CN101982464B - Annonaceous acetogenin compound and synthesis method and application thereof - Google Patents
Annonaceous acetogenin compound and synthesis method and application thereof Download PDFInfo
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Abstract
The invention discloses an R or S-shaped or racemic annonaceous acetogenin compound with a structure of a formula 1. In the formula, R1 is alkane of C2 to C10, five to seven-element naphthenic hydrocarbon or five-element alpha or beta unsaturated lactonic ring, or substituted benzene ring or naphthalene ring compound; R2 is H or OH; x is 0 to 5, y is 1 to 6, n is 3 to 5, and m is 7 to 19; and when x is 0, y is 1 and n is 3, R1 is alkane of C2 to C10, five to seven-element naphthenic hydrocarbon or substituted benzene ring or naphthalene ring, and R2 is H or OH; or when x is 1 to 5 and y is 6,the R1 is five-element alpha or beta unsaturated lactonic ring, and R2 is hydroxy. The preparation raw materials for the compound are cheap and easily obtained; the preparation method is simple and suitable for industrialized production; and the compound has high anti-tumor activity, and can be used for preparing anti-tumor medicaments. Formula 1.
Description
Technical field
The present invention relates to a kind of lactone compound, relate to a kind of annonaceous acetogenins and synthetic method and application of simplification specifically.
Background technology
Current, cancer has become one of biggest threat of human health.According to the statistical figure of The World Health Organization (WHO), in recent years, the patient that cancer is died from the whole world every year was up on 7,000,000 people, and this numeral is very approaching with the number of dying from acute cardiovascular and cerebrovascular diseases.Cancer is about to replace first killer that cardiovascular and cerebrovascular diseases becomes human health.Present treatment method for cancer: as excision, radiotherapy, chemotherapy and gene therapy, all there is certain defective, big or treatment is not thorough as toxic side effect.Development along with organic isolation identification of modern times and chemical synthesising technology, numerous researchers all is devoted to from natural product to separate, identify to have excellent anti tumor promotion and natural compounds optionally, and attempt to obtain the lower compound of this natural content by the means of organic synthesis, and then be that lead compound carries out composition optimizes and obtains the more better compound of strong selectivity of activity with the natural compounds.
Annona lactone (Annonaceous acetogenin) is a class new type natural compound of separating from the annonaceae plant.Because they have stronger anti-tumor activity, attracted the researcher of lot of domestic and foreign to drop into wherein.(Mclaughlin，Paw?Paw?and?cancer：Annonaceous?Acetogenins?from?Discovery?toCommercial?Products.J.Nat.Prod.2008，71，1311-1321)。People such as Yao Zhujun, Jiang Sheng had once reported a class chiral anonace-lactone compounds (CN03141633.0), had following molecular formula:
X=C wherein
6-20Alkyl, n=1-3, m=0-5, k=1-10, j=0-10, this compounds is obtained through the deprotection of coupling, reduction and mineral acid by epoxy lactone fragment and the alkine compounds of chirality.This compounds has biological activity preferably to cancer cells, as the IC to liver cancer Bel7402
50Reach 0.42ug/ml.People such as Yao Zhu army has reported that again a class has the Annonaceousacetogenicompounds compounds (CN200710043519.8) of amido linkage link, has following structural formula subsequently:
Y=C wherein
6-20Alkyl.N=0-3,7-19, R
1, R
2, R
3, R
4, be H or C
1-C
10Alkyl, R
1, R
2, R
3, R
4It is identical or different group; This compounds has higher antitumour activity and selectivity, is Normocellular 100 times to the inhibition activity of cancer cells.But in these compounds, the left side side chain all is flexible stronger alkyl chain, does not obtain the compound of the dilactone five-membered cyclic structure of the left side side chain modifier of rigid structure and symmetry, and this can limit the research of later stage patent medicine.At this, we are by new synthetic method and approach, in the flexible molecule structure of Annona lactone, introduce the stronger ring texture of rigidity, with the antitumour activity of further raising compound and to cancer cells and Normocellular selectivity, prepare for finally developing the brand-new cancer therapy drug of a class.
Summary of the invention:
The problem to be solved in the present invention provides a kind of simplification Annona lactone analogue with rigid structure, and this analogue has optical activity and higher combined coefficient.
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.
Simplification Annona lactone analogue of the present invention is optical activity or the racemoid with following structural formula
In other words, this compound is:
Refer in particular to
Refer in particular to
Refer in particular to
R wherein
1Be C
2-C
10Alkane, five-seven-membered ring alkane or five yuan α, β unsaturated lactone ring or phenyl ring or the naphthalene nucleus that replaces, R
2Be H or OH, x=0-5, y=1-6, n=3-5, m=7-19; And when x=0, y=1, n=3, R at this moment
1Be C
2-C
10Alkane, phenyl ring and the naphthalene cycle compound of May Day seven-membered ring alkane or replacement, R
2Be H or OH; Or and when x=1-5, y=6, R at this moment
1Be five yuan α, β unsaturated lactone ring, R
2Be hydroxyl.
Simplification annonaceous acetogenins of the present invention can be with structural formula
Chirality alkynes and structural formula be
The unsaturated lactone epoxy compounds linked reaction takes place in the presence of n-Butyl Lithium and boron trifluoride diethyl etherate, reduce triple bond with p-toluene sulfonyl hydrazide then, under acid catalysis, remove protecting group again; Or by structural formula be
Alkene iodine compound and structural formula be
The unsaturated lactone terminal alkyne compound linked reaction takes place under the catalysis of triphenylphosphine palladium chloride and cuprous iodide, again with the two keys of p-toluene sulfonyl hydrazide reduction and triple bond.Can represent with following reaction formula:
Or with structural formula be
Alkene iodine compound and structure formula be
The unsaturated lactone terminal alkyne compound Sonogashira linked reaction takes place under the catalysis of triphenylphosphine palladium chloride and cuprous iodide, again with the two keys of p-toluene sulfonyl hydrazide reduction and triple bond.Available reaction formula is expressed as:
In the above-mentioned reaction formula, R wherein
1Be C
2-C
10Alkane, α, the β unsaturated lactone ring of five-seven-membered ring alkane or five yuan, and the phenyl ring or the naphthalene nucleus compounds that replace, x=0-5, y=1-6, n=3-5, m=7-19; And when x=0, y=1, n=3, R at this moment
1Be C
2-C
10Alkane, the phenyl ring of five-seven-membered ring alkane or replacement and naphthalene cycle compound; Or and when x=1-5, y=6, R at this moment
1Be five yuan α, β unsaturated lactone, MOM is methoxymethyl.
