CN102675273A - 3-aryl-8-allyl-7-hydroxy (methoxyl) coumarin and application in preparation of antitumor drugs - Google Patents
3-aryl-8-allyl-7-hydroxy (methoxyl) coumarin and application in preparation of antitumor drugs Download PDFInfo
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Abstract
The invention belongs to the technical field of new drug synthesis and in particular relates to 3-aryl-8-allyl-7-hydroxy (methoxyl) coumarin and application in preparation of antitumor drugs for liver cancer, cervical cancer and gastric cancer. By exploring synthesis of novel 3-aryl coumarin having a restraining effect on tumor cells, reference value for screening of the antitumor drugs is provided. By modifying a structure of the 3-aryl coumarin, according to structural characteristics of a transstilbene compound, aryl is introduced to 3-position of coumarin, 7-hydroxy (methoxyl)-3-aryl compound is synthesized, furthmore allyl is introduced to 8-position of the coumarin, and a series of novel 3-aryl-8-allyl-7-hydroxy (methoxyl) coumarin is synthesized. According to experiments, the compound can remarkably restrain proliferation of various types of cancer cells, induces cancer cells effectively including highly-transferred cancer cell apotosis, and can be used as drugs and drug components for curing cancers.
Description
Technical field
The invention belongs to the new drug synthesis technical field, be specifically related to one type of 3-aryl-8-allyl group-umbelliferone, 3-aryl-8-allyl group-ayapanin and the application in the anti-liver cancer of preparation, cervical cancer, cancer of the stomach medicine.
Background technology
Coumarin kind compound extensively is present in occurring in nature; Has multiple physiologically active; For example: antitumor, anti-oxidant, anti-HIV, antimicrobial and antibacterium, effect such as hypotensive; Coumarin kind compound is anticancer directly, can also produce antitumous effect through enhancing body immunizing power, therefore is widely used clinically.Coumarins verivate synthetic and that filter out high-efficiency low-toxicity has become one of important directions of medicament research and development work.
The 3-aryl-coumarin is meant a compounds that on the C3-position of the female ring of tonka bean camphor, is connected with aryl, has multiple physiologically active.From Glycyrrhiza uralensis Fisch., separate obtain a kind of 3-aryl-coumarin (glycycoumarin, Glycycoumarin), finding has stronger restraining effect to some tumour cells, can be used as drug development guide's thing (combination of Chinese tradiational and Western medicine journal .2007,5:56-60.).Ibrim from plant, separate obtain a series of have antibiotic, anti-inflammatory, anti-platelet aggregation, bioactive 3-aryl-coumarin such as antitumor (Nat Prod Res.2007,21:857-866.).Yet the 3-aryl-coumarin is more rare at nature, and the structure more complicated.For developing its using value at aspects such as treatment diseases; People are that structure activity relationship is transformed, studied to parent nucleus with the 3-aryl-coumarin in a large number; And multiple have good physiologically active 3-aryl-coumarin (Chem.Pharm.Bull.1997,45:1485-1492 have been synthesized; Bioorg.Med.Chem.2007,15:1516-1524; Chinese J.Org.Chem.2000,20:510-513).Bibliographical information, the substituted 3-aryl-coumarin in 6-position can significantly suppress people's MAO-B (hMAO-B) activity (J.Med.Chem., 2011,54:7127-7137).The substituted 3-aryl-coumarin in 7-position to human breast cancer cell MCF-7, MDA-MB-231 show significant inhibition ability (Bioorg.Med.Chem.Lett.2010,20:7426-7428.).For the 7-methoxyl group-aryl of 3-aryl-coumarin 3-position and the methoxyl group of 7-position is its effective group that keeps anti-tumor activity.
