
1～C
10, described heterogeneous ring compound be recommended as contain N, O, S five to the saturated or aromatic nucleus of seven-membered ring.
A step or a multistep during the reaction conditions of synthetic method of the present invention further is recommended as and comprises the steps:
Above-mentioned chirality alkynes, epoxy unsaturated lactone, n-Butyl Lithium and boron trifluoride diethyl etherate mol ratio are 1-3: 1: 1-3: 1-3, in polar solvent and room temperature to-78 ℃ the reaction 0.5-3h.
Compound 5, methane sulfonyl chloride and triethylamine mol ratio are 1: 1-3: during 2-6, in polar solvent and 0 ℃ behind the reaction 15-45min, obtain chipal compounds 4 to the room temperature.
The organic amine mol ratio that contains lone-pair electron on compound 4 and the nitrogen-atoms is 1: during 1-5, at room temperature react 1-10h, obtain chipal compounds 3.Contain the organic amine lauryl amine, dimethylamine, 1.8-phenodiazine-dicyclo [5,4,0] undecane-7-alkene (DBU) of lone-pair electron etc. on the described nitrogen-atoms, but be best with DBU.
Chipal compounds 3, p-toluene sulfonyl hydrazide and sodium-acetate mol ratio are 1: 100-200: 100-200 reacts 1-10h in room temperature under refluxing in one or more polar solvents, obtain chipal compounds 2.
In polar solvent and 0 ℃ to room temperature, chipal compounds 2 usefulness mineral acid catalysis deprotections successions final product 1.
Described polar solvent can be CH
2Cl
2, CH
3OH, tetrahydrofuran (THF) (THF), glycol dimethyl ether and water etc.
Molecular formula is
The preparation method of chirality alkynes, can be to be by molecular formula
Compound with
Substitution reaction takes place under the sodium hydride condition; Then under the phase-transfer catalyst effect with chiral epichlorohydrin generation coupling; Then with the coupling under boron trifluoride diethyl etherate butyllithium condition of trimethyl silicane alkynes; Protect newborn hydroxyl with the chloromethyl methyl ether effect again, under the tetrabutyl ammonium fluoride effect, remove silica-based protection at last, X wherein, Y R
1, R
2, n as previously mentioned, P=MOM or TBS, the MOM=methoxymethyl, the TBS=dimethyl tertiary butyl is silica-based.Can represent with following reaction formula:
The synthetic method of chirality alkynes can further describe for: compound 7, compound 8 and sodium hydride mol ratio are 1: 1-5: 1-5 0 ℃ of reaction 4-10 hour to room temperature to 100 ℃ and the polar solvent, obtains compound 9.
Compound 9, epoxy chloropropane and phase-transfer catalyst mol ratio are 1: 1-5: 0.1-0.5, reacted 1-10 hour to room temperature and 50%NaOH solution at 0 ℃, and obtain compound 10.Described phase-transfer catalyst is a 4-butyl ammonium hydrogen sulfate.
Compound 10, trimethyl silicane alkynes, n-Butyl Lithium and boron trifluoride diethyl etherate mol ratio are 1: 1-5: 1-5: 1-5, reaction is 1-4 hour in-78 ℃ and polar solvent, obtains compound 11.
Compound 11, chloromethyl methyl ether, diisopropyl ethyl amine mol ratio 1: 5-10: 10-15 reacted 2-10 hour to room temperature and polar solvent at 0 ℃, obtained compound 12.
Compound 12 and tetrabutyl ammonium fluoride mol ratio 1: 1-2 react 15-60min at 0 ℃ to room temperature and polar solvent, obtain compound 6.
The invention provides a kind of new synthetic intermediate, molecular formula is:
Be recommended as
X wherein, Y, R
1, R
2, m, n as previously mentioned, P=MOM or TBS, the MOM=methoxymethyl, the TBS=dimethyl tertiary butyl is silica-based.
Compound of the present invention has high antitumour activity and selectivity, with the data instance of example 9, to the IC of human body lactiferous ducts cancer (MDA-MB-468)
50(μ M) reach＜0.04, and to cancer cells (BEL-7404, inhibition activity MDA-MB-468) is that (Chang about LO2) 100 times, has selectivity preferably to normal cell.Can be used for cancer therapy drug.And the preparation method is simple and easy, is a kind of method that is suitable for suitability for industrialized production.