During preparation method of the present invention further is recommended as and comprises the steps one step or multistep:
Above-mentioned chirality alkynes, unsaturated epoxy lactone, the mol ratio of n-Butyl Lithium and boron trifluoride diethyl etherate is 1-3: 1: 1-3: 1-3 reacts 0.5-6h with room temperature to-78 ℃ in polar solvent.Obtain chipal compounds 3.
The mol ratio of chipal compounds 3, p-toluene sulfonyl hydrazide and sodium-acetate is 1: 100-200: 100-200, in polar solvent, room temperature obtains chipal compounds 4 to the reaction 1-10h down that refluxes.
At room temperature with polar solvent in, chipal compounds 4 reacts 2-6h under the catalysis of mineral acid, obtain final product 5.
The mol ratio of above-mentioned alkene iodine, unsaturated lactone Terminal Acetylenes, triphenylphosphine palladium chloride and cuprous iodide is 1: 2.2: 0.04-0.06: 0.08-0.12, under polar solvent and room temperature, react 3-10h, and obtain chiral precurser compound 8.
The mol ratio of chiral precurser compound 8, p-toluene sulfonyl hydrazide and sodium-acetate is 1: 100-200: 100-200, in polar solvent, room temperature obtains final product 9 to the reaction 1-10h down that refluxes.
Described polar solvent can be methylene dichloride, tetrahydrofuran (THF), glycol dimethyl ether, methyl alcohol or water etc.
Structural formula is
Chirality alkynes (when x=0, preparation method y=1) by structural formula is
Compound with
Coupling takes place under the effect of n-Butyl Lithium and boron trifluoride diethyl etherate; protect newly-generated hydroxyl with the chloromethyl methyl ether effect then; reduction triple bond and remove benzyl protecting group under the effect of Pd/C and hydrogen again; and then under the effect of phase-transfer catalyst with chiral epichlorohydrin generation coupling; under the effect of trimethylsilyl acetylene, n-Butyl Lithium and boron trifluoride diethyl etherate coupling takes place again; protect newly-generated hydroxyl with the chloromethyl methyl ether effect then; last silica-based protecting group, the wherein R of under the effect of tetrabutyl fluoride amine, removing
1, x, y as previously mentioned, MOM is methoxymethyl, Bn is benzyl, reaction process can be represented with following reaction formula:
Chirality alkynes synthetic can further describe for: the mol ratio of compound 10,11, n-Butyl Lithium, boron trifluoride diethyl etherate is 1-3: 1: 1-3: 1-3 in polar solvent and room temperature to-78 ℃ of reaction 0.5-6h.Obtain chipal compounds 12; The mol ratio of compound 12, chloromethyl methyl ether, diisopropyl ethyl amine is 1: 5-10: 6-12 0 ℃ to room temperature and the polar solvent reaction 12-16h obtain compound 13; Compound 13 obtains 14 with hydrogen balloon reduction 12-16h in polar solvent under the catalysis of 10% Pd/C of catalytic amount and a small amount of Glacial acetic acid; The mol ratio of compound 14, epoxy chloropropane, phase-transfer catalyst is 1: 1.2: 0.05-0.1, and reaction 10-12h obtains 15 in the sodium hydroxide solution of room temperature and 50%; The mol ratio of compound 15, trimethylsilyl acetylene, n-Butyl Lithium and boron trifluoride diethyl etherate is 1: 1-3: 1-3: 1-3, and reaction 3-5h obtains 16 in-78 ℃ polar solvent; Compound 16, chloromethyl methyl ether, diisopropyl ethyl amine mol ratio are 1: 5-10: 6-12,0 ℃ to room temperature and the polar solvent reaction 12-16h obtain 17; Compound 17 is 1 with the mol ratio of tetrabutyl fluoride amine: 1-2,0 ℃ to room temperature and the polar solvent reaction 1-2h obtain compound 1.
Structural formula is
The preparation method of alkene iodine compound (x=1-5) by structural formula be
Compound with
Under the effect of sodium hydride and phase-transfer catalyst substitution reaction takes place, under the effect of tributyl tin hydrogen, Diisopropyl azodicarboxylate and iodine addition takes place then, wherein x, y are as previously mentioned.Reaction process can be represented with following reaction formula:
Alkene iodine compound synthetic can further describe for: compound 16,19, sodium hydride, phase-transfer catalyst mol ratio be 1: 2-3: 2-3: 0.05-0.1,0 ℃ to room temperature and the polar solvent reaction 10-12h obtain 20; Compound 20, Bu
3The mol ratio of SnH, AIBN and iodine is 1: 2-3: 0.1-0.3: 2-4 obtains compound 6 130 ℃ to 0 ℃ reactions.
Compound of the present invention has higher anti-cancer activity and selectivity, can be used for developing cancer therapy drug, and raw material is cheap and easy to get, and the preparation method is simple and easy, is a kind of method that is suitable for developing into suitability for industrialized production.
Embodiment
To help to understand the present invention by following example, but not limit content of the present invention.
The synthetic of target compound is example with following reaction and compound.
Embodiment 1
Get 0.07moL compound 20 in the single port bottle, add the 1.6g benzyltriethylammoinium chloride, 0.084moL compound 21 stirs 3min under the room temperature, the sodium hydroxide solution 55mL of slow adding 50%, vigorous stirring reaction 3.5h under the room temperature adds the 40mL shrend reaction of going out, the extracted with diethyl ether of reaction solution usefulness 40mL * 3, merge organic phase and use the washing of saturated ammonium chloride and sodium chloride solution successively, anhydrous sodium sulfate drying concentrates and column chromatography obtains colourless liquid 22 (11.7g, 80%).