Why the 3-aryl-coumarin has numerous physiologically actives, possibly very big related (Bioorg.Med.Chem.Lett.2006,16:257-261 arranged with contained trans stilbene skeleton (trans-stilbene compounds) in its structure; Chin.Chem.Lett.2010,21:1295-1298; Bioorg.Med.Chem.2010,18:3543-3550).The trans-stilbene compounds has been confirmed to be one type of important crude substance at present, in various fields higher biological activity is arranged.For example; White reed lamb's-quarters alcohol (Resveratrol), the white reed lamb's-quarters alcohol of oxidation, Pterostilene, different single leaf Schuttgelb (Isorhapotigenin) etc.; Bringing into play important effect (Int.J.Biochem.Cell Biol.2005,37:1709-1726 at treatment cancer, heart trouble, apoplexy, senile dementia and antiproliferative, aspect anti-infective; Curr.Clin.Pharm.2006,1:81-101; Bioorg.Med.Chem.2007,15:1160-1167).
Summary of the invention
The present invention has the synthetic of inhibiting novel 3-aryl-coumarin to explore to tumour cell, for the screening of cancer therapy drug provides the value reference.For this reason, we carry out structure of modification to the 3-aryl-coumarin, according to the constructional feature of trans-stilbene compounds; Aryl is incorporated into the 3-position of tonka bean camphor, synthetic 7-hydroxyl-3-aryl compound and 7-methoxyl group-3-aryl compound, the 8-position of further allyl group being introduced tonka bean camphor; 3-aryl-8-allyl group-umbelliferone that synthesizing series is novel and 3-aryl-8-allyl group-ayapanin (compound 5a among the corresponding embodiment; 5b, 6a, 6b).At last, use mtt assay synthetic 3-aryl-coumarin to be done the screening and the evaluation of four kinds of people source cancer cells (SK-HEP-1, HepG2, SGC7901, HeLa) anti tumor activity in vitro.
The object of the invention provides one type of 3-aryl-8-allyl group-umbelliferone and 3-aryl-8-allyl group-ayapanin [unified being abbreviated as: 3-aryl-8-allyl group-7-hydroxyl (methoxyl group) tonka bean camphor] with broad-spectrum anti-tumor activity; It is that transform C3 position to tonka bean camphor, obtains through chemical process is synthetic.
The structural formula of 3-aryl of the present invention-8-allyl group-umbelliferone is shown in (I), and the structural formula of 3-aryl-8-allyl group-ayapanin is shown in (II):
R wherein
1And R
2Identical, be methoxyl group; Or R
1Be chlorine, R
2Be hydrogen.
The concrete scheme of the present invention is mainly carried out through following equation:
Reaction reagent and condition: (a) substituted toluylic acid, diacetyl oxide, triethylamine, 2N sodium hydroxide; (b) methyl iodide, salt of wormwood, N, dinethylformamide; (c) allyl bromide 98, salt of wormwood, N, dinethylformamide; (d) phenyl ether refluxes; (e) hydroiodic acid HI of massfraction 45%, diacetyl oxide, acetate.
Above-mentioned technology comprises the same analog derivative of preparation 3-aryl-8-allyl group-7-hydroxyl (methoxyl group) tonka bean camphor; Promptly change over the phenyl ring that has hydroxyl, chlorine by phenyl on the position at 3-aryl-8-allyl group-7-hydroxyl (methoxyl group) tonka bean camphor C3; Owing to also possessed its pharmacologically active body frame structure; Under the situation that does not change flesh and blood of the present invention, still belong to protection scope of the present invention.
Through the pharmacological experiment screening, above-claimed cpd can be used to prepare the medicine that suppresses growth of tumour cell and inducing apoptosis of tumour cell.
Compound of the present invention can be used for pharmaceutical compositions; The compound that this pharmaceutical composition contains the above-mentioned general formula of treating significant quantity is an activeconstituents; And contain one or more pharmaceutically acceptable carriers, perhaps contain one or more pharmaceutically acceptable, with this compound together to treating effective medicine.
Compound of the present invention and pharmaceutical composition can be used for preparation treatment antitumor drug.
The carrier of preceding text is meant the pharmaceutical carrier that pharmaceutical field is conventional, comprises thinner, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier.
Compound of the present invention and pharmaceutical composition can administered through oral or modes such as rectum, vein, intramuscular injection or parenteral admin be applied to the patient of this treatment.