Embodiment
To help to understand the present invention by following embodiment, but not limit content of the present invention.
Embodiment 1
4.76mmol 60% sodium hydride is dissolved among the 10mL DMF, be cooled to 0 ℃ of 15mL DMF solution that slowly splashes into raw material 4.76mmol glycol, after stirring 30 minutes under this temperature, slowly splash into the 15mL DMF solution of raw material 2.38mmol 14, drip complete reaction solution and slowly be warming up to 80 ℃, reacted 15 hours.Be cooled to room temperature, the saturated ammonium chloride cancellation, system is separated organic phase water, saturated ammonium chloride and saturated sodium-chloride washing successively with the dilution of 150mL ethyl acetate, and anhydrous sodium sulfate drying filters, and concentrates, and column chromatography obtains weak yellow liquid 16 (0.53g, 82%).
[α]
D 25＝+3.6(c 3.1，CHCl
3)；
1H NMR(400MHz，CDCl
3)δ：0.88(3H，t，J＝7.0Hz)，1.23(16H，m)，1.52(2H，m)，3.37(3H，s)，3.38(3H，s)，3.39(3H，s)，3.53-3.78(8H，m)，3.87(1H，dd，J＝5.5，10.0Hz)，4.64(5H，m)，4.75(1H，d，J＝6.8Hz)ppm；
13C NMR(100MHz，CDCl
3)δ：97.0，96.8，96.0，79.7，77.0，73.7，70.8，69.0，67.1，55.5，55.47，55.43，32.1，32.0，29.8，29.7，29.4，25.5，22.7，14.1 ppm；IR(film)：3479，2925，2854，1464，1378，1213，1152，1111，1038，918cm
-1；MS(ESI，m/z)：461(M
++Na)；
HRMS (ESI), C
22H
46O
8Na calculated value 461.3084, measured value 461.3095.
Embodiment 2
In the 40mL cyclohexane solution of raw material 4.8mmol 16 and 9.6mmol epoxy chloropropane, add phase-transfer catalyst 0.21g 4-butyl ammonium hydrogen sulfate, postcooling to 0 ℃ stirs, slowly drip the 10mL 50%NaOH aqueous solution, stir under the room temperature after 10 hours, system is diluted with the 100mL ether, separate organic phase, water and saturated sodium-chloride washing successively, anhydrous sodium sulfate drying concentrates, column chromatography obtains colourless liquid 17 (1.42g, 60%).
[α]
D 25＝-15.5(c 2.1，CHCl
3)；
1H NMR(500MHz，CDCl
3)δ：0.88(3H，t，J＝7.0Hz)，1.26(16H，m)，1.55(2H，m)，2.60(1H，m)，2.77(1H，dd，J＝4.2，5.0Hz)，3.15(1H，m)，3.36(6H，m)，3.37(3H，s)，3.54-3.76(10H，m)，3.84(1H，m)，4.63(5H，m)，4.77(1H，d，J＝6.7Hz)ppm；
13C NMR(100MHz，CDCl
3)δ：96.7，96.6，95.9，79.38，79.32，76.4，73.8，72.2，72.0，67.1，66.8，55.3，55.2，50.8，44.2，32.0，31.8，29.6，29.5，29.2，25.3，22.5，13.9ppm；IR(film)：2926，2855，1458，1214，1152，1111，1039，918cm
-1；
MS(ESI，m/z)：517(M
++Na)；
HRMS (ESI), C
25H
50O
9Na calculated value 517.3347, measured value 517.3365.