[α]
25 D：6.1(c?2.6，CHCl
3)。
1H?NMR(400MHz，CDCl
3)：δ7.35-7.27(m，5H)，4.58(s，2H)，3.80(dd，J＝11.6，3.0Hz，1H)，3.75-3.63(m，4H)，3.45(dd，J＝11.6，5.8Hz，1H)，3.18-3.16(m，1H)，2.80-2.78(m，1H)，2.62(dd，J＝5.0，2.7Hz，1H)ppm；HRMS(ESI)：C
12H
16O
3?calculated[M+H]
+?209.1172，found?209.1175，[M+Na]
+231.0992，found?231.0988.
Embodiment 2
Under-78 ℃ and argon shield, in the 20mL anhydrous tetrahydrofuran solution of 13mmol compound 23, slowly drip 13mmol n-BuLi (2.5M in hexane), behind the reaction 45min, slowly add 13mmolBF
3Et
2O; behind the reaction 30min; the 5mL anhydrous tetrahydrofuran solution that slowly adds 6.5mmol compound 22; continue stirring reaction 3h; saturated ammonium chloride solution cancellation reaction with 5mL; decompression spins off tetrahydrofuran (THF); extracted with diethyl ether with 15mL * 3; merge organic phase and use the washing of saturated sodium bicarbonate and saturated nacl aqueous solution successively; anhydrous sodium sulfate drying; concentrate the intermediate that obtains and be dissolved in the anhydrous methylene chloride of 20mL, add the diisopropyl ethyl amine of 52mmol under the nitrogen protection, be cooled to the MOMCl that slowly adds 32.5mmol after 0 ℃; stirring reaction 20h under the room temperature; saturated ammonium chloride cancellation reaction with 5mL spins off methylene dichloride, with the ethyl acetate extraction of 15mL * 3; merge organic phase and use the washing of saturated ammonium chloride and sodium-chlor successively; anhydrous sodium sulfate drying concentrates and column chromatography obtains light yellow liquid compound 24 (1.51g, 76%).
[α]
25 D＝11.9(C＝0.55，CHCl
3)；
1H?NMR(400MHz，CDCl
3)：δ7.41-7.26(m，10H)，4.80(s，2H)，4.58(s，2H)，4.01-3.99(m，1H)，3.74-3.65(m，6H)，3.43(s，3H)，2.76-2.72(m，2H)ppm；
13C?NMR(100MHz，CDCl
3)：δ138.4，131.6，128.3，128.3，127.7，127.6，127.5，123.8，96.1，86.4，82.1，74.8，73.3，72.9，71.0，69.6，55.5，22.9ppm；MS(ESI，m/z)：355[M+1]
+；
Embodiment 3
The intermediate 24 of 4.26mmol is dissolved in the dehydrated alcohol of 20ml, the Pd/C that adds 0.302g (20%m) 10%, 2.0mL Glacial acetic acid, under the hydrogen balloon effect, react 16h, use diatomite filtration, washing with alcohol concentrates and obtains intermediate, add 21 of 5.11mmol under the room temperature, 0.18g benzyltriethylammoinium chloride slowly adds the NaOH aqueous solution of 3.5mL 50%, behind the stirring at room reaction 22h, water dilution with 3mL, the extracted with diethyl ether of 15mL * 3 merges organic phase and washs anhydrous sodium sulfate drying with saturated ammonium chloride and sodium-chlor successively, concentrating also, column chromatography obtains light yellow liquid compound 25 (0.99g, 72%).
[α]
25 D＝-1.8(C＝1.11，CHCl
3)；
1H?NMR(400MHz，CDCl
3)：δ7.28-7.15(m，5H)，4.76(d，J＝6.8Hz，1H)，4.64(d，J＝6.8Hz，1H)，3.77(dd，J＝11.7，2.8Hz，1H)，3.74-3.38(m，8H)，3.36(s，3H)，3.14-3.12(m，1H)，2.77(t，J＝4.4Hz，1H)，2.63(t，J＝7.4Hz，2H)，2.60-2.57(m，1H)，1.77-1.55(m，4H)ppm；
13C?NMR(100MHz，CDCl
3)：δ142.3，128.4，128.3，125.7，96.1，76.1，74.1，71.9，70.8，55.4，50.8，44.1，35.9，31.7，27.1ppm；
MS(ESI，m/z)：325[M+1]
+；342[M+18]
+，347[M+23]
+；
HRMS (ESI): C
18H
28O
5Calculated value [M+Na]
+347.1829 found 347.1829;
Embodiment 4
Under-78 ℃ and argon shield, in the 12mL anhydrous tetrahydrofuran solution of 6mmol trimethylsilyl acetylene, slowly drip 6mmol n-BuLi (2.5M in hexane), behind the reaction 45min, slowly add 6mmolBF
3Et
2O; behind the reaction 30min; the 4mL anhydrous tetrahydrofuran solution that slowly adds 3mmol compound 25; continue stirring reaction 3h; saturated ammonium chloride solution cancellation reaction with 5mL; decompression spins off tetrahydrofuran (THF); extracted with diethyl ether with 15mL * 3; merge organic interdependent time and use saturated sodium bicarbonate and sodium chloride solution washing; anhydrous sodium sulfate drying; concentrating the intermediate that obtains is dissolved in the anhydrous methylene chloride of 12mL; the diisopropyl ethyl amine that adds 24mmol under the nitrogen protection; be cooled to the MOMCl that slowly adds 15mmol after 0 ℃; stirring reaction 20h under the room temperature; saturated ammonium chloride cancellation reaction with 5mL; spin off methylene dichloride, with the ethyl acetate extraction of 15mL * 3, merge organic phase and use the washing of saturated ammonium chloride and sodium-chlor successively; anhydrous sodium sulfate drying; concentrate and to obtain in the tetrahydrofuran solution that intermediate is dissolved in 15mL ,-10 ℃ of TBAF (1.0M in THF) that slowly add 3.6mmol add the 3ml saturated ammonium chloride solution behind the stirring reaction 1h; spin off tetrahydrofuran (THF); with the extracted with diethyl ether of 10mL * 3, the merging organic phase is full uses and the sodium chloride solution washing anhydrous sodium sulfate drying; concentrating also, column chromatography obtains light yellow liquid compound 26 (0.84g, 70%).