Compound of the present invention and pharmaceutical composition can prepare various formulations such as tablet, granule, electuary, capsule, suppository, sprays, sustained release dosage and injection according to the conventional working method of pharmaceutical field.
In the pharmaceutical composition of the present invention; By weight, preferably contain 0.1%～99.5% compound of the present invention, further preferably contain 10～90% compound of the present invention; More preferably contain 20～80% compound of the present invention, preferably contain 70% compound of the present invention.
Formulation rate of the present invention can be according to variations such as route of administration, patient age, body weight, disease type and severity, and per daily dose is 0.01～10mg/kg.
Description of drawings
Fig. 1 (a): the nuclear-magnetism figure of 3-among the embodiment 3 (2, the 4-Dimethoxyphenyl)-umbelliferone (2a);
Fig. 1 (b): the nuclear-magnetism figure of 3-among the embodiment 4 (2-chloro-phenyl-)-umbelliferone (2b);
Fig. 1 (c): the nuclear-magnetism figure of 3-among the embodiment 5 (2, the 4-Dimethoxyphenyl)-ayapanin (3a);
Fig. 1 (d): the nuclear-magnetism figure of 3-among the embodiment 6 (2-chloro-phenyl-)-ayapanin (3b);
Fig. 1 (e): the nuclear-magnetism figure of 3-among the embodiment 7 (2, the 4-Dimethoxyphenyl)-7-allyloxy tonka bean camphor (4a);
Fig. 1 (f): the nuclear-magnetism figure of 3-among the embodiment 8 (2-chloro-phenyl-)-7-allyloxy tonka bean camphor (4b);
Fig. 1 (g): the nuclear-magnetism figure of 3-among the embodiment 9 (2, the 4-Dimethoxyphenyl)-8-allyl group-umbelliferone (5a);
Fig. 1 (h): the nuclear-magnetism figure of 3-among the embodiment 10 (2-chloro-phenyl-)-8-allyl group-umbelliferone (5b);
Fig. 1 (i): the nuclear-magnetism figure of 3-among the embodiment 11 (2, the 4-Dimethoxyphenyl)-8-allyl group-ayapanin (6a);
Fig. 1 (j): the nuclear-magnetism figure of 3-among the embodiment 12 (2-chloro-phenyl-)-8-allyl group-ayapanin (6b);
Fig. 1 (k): the nuclear-magnetism figure of 3-among the embodiment 13 (2, the 4-dihydroxy phenyl)-umbelliferone (7);
Fig. 2: the 3-aryl-coumarin suppresses the survival rate figure of people source liver cancer cell SK-HEP-1;
Fig. 3: the 3-aryl-coumarin suppresses the survival rate figure of people source liver cancer cell HepG-2;
Fig. 4: the 3-aryl-coumarin suppresses the survival rate figure of people source stomach cancer cell SGC-7901;
Fig. 5: the 3-aryl-coumarin suppresses the survival rate figure of people source cervical cancer cell HeLa;
Embodiment
Embodiment 1:2,4-Dihydroxy benzaldehyde (1) synthetic
(11g 0.1mol) is dissolved among the DMF (100mL), stirs down, slowly adds POCl with Resorcinol
3(7.6mL).After dripping, continue to stir 2h, the massfraction that adds 50 ℃ then is 50% NaOAc solution (75mL) dissolving, gets orange-yellow solution.Extracted with diethyl ether is used in cooling, the washing of ether layer, anhydrous MgSO
4After the drying, evaporated under reduced pressure gets bullion.Bullion water recrystallization gets white needle-like crystals 2,4-Dihydroxy benzaldehyde (9.66g, productive rate 70%).
Embodiment 2:2,4-dimethoxyphenylacetic acid and 2-chlorobenzene acetic acid
With 2, and the 4-dimethoxy-acetophenone (3.6g, 20.0mmol), (1.28g 40.0mmol) mixes heating reflux reaction 6h with morpholine (3.5mL) to sublimed sulphur.Unreacted morpholine is removed in underpressure distillation, obtains brown oil.Under agitation in this brown oil, add 2.0NNaOH (80mL), reflux 3h then, cool to room temperature adds dichloromethane extraction, and water is cooled to 10 ℃, adds massfraction and be 30% hcl acidifying.The solid of separating out is used ethyl alcohol recrystallization again behind washing and drying, obtain pure white needle-like crystals 2,4-dimethoxyphenylacetic acid (3.13g, productive rate 80%).