Embodiment 3
Under-78 ℃ and the nitrogen protection, in the 5mL of 4.38mmol trimethylsilyl acetylene anhydrous tetrahydro furan, slowly drip 4.38mmol n-BuLi (1.6M in hexane), stirs after 30 minutes adding 4.38mmolBF
3Et
2O, continue to stir after 30 minutes, slowly splash into the 15mL anhydrous tetrahydrofuran solution of compound 1.46mmol 17, react after 2 hours, the saturated ammonium chloride cancellation, system is diluted with the 50mL ether, separate organic phase successively with saturated sodium bicarbonate and saturated sodium-chloride washing, anhydrous sodium sulfate drying, concentrate and to obtain intermediate and be dissolved in the 10mL anhydrous methylene chloride, add the 21.9mmol diisopropyl ethyl amine under the room temperature, be cooled to 0 ℃, slowly inject 14.6mmol MOMCl, reaction is 5 hours under the room temperature, the saturated sodium bicarbonate cancellation, system is diluted with the 50mL methylene dichloride, separate organic phase and use 1N HCI successively, saturated sodium bicarbonate and saturated sodium-chloride washing, anhydrous sodium sulfate drying concentrates and to obtain thick product and be dissolved in the 10mL tetrahydrofuran (THF), and the ice-water bath cooling adds 1.6mmol TBAF (1M in THF) down, reacts after 30 minutes, system is diluted with the 50mL ether, separate organic phase successively with saturated ammonium chloride and saturated sodium-chloride washing, anhydrous sodium sulfate drying concentrates, column chromatography obtains colourless liquid 18 (0.86g, 88%).
[α]
D 25＝-18.1(c 2.95，CHCl
3)；
1H NMR(500MHz，CDCl
3)δ：0.88(3H，t，J＝7.0Hz)，1.26(14H，m)，1.40(2H，m)，1.55(2H，m)，1.99(1H，dd，J＝2.6，2.6 Hz)，2.52(2H，m)，3.36(6H，s)，3.37(3H，s)，3.39(3H，s)，3.55-3.76(9H，m)，3.79(1H，m)，3.85(1H，m)，4.62(5H，m)，4.74(3H，m)ppm；
IR(film)：3274，2928，2858，2824，1467，1214，1153，1110，1039，919cm
-1；
MS(ESI，m/z)：587(M
++Na)；
Ultimate analysis C
29H
56O
10(%): calculated value C, 61.68; H, 9.99. measured value C, 61.85; H, 10.25.
Embodiment 4
Under-78 ℃ and the nitrogen protection, in the anhydrous tetrahydro furan 5mL of compound 181-4mmol, slowly drip n-BuLi 1-4mmol, stirs after 30 minutes adding BF
3Et
2O 1-4mmol, continue to stir after 30 minutes, slowly splash into the anhydrous tetrahydro furan 5mL solution of compound 19 1.44mmol, react after 2 hours the saturated ammonium chloride cancellation, system is diluted with ether (50mL), separate organic phase successively with saturated sodium bicarbonate and saturated sodium-chloride washing, anhydrous sodium sulfate drying concentrates, column chromatography obtains weak yellow liquid 20 (0.60g, 58%).
1H NMR(500MHz，CDCl
3)δ：0.88(3H，t，J＝7.0Hz)，1.26(24H，m)，1.40(3H，d，J＝6.8Hz)，1.54(6H，m)，2.26(2H，t，J＝7.3Hz)，2.47(4H，m)，3.36(6H，s)，3.37(3H，s)，3.38(3H，s)，3.37(1H，m)，3.56-3.85(12H，m)，4.62(4H，s)，4.63(1H，d，J＝6.7Hz)，4.72(2H，s)，4.76(1H，d，J＝6.8Hz)，4.99(1H，dq，J＝1.5，6.7Hz)，6.99(1H，d，J＝1.0Hz)ppm；
IR(film)：3487，2926，2856，2249，1757，1465，1320，1314，1152，1111，1038，919，733cm
-1；
MS(ESI，m/z)：825(M
++Na)；
HRMS (ESI), C
43H
78O
13Na calculated value 825.5334, measured value 825.5362.
Embodiment 5
The anhydrous methylene chloride 5mL of compound 20 0.31mmol is cooled to 0 ℃, add triethylamine 0.5-1.5mmol, slowly be added dropwise to Methanesulfonyl chloride 0.4-1.0mmol, reaction is after 30 minutes under the room temperature, in system, add DBU 0.5-1.5mmol, continue reaction after 4 hours, the saturated ammonium chloride cancellation, reaction system is diluted with methylene dichloride (50mL), separate organic phase successively with 1N HCl, saturated sodium bicarbonate and saturated sodium-chloride washing, anhydrous sodium sulfate drying concentrates, column chromatography obtains weak yellow liquid 21 (0.15g, 62%).