[α]
25 D＝3.2(C＝1.20，CHCl
3)；
1H?NMR(400MHz，CDCl
3)：δ7.30-7.16(m，5H)，4.76(d，J＝6.8Hz，1H)，4.74(s，2H)，4.65(d，J＝6.8Hz，1H)，3.91-3.85(m，1H)，3.76-3.71(m，1H)，3.66-3.47(m，8H)，3.40(s，3H)，3.37(s，3H)，2.64(t，J＝3.5Hz，2H)，2.44-2.58(m，2H)，2.00(t，J＝2.0Hz，1H)，1.81-1.56(m，4H)ppm；
13C?NMR(100MHz，CDCl
3)：δ142.3，128.4，128.2，125.7，96.1，80.7，76.2，74.4，74.1，72.5，70.9，70.7，69.9，55.5，55.4，35.9，31.7，27.1，21.9ppm；MS(ESI，m/z)：417[M+23]
+；
HRMS (ESI): C
22H
34O
6Calculated value [M+Na]
+417.2248 found 417.2253;
Embodiment 5
Under-78 ℃ and argon shield, in the 6mL anhydrous tetrahydrofuran solution of 1-2mmol compound 26, slowly drip 1-2mmol n-BuLi (1.6M in hexane), behind the reaction 45min, slowly add 1-2mmolBF
3Et
2O, behind the reaction 30min, slowly add the 3mL anhydrous tetrahydrofuran solution of 1mmol compound 27, continue stirring reaction 3h, with the saturated ammonium chloride solution cancellation reaction of 5mL, decompression spins off tetrahydrofuran (THF), with the extracted with diethyl ether of 10mL * 3, merge organic interdependent time and use saturated sodium bicarbonate and saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, concentrating also, column chromatography obtains weak yellow liquid compound 28 (0.20g, 63%).
[α]
25 D＝12.9(C＝0.36，CHCl
3)；
1H?NMR(400MHz，CDCl
3)：δ7.29-7.17(m，5H)，6.98(d，J＝1.3Hz，1H)，4.99(dq，J＝6.8，1.6Hz，1H)，4.76(d，J＝6.8Hz，1H)，4.73(s，2H)，4.64(d，J＝6.8Hz，1H)，3.86-3.83(m，1H)，3.84-3.47(m，10H)，3.39(s，3H)，3.37(s，3H)，2.63(t，J＝7.5Hz，2H)，2.50-2.30(m，4H)，，2.22(t，J＝7.3Hz，2H)，1.77-1.32(m，16H)，1.40(d，J＝6.8Hz，3H)ppm；
13C?NMR(100MHz，CDCl
3)：δ173.6，148.7，142.3，134.3，128.3，128.2，125.7，96.1，96.0，79.2，78.2，76.7，76.2，74.9，74.1，72.8，70.9，70.7，70.1，55.4，36.3，35.9，31.7，29.4，29.2，29.0，27.9，27.4，27.1，25.6，25.1，22.2，19.2ppm；
MS(ESI，m/z)：655[M+23]
+；
HRMS (ESI): C
36H
56O
9Calculated value [M+Na]
+655.3817 found 655.3817;
Embodiment 6
The p-toluene sulfonyl hydrazide of 0.32mmol compound 28 and 50-60mmol is dissolved in the glycol dimethyl ether of 20mL, be heated to backflow, in 6h, slowly be added drop-wise to the 20mL aqueous solution of the sodium-acetate of 80-100mmol in the above-mentioned reaction solution, continue stirring reaction 8h, the reaction solution cool to room temperature, the cold water that adds 5mL, ethyl acetate extraction with 25mL * 3, merge organic phase and use saturated ammonium chloride and the sodium-chlor washing, anhydrous sodium sulfate drying, concentrate and obtain thick product, it is dissolved in the tetrahydrofuran (THF) and methyl alcohol (volume ratio is 1: 2) solution of 2.4mL, slowly drips the dilute hydrochloric acid of 1.5mL 6N under the room temperature, behind the continuation stirring reaction 1.5h, add the saturated sodium bicarbonate solution neutralization, the ethyl acetate extraction of 10mL * 3 merges organic phase and washs anhydrous sodium sulfate drying with saturated sodium bicarbonate and sodium-chlor, concentrating also, column chromatography obtains thick liquid compound 29 (94.7mg, 54%).