The preparation method of 2-chlorobenzene acetic acid and 2, the 4-dimethoxyphenylacetic acid is similar, uses 2-chloro-acetophenone (3.08g; 20.0mmol), sublimed sulphur (1.28g; 40.0mmol) with morpholine (3.5mL) be raw material, obtain white needle-like crystals 2-chlorobenzene acetic acid (2.42g, productive rate 78%) according to above-mentioned implementation process.
Embodiment 3:3-(2, the 4-Dimethoxyphenyl)-umbelliferone (2a) is synthetic
With 2, (1.38g, 10.0mmol), 2, (1.96g 10.0mmol) and after diacetyl oxide (5mL) mixes, drips triethylamine (1.4mL) to the 4-dimethoxyphenylacetic acid to 4-Dihydroxy benzaldehyde 1 under nitrogen protection.Dropwise back backflow 8h, add triethylamine (0.2mL) behind the cool to room temperature.Continue backflow 8h, add triethylamine (0.1mL) once more, continue backflow 12h then.After reaction finishes, remove solvent under reduced pressure, in residue, add entry and ethyl acetate extraction.Organic layer is through saturated sodium carbonate, saturated common salt water washing, and anhydrous sodium sulfate drying removes solvent under reduced pressure.Add 2.0N NaOH (50mL) to resistates, be heated to 50 ℃ under stirring, the TLC detection reaction is complete.The hcl acidifying that adds massfraction 5% is regulated pH=2, separates out yellow mercury oxide, gets bullion behind the filtration drying.Bullion gets yellow-white powder 2 with the alcohol-water recrystallization again, 4-dimethoxyphenylacetic acid 2a (2.26g, productive rate 76%).m.p.245-247℃.
1H?NMR(300MHz，DMSO-d
6)：10.51(s，1H，-OH)，7.82(s，1H)，7.53(d，J＝8.4Hz，1H)，7.21(d，J＝8.4Hz，1H)，6.73-6.80(m，2H)，6.56-6.63(m，2H)，3.77(d，6H，-CH
3)。
Synthesizing of embodiment 4:3-(2-chloro-phenyl-)-umbelliferone (2b)
Under nitrogen protection with 2,4-Dihydroxy benzaldehyde 1 (1.38g, 10.0mmol), (1.56g 10.0mmol) and after diacetyl oxide (5mL) mixes, drips triethylamine (1.8mL) to the 2-chlorobenzene acetic acid.Dropwise back backflow 8h, add triethylamine (0.2mL) behind the cool to room temperature.Continue backflow 8h, add triethylamine (0.15mL) once more, continue backflow 15h then.After reaction finishes, remove solvent under reduced pressure, in residue, add entry and ethyl acetate extraction.Organic layer is through saturated sodium carbonate, saturated common salt water washing, and anhydrous sodium sulfate drying removes solvent under reduced pressure.Add 2.0N NaOH (50mL) to resistates, be heated to 50 ℃ under stirring, the TLC detection reaction is complete.The hcl acidifying that adds massfraction 5% is transferred pH=2, separates out yellow mercury oxide, gets bullion behind the filtration drying.Bullion obtains beige powder 3-(2-chloro-phenyl-)-umbelliferone 2b (2.01g, productive rate 74%) with the alcohol-water recrystallization again.m.p.218-220℃.