Embodiment 6
Compound 21 0.153mmol and p-toluene sulfonyl hydrazide 10-20mmol are dissolved among the glycol dimethyl ether 25mL, reflux, the 30mL aqueous solution of sodium-acetate 15-25mmol is slowly injected reaction solution in 5 hours, stirring and refluxing simultaneously, mixture is chilled to room temperature, decompression screws out solvent, and, merge organic interdependent inferior with water, saturated sodium bicarbonate and saturated sodium-chloride washing, anhydrous sodium sulfate drying with ethyl acetate (30mLx3) extraction residue water, concentrate, column chromatography obtains thick product.It is dissolved among the methyl alcohol 2.0mL, the ice-water bath cooling drips concentrated hydrochloric acid 0.5mL down, stirred 24 hours saturated sodium bicarbonate neutralization, ethyl acetate extraction (10mL * 3) under the room temperature, merge organic phase, bag and sodium-chlor washing, anhydrous sodium sulfate drying concentrates, column chromatography obtains product 22 (43mg, 46%).
1H NMR(400MHz，CDCl
3)δ：0.88(3H，t，J＝7.0Hz)，1.26-1.50(38H，m)，1.40(3H，d，J＝6.8Hz)，1.54(2H，m)，2.26(2H，t，J＝8.0Hz)，3.18(4OH，brs)，3.44(2H，m)，3.65(6H，m)，3.79(4H，m)，4.99(1H，dq，J＝1.6，6.8Hz)，6.99(1H，d，J＝1.5Hz)ppm；
IR(film)：3353，2925，2851，1749，1471，1326，1201，1144，1113，1033，880，720cm
-1；
MS(ESI，m/z)：637(M
++Na)；
Embodiment 7
The employing structural formula is
Chiral alcohol, operation is with implementing 1,2,3,4,5 and 6, the result obtains respectively
Compound 24,
Compound 27.
Compound 23
1H NMR(400MHz，CDCl
3)δ：0.88(3H，t，J＝7.0Hz)，1.26-1.50(38H，m)，1.40(3H，d，J＝6.8Hz)，1.54(2H，m)，2.26(2H，t，J＝8.0Hz)，3.39(2H，m)，3.44(4OH，brs)，3.75(10H，m)，4.99(1H，dq，J＝1.6，6.8Hz)，6.99(1H，d，J＝1.5Hz)ppm；
IR(film)：3356，2920，2851，1753，1469，1321，1084，1029，889，721cm
-1；
MS(ESI，m/z)：637(M
++Na)；
Compound 24
1H NMR(500MHz，CDCl
3)δ：0.88(3H，t，J＝7.1Hz)，1.26(32H，m)，1.40(3H，d，J＝6.8Hz)，1.44(6H，m)，1.54(2H，m)，2.26(2H+2OH，m)，3.31(2H，m)，3.52(2H，m)，3.73(2H，m)，3.79(2H，m)，3.94(2H，m)，3.99(2H，m)，4.99(1H，dq，J＝1.6，6.8Hz)，6.99(1H，J＝1.5Hz)ppm；
IR(filrm)：3500，2919，2850，1747，1467，1323，1138，1122，1079，1027，880，722cm
-1；
MS(ESI，m/z)：619(M
++Na)；
Compound 25
1H NMR(500MHz，CDCl
3)δ：0.88(3H，t，J＝7.1Hz)，1.26(32H，m)，1.40(3H，d，J＝6.8Hz)，1.44(6H，m)，1.54(2H，m)，2.26(2H，t，J＝7.7Hz)，2.30(2OH，brs)，3.33(2H，m)，3.51(2H，m)，3.77(4H，m)，3.94(2H，m)，3.99(2H，m)，4.99(1H，dq，J＝1.5，6.8Hz)，6.99(1H，J＝1.2Hz)ppm；
IR(film)：3500，2920，2851，1743，1467，1325，1147，1074，1031，953，727 cm