[α]
25 D＝6.6(C＝0.44，CHCl
3)；
1H?NMR(400MHz，CDCl
3)：δ7.29-7.15(m，5H)，6.99(d，J＝1.4Hz，1H)，4.99(dq，J＝7.5，1.6Hz，1H)，3.80(m，2H)，3.70-3.59(m，5H)，3.57(brs，1H，OH)，3.52(d，J＝2.8Hz，1H)，3.51(d，J＝2.8Hz，1H)，3.31(dq，J＝9.2，2.4Hz，2H)，2.96(brs，2H，OH)，2.63(t，J＝7.7Hz，2H)，2.26(dt，J＝11.2，7.3Hz，2H)，1.84-1.25(m，24H)，1.40(d，J＝6.8Hz，3H)ppm；
13C?NMR(125MHz，CDCl
3)：δ173.9，148.9，142.2，134.2，128.4，128.2，125.7，77.4，75.8，71.7，71.6，70.4，70.1，70.0，37.4，37.3，35.8，32.9，32.5，29.5，29.2，29.1，27.3，25.6，25.5，25.4，25.1，19.2ppm；
MS(EI，m/z)：549[M+1]
+，571[M+23]
+；
HRMS (ESI): C
32H
52O
7Calculated value [M+H]
+549.3786 found 549.3784;
The employing structural formula is
Alkynes, operation then obtains respectively with 1,2,3,4 and 5
Compound 30
Compound 33
Compound 30
[α]
25 D＝13.4(C＝1.1，CHCl
3)；
1H?NMR(400MHz，CDCl
3)：δ6.99(d，J＝1.2Hz，1H)，5.00(dq，J＝6.8，1.5Hz，1H)，3.79(m，2H)，3.71-3.62(m，5H)，3.58(brs，1H，OH)，3.55(d，J＝2.7Hz，1H)，3.52(d，J＝2.7Hz，1H)，3.32(dq，J＝9.5，2.8Hz，2H)，2.78(brs，2H，OH)，2.26(t，J＝7.6Hz，2H)，1.56-1.24(m，30H)，1.40(d，J＝6.8Hz，3H)，0.88(t，J＝6.8Hz，3H)ppm；
13C?NMR(100MHz，CDCl
3)：δ173.7，148.7，134.4，77.1，76.6，75.9，75.8，71.8，71.7，70.6，70.3，70.3，37.5，37.4，33.1，33.0，31.7，29.5，29.3，29.2，29.1，27.4，25.6，25.5，25.4，25.1，22.5，19.2，13.9ppm；
MS(EI，m/z)：515[M+1]
+；537[M+23]
+；
Compound 31
[α]
25 D＝24.7(C＝0.18，CHCl
3)；
1H?NMR(400MHz，CDCl
3)：δ6.98(d，J＝1.5Hz，1H)，4.98(dq，J＝6.8，1.7Hz，1H)，3.78(m，2H)，3.77-3.60(m，5H)，3.56(brs，1H，OH)，3.53(d，J＝2.6Hz，1H)，3.51(d，J＝2.6Hz，1H)，3.30(dq，J＝9.8，3.3Hz，2H)，2.94(brs，2H，OH)，2.25(dt，J＝13.9，6.6Hz，2H)，1.55-1.24(m，38H)，1.39(d，J＝6.8Hz，3H)，0.87(t，J＝6.7Hz，3H)ppm；
13C?NMR(125MHz，CDCl
3)：δ173.9，148.9，134.2，77.4，75.9，75.8，71.7，70.5，70.4，70.3，70.2，37.4，37.3，33.0，32.8，31.9，29.6，29.5，29.5，29.3，29.2，29.1，27.3，25.6，25.5，25.4，25.1，22.6，19.2，14.1ppm；
MS(EI，m/z)：571[M+1]
+；593[M+23]
+；
Compound 32
[α]
25 D＝18.9(C＝0.27，CHCl
3)；
1H?NMR(400MHz，CDCl
3)：δ6.98(d，J＝1.4Hz，1H)，4.98(dq，J＝6.8，1.6Hz，1H)，3.78(m，2H)，3.68-3.60(m，5H)，3.56(brs，1H，OH)，3.52(d，J＝2.4Hz，1H)，3.50(d，J＝2.4Hz，1H)，3.31(dq，J＝8.9，3.6Hz，2H)，2.99(brs，2H，OH)，2.24(dt，J＝7.6，7.2Hz，2H)，1.67-1.09(m，37H)，1.39(d，J＝6.5Hz，3H)，0.87-0.79(m，3H)ppm；
13C?NMR(125MHz，CDCl
3)：δ173.9，148.9，134.2，77.4，75.9，75.8，71.7，70.5，70.4，70.2，70.0，37.6，37.4，37.4，37.3，33.4，33.0，32.8，31.6，29.6，29.5，29.2，29.1，27.3，26.9，26.7，26.4，25.8，25.6，25.5，25.4，25.1，19.2ppm；
MS(EI，m/z)：569[M+1]
+；591[M+23]
+；
Compound 33
[α]
25 D＝7.0(C＝0.17，CHCl
3)；
1H?NMR(400MHz，CDCl
3)：δ7.34(brs，1H，OH)，6.98(d，J＝1.5Hz，1H)，6.67-6.63(m，3H)，4.98(dq，J＝6.8，1.6Hz，1H)，3.78(m，2H)，3.60-3.30(m，12H)，2.55(t，J＝7.5Hz，2H)，2.24(t，J＝7.9Hz，2H)，1.77-1.23(m，24H)，1.39(d，J＝6.8Hz，3H)ppm；
13C?NMR(100MHz，CDCl
3)：δ173.9，156.3，148.9，143.9，134.3，129.3，120.3，115.4，112.9，77.4，75.7，71.8，70.5，70.4，70.2，37.4，37.2，35.5，32.9，32.5，29.5，29.2，29.0，27.4，27.2，26.8，25.5，25.4，25.1，19.1ppm；
MS(ESI，m/z)：565[M+1]
+；587[M+23]
+；
Compound 34
[α]
25 D＝11.3(C＝0.90，CHCl
3)；
1H?NMR(400MHz，CDCl
3)：δ7.08(d，J＝4.6Hz，2H)，6.98(d，J＝1.5Hz，1H)，6.80(dd，J＝6.6，2.0Hz，2H)，4.98(dq，J＝6.8，1.6Hz，1H)，3.81-3.78(m，2H)，3.77(s，3H)，3.69-3.48(m，5H)，3.56(brs，1H，OH)，3.33-3.28(m，2H)，2.97(brs，2H，OH)，2.56(t，J＝7.6Hz，2H，)，2.24(dt，J＝7.7，1.5Hz，2H)，1.64-1.24(m，24H)，1.39(d，J＝6.8Hz，3H)ppm；
13C?NMR(100MHz，CDCl
3)：δ173.7，157.8，148.7，134.4，129.2，113.8，75.8，71.8，71.7，70.6，70.2，55.2，37.5，37.3，34.9，33.0，32.6，29.5，29.2，29.0，27.4，25.6，25.5，25.1，19.1ppm；
MS(ESI，m/z)：579[M+1]
+；601[M+23]
+；
Compound 35
[α]
25 D＝8.6(C＝0.29，CHCl
3)；
1H?NMR(400MHz，CDCl