1H?NMR(300MHz，DMSO-d
6)：10.69(s，1H，-OH)，8.01(s，1H)，7.42-7.61(m，5H)，6.79-6.86(m，2H)。
Synthesizing of embodiment 5:3-(2, the 4-Dimethoxyphenyl)-ayapanin (3a)
With 3-(2, the 4-Dimethoxyphenyl)-umbelliferone 2a (0.596g, 2.0mmol) and Anhydrous potassium carbonate (0.552g 4.0mmol) joins among the new exsiccant DMF (20mL), adds methyl iodide (3.0mmol) after stirring 30min, continues to stir 6h.After reaction finishes, pour in the cold water, suction filtration and the washing white precipitate of separating out re-use column chromatography purification, and (v/v) be eluent at 1: 5, obtains white solid 3a (0.599g, productive rate 96%) with ETHYLE ACETATE and sherwood oil.m.p.139-141℃.
1HNMR(300MHz，DMSO-d
6)：7.66(s，1H)，7.29-7.40(m，2H)，6.85(d，2H)，6.56(d，2H)，3.84(t，9H，-CH
3).
13CNMR (DMSO-d
6，75MHz)：162.20，161.17，158.28，155.25，141.45，131.42，128.55，122.49，116.96，113.27，112.32，104.50，100.42，99.02，55.68，55.39。
Synthesizing of embodiment 6:3-(2-chloro-phenyl-)-ayapanin (3b)
With 3-(2-chloro-phenyl-)-umbelliferone 2b (0.572g, 2.0mmol) and Anhydrous potassium carbonate (0.552g 4.0mmol) joins among the new exsiccant DMF (20mL), adds methyl iodide (3.0mmol) after stirring 30min, continues to stir 6h.After reaction finishes, pour in the cold water, suction filtration is also washed the white precipitate of separating out, and re-uses column chromatography purification, and (v/v) be eluent at 1: 5, obtains white solid 3b (0.543g, productive rate 95%) with ETHYLE ACETATE and sherwood oil.m.p.128-130℃.
1H?NMR(300MHz，DMSO-d
6)：7.69(s，1H)，7.32-7.47(m，5H)，6.88-6.90(m，2H)，3.90(s，3H).
13C?NMR(DMSO-d
6，75MHz)：162.91，160.11，155.74，142.74，133.98，133.68，131.45，129.81，129.74，129.00，126.75，123.40，112.77，100.59，55.78。
Synthesizing of embodiment 7:3-(2, the 4-Dimethoxyphenyl)-7-allyloxy tonka bean camphor (4a)
With 3-(2, the 4-Dimethoxyphenyl)-umbelliferone 2a (0.298g, 1.0mmol) and Anhydrous potassium carbonate (0.276g 2.0mmol) joins among the new exsiccant DMF (10mL), adds propylene bromine (1.5mmol) after stirring 30min, continues to stir 12h.After reaction finishes, pour in the cold water, suction filtration, washing gets white precipitate 4a (0.294g, productive rate 87%).Product is not purified directly to be used for next step reaction.m.p.110-112℃.
1HNMR(300MHz，DMSO-d
6)：7.66(s，1H)，7.29-7.39(m，2H)，6.85-6.88(m，2H)，6.54-6.57(m，2H)，6.01-6.10(m，1H，-CH
2CH＝CH
2)，5.33-5.48(m，2H，-CH
2CH＝CH
2)，4.61(d，2H，-CH
2CH＝CH
2)，3.82(d，6H，-CH
3)。
Synthesizing of embodiment 8:3-(2-chloro-phenyl-)-7-allyloxy tonka bean camphor (4b)
With 3-(2-chloro-phenyl-)-umbelliferone 2b is raw material, (0.272g, 1.0mmol) and Anhydrous potassium carbonate (0.276g 2.0mmol) joins among the new exsiccant DMF (10mL), adds propylene bromine (1.5mmol) after stirring 30min, continues to stir 12h.After reaction finishes, pour in the cold water, suction filtration, washing gets white precipitate 4b (0.265g, productive rate 83%).Product is not purified directly to be used for next step reaction.Productive rate 85%.m.p.118-119℃.