-1；MS(ESI，m/z)：619(M
++Na)；
Compound 26
1H NMR(500MHz，CDCl
3)δ：0.88(3H，t，J＝7.1Hz)，1.26-1.56(40H，m)，1.41(3H，d，J＝6.8Hz)，2.26(2H，t，J＝7.9Hz)，2.47(2OH，brs)，2.84(2H，m)，3.00(2H，m)，3.36(2H，dd，J＝7.9，9.4Hz)，3.53(2H，dd，J＝2.8，9.6Hz)，3.74(2H，m)，4.08(2H，m)，4.99(1H，dq，J＝1.4，6.6Hz)，6.99(1H，d，J＝1.4Hz)ppm；
IR(film)：3498，2926，2850，1745，1468，1324，1166，1121，1029，953，863，721cm
-1；
MS(ESI，m/z)：635(M
++Na)；
Compound 27
1H NMR(500MHz，CDCl
3)δ：0.88(3H，t，J＝7.0Hz)，1.26-1.56(40H，m)，1.41(3H，d，J＝6.8Hz)，2.26(2H，t，J＝7.7Hz)，2.83(2H，m)，2.99(1H，d，J＝3.4Hz)，3.02(1H，d，J＝3.6Hz)，3.33(2H，dd，J＝8.5，8.5Hz)，3.59(2H，dd，J＝2.9，9.5Hz)，3.74(2H，m)，4.09(2H，m)，4.99(1H，q，J＝6.6Hz)，6.99(1H，s)ppm；
IR(film)：3463，2924，2851，1750，1467，1320，1175，1087，1027，948，869，722cm
-1；
MS(ESI，m/z)：635(M
++Na)；
Embodiment 8
The employing structural formula is
With
With structural formula be respectively
Glycol reaction, operation as embodiment 1,2 and 3 with structural formula is respectively again
With structural formula be
Compound reaction, operation as implement 4,5 and 6.
The result obtains respectively
Compound 28
1H NMR(500MHz，CDCl
3)δ：0.88(3H，t，J＝7.1Hz)，1.26(18H，m)，1.41(3H，d，J＝6.8Hz)，1.44(6H，m)，1.55(2H，m)，2.26(2H，t，J＝7.7Hz)，2.30(2OH，brs)，3.33(2H，m)，3.51(2H，m)，3.77(4H，m)，3.94(2H，m)，3.99(2H，m)，4.99(1H，dq，J＝1.5，6.8Hz)，6.99(1H，J＝1.2Hz)ppm；
IR(film)：3498，2921，2850，1742，1466，1324，1146，1073，1030，952，726cm
-1；
MS(ESI，m/z)：521(M
++Na)；
Compound 29
1H NMR(500MHz，CDCl
3)δ：0.88(3H，t，J＝7.1Hz)，1.26(40H，m)，1.41(3H，d，J＝6.8Hz)，1.46(6H，m)，1.54(2H，m)，2.26(2H，t，J＝7.7Hz)，2.33(2OH，brs)，3.34(2H，m)，3.52(2H，m)，3.78(4H，m)，3.95(2H，m)，3.99(2H，m)，4.98(1H，dq，J＝1.5，6.8Hz)，6.98(1H，J＝1.2Hz)ppm；
IR(film)：3500，2920，2851，1743，1467，1325，1147，1074，1031，953，727cm
-1；
MS(ESI，rm/z)：675(M
++Na)；
Compound 30
1H NMR(500MHz，CDCl
3)δ：0.89(3H，t，J＝7.1Hz)，1.28(30H，m)，1.41(3H，d，J＝6.8Hz)，1.45(6H，m)，1.56(2H，m)，2.27(2H，t，J＝7.7Hz)，2.40(2OH，brs)，3.34(2H，m)，3.53(2H，m)，3.79(4H，m)，3.96(2H，m)，4.00(2H，m)，5.00(1H，dq，J＝1.5，6.8Hz)，7.00(1H，J＝1.2Hz)ppm；
IR(film)：3499，2920，2849，1742，1466，1324，1146，1072，1030，952，726cm
-1；
MS(ESI，m/z)：633(M
++Na)；
Compound 31
1H NMR(500MHz，CDCl
3)δ：0.88(3H，t，J＝7.1Hz)，1.25(58H，m)，1.40(3H，d，J＝6.8Hz)，1.45(6H，m)，1.55(2H，m)，2.27(2H，t，J＝7.7Hz)，2.30(2OH，brs)，3.32(2H，m)，3.50(2H，m)，3.76(4H，m)，3.93(2H，m)，3.98(2H，m)，4.99(1H，dq，J＝1.5，6.8Hz)，6.99(1H，J＝1.2Hz)ppm；
IR(film)：3501，2922，2853，1743，1467，1325，1147，1074，1031，953，725cm
-1；
MS(ESI，m/z)：801(M
++Na)；
Compound 32