3)：δ7.58(dd，J＝7.1，1.7Hz，2H)，7.51(d，J＝8.2Hz，2H)，7.42(dd，J＝7.8，7.6Hz，2H)，7.34-7.32(m，1H)，7.25(dd，J＝8.2，1.6Hz，2H)，6.97(d，J＝1.5Hz，1H，)，4.98(dq，J＝6.8，1.7Hz，1H)，3.82(m，2H)，3.70-3.61(m，5H)，3.57(brs，1H，OH)，3.54(d，J＝2.6Hz，1H)，3.51(d，J＝2.6Hz，1H)，3.33(dq，J＝8.8，2.6Hz，2H)，2.97(brs，2H，OH)，2.68(t，J＝7.6Hz，2H)，2.25(dt，J＝13.8，1.2Hz，2H)，1.55-1.26(m，24H)，1.39(d，J＝6.8Hz，3H)ppm；
13C?NMR(100MHz，CDCl
3)：δ173.6，148.7，141.4，141.2，138.8，134.4，128.9，128.6，127.0，126.9，75.8，71.8，71.7，70.6，70.2，37.5，37.3，35.4，33.0，32.7，29.5，29.2，29.0，27.4，27.2，25.6，25.5，25.5，25.1，19.1ppm；
MS(ESI，m/z)：625[M+1]
+；647[M+23]
+；
Compound 36
[α]
25 D＝4.2(C＝0.33，CHCl
3)
1H?NMR(400MHz，CDCl
3)：δ7.67-7.64(d，J＝7.1，1.7Hz，2H)，7.53(s，1H)，7.28(dd，J＝8.4，1.6Hz，1H)，7.12-7.10(m，2H)，6.97(d，J＝1.4Hz，1H)，4.98(dq，J＝6.8，1.3Hz，1H)，3.90(s，3H)，3.80(m，2H)，3.68-3.59(m，5H)，3.57(brs，1H，OH)，3.52(d，J＝2.7Hz，1H)，3.50(d，J＝2.7Hz，1H)，3.31(dt，J＝9.0Hz，2H)，2.95(brs，2H，OH)，2.76(t，J＝7.6Hz，2H)，2.25(dt，J＝7.3，7.2Hz，2H)，1.78-1.25(m，24H)，1.39(d，J＝6.8Hz，3H)ppm；
13C?NMR(100MHz，CDCl
3)：δ173.6，157.2，148.7，137.43，134.4，133.0，129.2，128.8，127.8，126.7，126.2，118.5，105.9，77.2，75.8，71.8，71.7，70.6，70.2，55.3，37.5，37.3，35.8，33.0，32.6，29.5，29.2，29.0，27.4，27.2，25.6，25.5，25.1，19.1ppm；
MS(ESI，m/z)：629[M+1]
+；651[M+23]
+；
Embodiment 7
Compound 37 with 1.64mmol; 3.95mmol tributyl tin hydrogen (TBTH) and the Diisopropyl azodicarboxylate (AIBN) of 0.33mmol under nitrogen protection, be heated to 130 ℃ of reaction 3h; be cooled to the anhydrous diethyl ether that adds 2mL after 0 ℃; and then in 0 ℃ of 6mL anhydrous ether solution that slowly drips 3.6mmol iodine down; continue stirring reaction 3h; add the Potassium monofluoride of 3.6mmol and the water stirring reaction 5min of 1mL; use diatomite filtration; filtrate is washed with saturated sodium thiosulfate; anhydrous sodium sulfate drying; concentrating also, column chromatography obtains yellow liquid compound 38 (0.5479g, 76%).
1H?NMR(400MHz，CDCl
3)：δ6.66-6.59(m，2H)，6.43-6.37(m，2H)，4.13-3.95(m，4H)，3.64-3.60(m，8H)ppm；
MS(ESI，m/z)：438([M+1]
+，460[M+23]
+；
Embodiment 8
0.14mmol compound 38,0.028mmol triphenylphosphine palladium chloride and 0.028mmol cuprous iodide are dissolved in the 2mL anhydrous triethylamine; stirring at room reaction 1h under the nitrogen protection; the 1mmL anhydrous triethylamine solution that adds 0.30mmol compound 39 then; continue stirring reaction 2h, with 1mL saturated ammonium chloride solution cancellation reaction, 10mL * 3 extracted with diethyl ether; the saturated sodium-chloride washing; anhydrous sodium sulfate drying concentrates and column chromatography obtains light yellow liquid compound 40 (70.4mg, 72%).
1H?NMR(400MHz，CDCl
3)：δ6.98(s，2H)，6.14-6.08(m，2H)，5.74-5.47(m，2H)，4.99(dq，J＝13.0，6.3Hz，2H)，4.05(d，J＝5.4Hz，4H)，3.76-3.72(m，2H)，3.65-3.59(m，8H)，2.55-2.39(m，4H)，2.25(t，J＝7.3Hz，4H)，1.64-1.25(m，24H)，1.39(d，J＝6.8Hz，6H)ppm；
13C?NMR(100MHz，CDCl
3)：δ173.8，148.8，138.8，134.3，111.9，86.9，80.9，70.9，70.7，70.1，69.7，36.3，29.4，29.2，29.1，28.4，27.4，25.5，25.2，19.2ppm；
MS(ESI，m/z)：711[M+1]
+，733[M+23]
+；
Embodiment 9
The p-toluene sulfonyl hydrazide of 0.036mmol compound 40 and 2.16-2.88mmol is dissolved in the glycol dimethyl ether of 3mL, be heated to backflow, in 3h, slowly be added drop-wise to the 3mL aqueous solution of the sodium-acetate of 2.88-3.60mmol in the above-mentioned reaction solution, continue stirring reaction 8h, the reaction solution cool to room temperature, the cold water that adds 1mL, ethyl acetate extraction with 6mL * 3, merge organic phase and use saturated ammonium chloride and the sodium-chlor washing, anhydrous sodium sulfate drying, concentrating also, column chromatography obtains white waxy solid compound 41 (20.0mg, 77%).