1H NMR(500MHz，CDCl
3)δ：0.88(3H，t，J＝7.1Hz)，1.26(42H，m)，1.40(3H，d，J＝6.8Hz)，1.44(6H，m)，1.54(2H，m)，2.26(2H，t，J＝7.7Hz)，2.30(2OH，brs)，3.33(2H，m)，3.51(2H，m)，3.77(4H，m)，3.94(2H，m)，3.99(2H，m)，4.99(1H，dq，J＝1.5，6.8Hz)，6.99(1H，J＝1.2Hz)ppm；
IR(film)：3500，2920，2851，1743，1467，1325，1147，1074，1031，953，727 cm
-1；
MS(ESI，m/z)：689(M
++Na)；
Compound 33
1H NMR(500MHz，CDCl
3)δ：0.88(3H，t，J＝7.1Hz)，1.24(66H，m)，1.40(3H，d，J＝6.8Hz)，1.46(6H，m)，1.56(2H，m)，2.28(2H，t，J＝7.7Hz)，2.38(2OH，brs)，3.34(2H，m)，3.53(2H，m)，3.78(4H，m)，3.95(2H，m)，3.99(2H，m)，4.99(1H，dq，J＝1.5，6.8Hz)，6.99(1H，J＝1.2Hz)ppm；
IR(film)：3499，2919，2850，1743，1467，1325，1147，1074，1031，953cm
-1；
MS(ESI，m/z)：857(M
++Na).
Embodiment 9 biological activity tests
To BEL-7404, SK-Hep 1 according to the MTT method for compound 22,23,24,25,26,27, MDA-MB-468, and the cancer cells of HCT116 and Chang are during the Normocellular Lethal Dose 50 of LO2 is measured and is listed in the table below
| Compound | IC 50(μM) | |||||
| MDA-MB -435S | HCT116 | BEL-7404 | SK-Hepl | Chang | LO2 | |
| 22 23 24 | ＜0.04 ＜0.04 ＜0.04 | 3.79 5.09 ～10 | 0.063 0.051 0.12 | 0.687 0.72 1.17 | ＞10 4.02 3.58 | 4.05 2.67 2.24 |
| 25 26 27 | 0.07 0.046 0.059 | ＞10 0.605 ＞10 | 0.091 0.049 0.13 | 0.987 ＞2.6 1.76 | ＞8 5.8 ＞15 | ＞12 ＞10 3.98 |
Claims (14)
1. chiral anonace-lactone compound with conformation limiting structure is characterized in that having the optically active compound of following structural formula:
Wherein, X=O, S, n=0-5, m=7-19, Y=C
6-20Alkyl, R
1, R
2Be (CH
2)
LR
3, L=0-5 wherein, R
3Be H, OR
4, SR
4Or NR
4R
5, when n=0 or 1, R
1And R
2Be (CH
2)
LR
3Or link to each other forming the heterogeneous ring compound of ring texture, ring texture is five, six or seven-membered ring; R
1, R
2It is identical or different group;
And when X is O and L when being 0, R
3Only be OR
4, SR
4Or NR
4R
5
R
5Or R
4Be H, C
1～C
10Alkyl, C
1～C
10Acyl group, contain five to the seven yuan of saturated rings of N, O, S or the heterogeneous ring compound of aromatic nucleus, R
5, R
4It is identical or different group.
2. chiral anonace-lactone compound as claimed in claim 1 is characterized in that having following structural formula:
Y wherein, X, R
1, R
2, m is described in n such as the claim 1.
3. chiral anonace-lactone compound as claimed in claim 1 is characterized in that having following structural formula:
Y wherein, X, R
1, R
2, m is described in n such as the claim 1.