[α]
25 D＝6.4(C＝0.16，CHCl
3)；
1H?NMR(400MHz，CDCl
3)：δ6.98(d，J＝2.8Hz，2H)，4.98(dq，J＝6.8，1.7Hz，2H)，3.64-3.55(m，12H)，3.44(t，J＝6.7Hz，4H)，2.25(t，J＝7.2Hz，4H)，1.59-1.30(m，44H)，1.39(d，J＝6.8Hz，6H)ppm；
13C?NMR(125MHz，CDCl
3)：δ173.9，148.9，134.2，77.4，71.8，71.4，70.6，70.0，37.4，29.5，29.2，29.1，27.3，26.0，25.6，25.5，25.1，19.2ppm；
MS(ESI，m/z)：723[M+1]
+，745[M+23]
+；
The employing structural formula is
The alkene iodine compound, operation then obtains respectively with 6,7 and 8
Compound 43
Compound 45
Compound 42
[α]
25 D＝8.2(C＝0.15，CHCl
3)；
1H?NMR(400MHz，CDCl
3)：δ6.98(d，J＝1.1Hz，2H)，4.99(dq，J＝12.8，5.9Hz?2H)，4.26-4.20(m，2H)，3.66-3.42(m，10H)，2.26(t，J＝7.5Hz，4H)，1.49-1.28(m，44H)，1.40(d，J＝6.8Hz，6H)ppm；
13C?NMR(100MHz，CDCl
3)：δ173.9，148.9，134.3，71.9，71.5，70.1，68.2，37.5，31.9，29.7，29.4，29.1，27.4，26.1，25.6，25.2，22.7，19.2ppm；
MS(ESI，m/z)：679[M+1]
+，701[M+23]
+；
Compound 43
[α]
25 D＝12.7(C＝0.16，CHCl
3)；
1H?NMR(400MHz，CDCl
3)：δ6.98(d，J＝1.1Hz，2H)，4.99(dq，J＝6.8，1.4Hz，2H)，3.65-3.56(m，16H)，3.44(t，J＝6.8Hz，4H)，2.26(t，J＝7.3Hz，4H)，1.59-1.25(m，44H)，1.40(d，J＝6.8Hz，6H)ppm；
13C?NMR(100MHz，CDCl
3)：δ173.8，148.8，134.3，77.2，71.9，71.4，70.6，70.1，37.5，29.6，29.5，29.3，29.1，27.4，26.1，25.6，25.2，19.2ppm；
MS(ESI，m/z)：789[M+23]
+；
Compound 44
[α]
25 D＝14.4(C＝0.14，CHCl
3)；
1H?NMR(400MHz，CDCl
3)：δ6.98(d，J＝1.5Hz，2H)，4.98(dq，J＝6.8，1.7Hz，2H)，3.65-3.56(m，20H)，3.44(t，J＝6.8Hz，4H)，2.26(t，J＝7.4Hz，4H)，1.42-1.25(m，44H)，1.40(d，J＝6.8Hz，6H)ppm；
13C?NMR(125MHz，CDCl
3)：δ173.9，148.9，134.3，77.4，71.9，71.4，70.6，70.5，70.0，37.4，29.5，29.2，29.1，27.4，26.0，25.6，25.1，19.2ppm；
MS(ESI，m/z)：811?[M+1]
+；833[M+23]
+；
Compound 45
[α]
25 D＝9.5(C＝0.19，CHCl
3)；
1H?NMR(400MHz，CDCl
3)：δ6.98(d，J＝1.4Hz，2H)，4.99(dq，J＝6.8，1.7Hz，2H)，3.65-3.56(m，24H)，3.44(t，J＝6.7Hz，4H)，2.26(t，J＝7.3Hz，4H)，1.59-1.25(m，44H)，1.40(d，J＝6.8Hz，6H)ppm；
13C?NMR(125MHz，CDCl
3)：δ173.9，148.9，134.3，77.4，75.6，73.7，71.9，71.4，70.6，70.0，37.4，29.7，29.5，29.2，29.1，27.4，26.0，25.6，25.1，19.2ppm；
MS(ESI，m/z)：855[M+1]
+；877[M+23]
+；
Embodiment 10 biological activity tests
Detect principle according to cell inhibitory effect, by mtt assay prepared novel Annona lactone analogue is carried out cytoactive and suppress experiment, concrete experimental procedure is as follows:
(1) collect the logarithmic phase cell, adjust concentration of cell suspension, every hole adds the 100ul cell suspension in 96 orifice plates.Every porocyte quantity is about 7000, at 5%CO
2, 37 ℃ of overnight incubation are adherent fully to cell.
(2) the drug level gradient is set, each concentration gradient arranges 3 multiple holes, with drug dilution in the corresponding substratum to required final concentration, original substratum in sucking-off 96 orifice plates adds the substratum 100ul that contains required final concentration medicine for preparing, at 5%CO
2, hatch for 37 ℃.And blank group (only contain the 100ul substratum, do not contain cell, each hole of subsequent disposal and other is identical) and control group (containing cell and substratum) be set simultaneously.
(3) every hole adds 10ulMTT solution (5mg/ml) during drug treating to 44 hour, continues to cultivate 4h (drug treating cell totally 48 hours).
(4) blot nutrient solution in the clear opening (occurring suspending as cell, then the centrifugal 5min of first 2500rpm sucking-off substratum again).Every hole adds the 150ul dimethyl sulfoxide (DMSO), vibrates to crystallisate fully to dissolve.Detect the light absorption value in each hole, OD490nm place in microplate reader.
(5) calculate inhibiting rate: inhibiting rate=1-(dosing group OD value-blank group OD value)/(control group OD value-blank group OD value)=(control group OD value-dosing group OD value)/(OD value of control group OD value-blank group)
(6) by above-mentioned experimental procedure triplicate, draw the mean value of three inhibiting rates, utilize IC
50Counter is calculated the IC of medicine
50Value.