4. the chiral anonace-lactone compound described in claim 1 is characterized in that having following structural formula:
Y wherein, X, R
1, R
2, m is described in n such as the claim 1.
5. the chiral anonace-lactone compound described in claim 1 is characterized in that having following structural formula:
R wherein
1, R
2Described in claim 1.
6. the chiral anonace-lactone compound described in claim 1 is characterized in that having following structural formula:
7. the synthetic intermediate of the chiral anonace-lactone compound described in claim 1 is characterized in that having following structural formula:
X in the formula, Y, R
1, R
2, m, described in n such as the claim 1, P=MOM or TBS, the MOM=methoxymethyl, the TBS=dimethyl tertiary butyl is silica-based,
Or
8. the preparation method of a chiral anonace-lactone compound, at least one step in it is characterized in that comprising the steps: be by structural formula
Or
Chirality alkine compounds and molecular formula be
Epoxy unsaturated lactone compound, linked reaction takes place in the presence of n-Butyl Lithium and boron trifluoride diethyl etherate; Protect hydroxyl with methylsulfonyl again; Handle with the organic amine compound that lone-pair electron are arranged on the nitrogen-atoms then and obtain to contain two keys and three key compounds; Then with two keys of p-toluene sulfonyl hydrazide reduction and triple bond, acid catalysis removes blocking group, X=O wherein, S, n=0-5, m=7-19, Y=C
6-20Alkyl, R
1, R
2Be (CH
2)
LR
3, L=0-5 wherein, R
3Be H, OR
4, SR
4Or NR
4R
5, when n=0 or 1, R
1And R
2Be (CH
2)
LR
3Or link to each other to form and to contain heteroatomic ring texture, ring texture is five, six or seven-membered ring; R
1, R
2It is identical or different group; R
5, R
4Be H, C
1～C
10Alkyl, C
1～C
10Acyl group or contain five to seven yuan of saturated or heteroaromatic compounds of N, O, S, R
5, R
4It is identical or different group; P=MOM or TBS, the MOM=methoxymethyl, the TBS=dimethyl tertiary butyl is silica-based.
9. the preparation method of chiral anonace-lactone compound as claimed in claim 1 is characterized in that by step (4) in the following method, (3)～(4), (2)～(4) or (1)～(4) make:
(1) described chirality alkynes, epoxy unsaturated lactone, n-Butyl Lithium and boron trifluoride diethyl etherate mol ratio are 1-3: 1: 1-3: 1-3, in polar solvent, under-78 ℃, react 0.5-5h with room temperature, and obtain
(2) product of above-mentioned (1), methane sulfonyl chloride and triethylamine mol ratio are 1: 1-3: 2-6, at 0 ℃ to room temperature and the polar solvent behind the reaction 15-45min, add the organic amine compound that lone-pair electron are arranged on the nitrogen-atoms with the relative mol ratio 1-5 of product of above-mentioned (1), at room temperature react 1-10h, obtain
(3) product of above-mentioned (2), p-toluene sulfonyl hydrazide and sodium-acetate mol ratio are 1: 100-200: 100-200 reacts 1-10h in room temperature under refluxing in polar solvent, obtain
(4) in polar solvent and 0 ℃ to room temperature, the product of above-mentioned (3) mineral acid catalytic reactions 10-20h, in the above-mentioned molecular formula, X, Y, R
1, R
2, m, described in n such as the claim 8, P=MOM or TBS, the MOM=methoxymethyl, the TBS=dimethyl tertiary butyl is silica-based.
10. the preparation method of chiral anonace-lactone analogue as claimed in claim 8 is characterized in that the organic amine compound that described nitrogen-atoms contains lone-pair electron is 1.8-phenodiazine-dicyclo [5,4,0] undecane-7-alkene.
11. the preparation method of chiral anonace-lactone analogue as claimed in claim 8 is characterized in that described molecular formula is
The preparation of chirality alkynes comprise the steps at least one step: by molecular formula be
Compound with
Substitution reaction takes place under the sodium hydride condition; Then under the phase-transfer catalyst effect with chiral epichlorohydrin generation coupling; Then with the coupling under boron trifluoride diethyl etherate butyllithium condition of trimethyl silicane alkynes; Protect newborn hydroxyl with the chloromethyl methyl ether effect again, under the tetrabutyl ammonium fluoride effect, remove silica-based protection at last, X wherein, Y, R
1, R
2, described in n such as the claim 8, P=MOM or TBS, the MOM=methoxymethyl, the TBS=dimethyl tertiary butyl is silica-based.
12. the method for the preparation of chiral anonace-lactone compound as claimed in claim 11 is characterized in that making by following method:
(1) molecular formula is
Compound, molecular formula be
Compound and sodium hydride mol ratio be 1: 1-5: 1-5 0 ℃ of reaction 4-10 hour to room temperature to 100 ℃ and the polar solvent, obtains
(2) product of above-mentioned (1), epoxy chloropropane and phase-transfer catalyst mol ratio are 1: 1-5: 0.1-0.5, reacted 1-10 hour to room temperature and 50%NaOH solution at 0 ℃, and obtain
(3) product of above-mentioned (2), trimethyl silicane alkynes, n-Butyl Lithium and boron trifluoride diethyl etherate mol ratio are 1: 1-5: 1-5: 1-5, reaction is 1-4 hour in-78 ℃ and polar solvent, obtains
(4) product of above-mentioned (3), chloromethyl methyl ether, diisopropyl ethyl amine mol ratio 1: 5-10: 10-15 reacted 2-10 hour to room temperature and polar solvent at 0 ℃, obtained
(5) product and tetrabutyl ammonium fluoride mol ratio 1: 1-2 in above-mentioned (4) react 15-60min at 0 ℃ to room temperature and polar solvent, obtain
13. preparation method as claimed in claim 12 is characterized in that described phase-transfer catalyst is a 4-butyl ammonium hydrogen sulfate.
14. one kind as claim 1,2,3,4,5, the purposes of 6 or 7 described chiral anonace-lactone compounds in the preparation cancer therapy drug.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102070573A (en) * | 2011-02-28 | 2011-05-25 | 南京中医药大学 | Mono-tetrahydrofuran type sugar apple lactone compound with anti-tumor activity and application thereof |
| CN102153529A (en) * | 2011-02-28 | 2011-08-17 | 南京中医药大学 | Single-tetrahydrofuran-type annonaceous acetogenin compounds with antitumor activity and application thereof |
| CN106543117A (en) * | 2016-11-10 | 2017-03-29 | 南京中医药大学 | With double tetrahydrofuran type Annonaceousacetogenicompounds compounds and preparation method and application between anti-tumor activity |
| JP2021038173A (en) * | 2019-09-04 | 2021-03-11 | 信越化学工業株式会社 | Dialkoxyalkadienyne compound and process for preparing the same and process for preparing dienynal compound |
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2007
- 2007-07-06 CN CN2007100435200A patent/CN101108840B/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102070573A (en) * | 2011-02-28 | 2011-05-25 | 南京中医药大学 | Mono-tetrahydrofuran type sugar apple lactone compound with anti-tumor activity and application thereof |
| CN102153529A (en) * | 2011-02-28 | 2011-08-17 | 南京中医药大学 | Single-tetrahydrofuran-type annonaceous acetogenin compounds with antitumor activity and application thereof |
| CN102070573B (en) * | 2011-02-28 | 2012-06-20 | 南京中医药大学 | Mono-tetrahydrofuran type sugar apple lactone compound with anti-tumor activity and application thereof |
| CN102153529B (en) * | 2011-02-28 | 2012-07-18 | 南京中医药大学 | Single-tetrahydrofuran-type annonaceous acetogenin compounds with antitumor activity and application thereof |
| CN106543117A (en) * | 2016-11-10 | 2017-03-29 | 南京中医药大学 | With double tetrahydrofuran type Annonaceousacetogenicompounds compounds and preparation method and application between anti-tumor activity |
| JP2021038173A (en) * | 2019-09-04 | 2021-03-11 | 信越化学工業株式会社 | Dialkoxyalkadienyne compound and process for preparing the same and process for preparing dienynal compound |
| JP7197446B2 (en) | 2019-09-04 | 2022-12-27 | 信越化学工業株式会社 | Dialkoxyalkadienyne compound, method for producing same, and method for producing dieninal compound |
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