Compound 29,30,31,32,33,34,35,36 is measured the medium lethal dose of HCT116, HT29, A549, MCF7, SGC7901 and Bel7402 cancerous cell line according to mtt assay and is listed in the table below in 1:
Table 1: the IC of the different carcinoma cell of compound 29-36
50Value
Compound 41,42,43,44 and 45 is measured the medium lethal dose of HCT116, HT29, MCF7 and SGC7901 cancerous cell line according to mtt assay and is listed in the table below in 2:
Table 2: the IC of the different carcinoma cell of compound 41-45
50Value
The present invention has developed a kind of method of the annonaceous acetogenins of synthesizing new fast and effectively, and raw material is cheap and easy to get, and the preparation method is simple and easy, is adapted to suitability for industrialized production.Freshly prepd compound shows to have higher anti-tumor activity through biological activity test, especially when in molecule, introducing biphenyl group, and the IC of the 35 pairs of S6C7901 cancer cells of compound that obtain
50Value can reach 20nM, and this shows suitably introduces hydrophobic nature and the stronger group of rigidity in the sweetsop compound molecule, can improve the anti-tumor activity of this compounds effectively.
Claims (8)
1. one kind has the R of following structure or the annonaceous acetogenins of S configuration or racemization,
R
2Be H or OH, m=7-19.
2. one kind has the R of following structure or the annonaceous acetogenins of S configuration or racemization,
R wherein
2Be H or OH, x=0-5, m=7-19.
3. the preparation method of an annonaceous acetogenins as claimed in claim 1 or 2 is characterized in that comprising the steps: by structural formula being
Chirality alkine compounds and structural formula be
The unsaturated lactone epoxy compounds linked reaction takes place in the presence of n-Butyl Lithium and boron trifluoride diethyl etherate, reduce triple bond with p-toluene sulfonyl hydrazide then, under acid catalysis, remove blocking group again; Or by structural formula be
Alkene iodine compound and structural formula be
The unsaturated lactone terminal alkyne compound linked reaction takes place under the catalysis of triphenylphosphine palladium chloride and cuprous iodide, again with the two keys of p-toluene sulfonyl hydrazide reduction and triple bond; R wherein
1Be five yuan α, β unsaturated lactone ring, or the phenyl ring or the naphthalene cycle compound that replace, x=0-5, y=1-6, m=7-19; And when x=0, y=1, R at this moment
1Be phenyl ring and the naphthalene nucleus that replaces, R
2Be H or OH; Or and when x=1-5, y=6, R at this moment
1Be five yuan α, β unsaturated lactone ring;
MOM is methoxymethyl.
4. preparation method as claimed in claim 3 is characterized in that:
(1) mol ratio of described chirality alkynes, unsaturated lactone epoxy, n-Butyl Lithium, boron trifluoride diethyl etherate is 1-3:1:
1-3:1-3 arrives-78 ℃ of reaction 0.5-6h with room temperature in polar solvent, obtain
(2) mol ratio of the product of above-mentioned (1), p-toluene sulfonyl hydrazide and sodium-acetate is 1:100-200:100-200, and in polar solvent, room temperature obtains to the reaction 1-10h down that refluxes
(3) at room temperature with polar solvent in, the product of above-mentioned (2) reacts 2-6h under the catalysis of mineral acid, obtain
(4) mol ratio of described alkene iodine, unsaturated lactone Terminal Acetylenes, triphenylphosphine palladium chloride and cuprous iodide is 1:2.2:
0.04-0.06:0.08-0.12, under polar solvent and room temperature, react 3-10h, obtain
(5) mol ratio of the product of above-mentioned (4), p-toluene sulfonyl hydrazide and sodium-acetate is 1:100-200:100-200, and in polar solvent, room temperature obtains to the reaction 1-10h down that refluxes
In the above-mentioned molecular formula, R
1, x, y, m be as described in the claim 3, MOM is methoxymethyl.
5. as preparation method as described in the claim 3, it is characterized in that described structural formula is
The preparation of chirality alkynes comprise the steps: by structural formula be
Compound under the effect of phase-transfer catalyst with chiral epichlorohydrin generation coupling, with structural formula be then
Compound coupling under the effect of n-Butyl Lithium and boron trifluoride diethyl etherate; protect newly-generated hydroxyl with the chloromethyl methyl ether effect; under the effect of Pd/C and hydrogen, reduce triple bond and remove benzyl protecting group more simultaneously; then under the phase-transfer catalyst effect with the chiral epichlorohydrin coupling; again with the coupling under the effect of n-Butyl Lithium and boron trifluoride diethyl etherate of trimethylsilyl acetylene compound; protect newly-generated hydroxyl with the chloromethyl methyl ether effect again; under the effect of tetrabutyl fluoride amine, remove silica-based protecting group at last, wherein R
1, x, y be as described in the claim 3, MOM=methoxymethyl, Bn=benzyl.
6. preparation method as claimed in claim 3 is characterized in that, described structural formula is
The preparation of alkene iodine compound, comprise the steps:
(1) structural formula is
Compound,
The mol ratio of sodium hydride, phase-transfer catalyst is 1:2-3:2-3:0.05-0.1, reacts 10-12h at 0 ℃ to room temperature and polar solvent, obtains
(2) above-mentioned (1) obtain compound, tributyl tin hydrogen, Diisopropyl azodicarboxylate, the mol ratio of iodine be 1:2-3:
0.1-0.3:2-4,130 ℃ to 0 ℃ reactions, obtain
7. preparation method as claimed in claim 5 is characterized in that, described phase-transfer catalyst is tetrabutylammonium iodide.
8. claim 1 or the 2 described annonaceous acetogenins application in the preparation antitumor drug.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5739358A (en) * | 1996-10-03 | 1998-04-14 | Regents Of The University Of Minnesota | Synthesis of acetogenins |
| CN1263890A (en) * | 1999-12-24 | 2000-08-23 | 中国科学院上海有机化学研究所 | Chiral anonace-lactone compounds,and its synthesizing process and application |
| CN101168538A (en) * | 2007-11-15 | 2008-04-30 | 华东理工大学 | Annonaceousacetogenins compounds and preparation method thereof |
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2010
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5739358A (en) * | 1996-10-03 | 1998-04-14 | Regents Of The University Of Minnesota | Synthesis of acetogenins |
| CN1263890A (en) * | 1999-12-24 | 2000-08-23 | 中国科学院上海有机化学研究所 | Chiral anonace-lactone compounds,and its synthesizing process and application |
| CN101168538A (en) * | 2007-11-15 | 2008-04-30 | 华东理工大学 | Annonaceousacetogenins compounds and preparation method thereof |
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