1H?NMR(300MHz，DMSO-d
6)：7.69(s，1H)，7.32-7.50(m，5H)，6.89-6.92(m，2H)，6.02-6.11(m，1H，-CH
2CH＝CH
2)，5.34-5.49(m，2H，-CH
2CH＝CH
2)，4.62-4.64(m，2H，-CH
2CH＝CH
2)。
Synthesizing of embodiment 9:3-(2, the 4-Dimethoxyphenyl)-8-allyl group-umbelliferone (5a)
Under nitrogen protection, (0.338g, phenyl ether 1.0mmol) (5mL) vlil 2h pour into after the cooling among the 2.0N NaOH (10mL), stir 30min with compound 4a.Dichloromethane extraction, water layer are used the ethyl acetate extraction product again with the hcl acidifying of massfraction 5%.Merge organic layer, use saturated sodium carbonate, saturated common salt water washing successively, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, residue is purified with column chromatography, with ETHYLE ACETATE, sherwood oil and chloroform (1: 3: 7, v/v) be eluent.Finally obtain white powder 5a (0.236g, productive rate 70%).m.p.168-170℃.
1H?NMR(300MHz，CDCl
3)：7.65(s，1H)，7.26-7.31(m，2H)，6.80(d，J＝8.1?Hz，1H)，6.56(d，2H)，6.12(s，1H，-OH)，5.98-6.07(m，1H，-CH
2CH＝CH
2)，5.14-5.25(m，2H，-CH
2CH＝CH
2)，3.83(d，6H，-CH
3)，3.70(d，2H，-CH
2CH＝CH
2).
13C?NMR(DMSO-d
6，75MHz)：161.25，158.34，157.95，152.73，142.83，135.04，131.51，126.67，116.26，113.23，104.60，99.06，55.73，55.45，27.03。
Synthesizing of embodiment 10:3-(2-chloro-phenyl-)-8-allyl group-umbelliferone (5b)
Under nitrogen protection, (0.312g, phenyl ether 1.0mmol) (5mL) vlil 2.5h pour into after the cooling among the 2.0N NaOH (10mL), stir 30min with compound 4b.Dichloromethane extraction, water layer are used the ethyl acetate extraction product again with the hcl acidifying of massfraction 5%.Merge organic layer, use saturated sodium carbonate, saturated common salt water washing successively, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, residue is purified with column chromatography, with ETHYLE ACETATE, sherwood oil and chloroform (1: 3: 7, v/v) be eluent.Finally obtain white powder 5b (0.221g, productive rate 71%).m.p.162-163℃.
1H?NMR(300MHz，CDCl
3)：7.69(s，1H，-OH)，7.47-7.50(m，1H)，7.39-7.42(m，1H)，7.29-7.35(m，3H)，6.85(d，J＝8.4Hz，1H)，6.10(s，1H，-OH)，5.99-6.08(m，1H，-CH
2CH＝CH
2)，5.17-5.27(m，2H，-CH
2CH＝CH
2)，3.71(d，2H，-CH
2CH＝CH
2).
13C?NMR(DMSO-d
6，75MHz)：158.62，153.09，144.02，144.01，134.74，133.91，133.76，131.49，129.83，129.77，127.13，126.80，122.46，116.47，113.48，113.33，112.61，26.99。
Synthesizing of embodiment 11:3-(2, the 4-Dimethoxyphenyl)-8-allyl group-ayapanin (6a)
With 3-(2; The 4-Dimethoxyphenyl)-8-allyl group-ayapanin 5a (0.676g, 2.0mmol) and Anhydrous potassium carbonate (0.552g 4.0mmol) joins among the new exsiccant DMF (20mL); Add methyl iodide (3.0mmol) after stirring 30min, continue to stir 6h.After reaction finishes, pour in the cold water white precipitate that suction filtration and washing are separated out into; Re-use column chromatography purification, with ETHYLE ACETATE and sherwood oil (1: 5, v/v) be eluent; Obtain white solid 3-(2, the 4-Dimethoxyphenyl)-8-allyl group-ayapanin 6a (0.661g, productive rate 94%).m.p.134-136℃.
1H?NMR(300MHz，CDCl
3)：7.64(s，1H)，7.29-7.34(m，2H)，6.85(d，2H)，6.55(d，2H)，5.96-6.04(m，1H，(m，1H，-CH
2CH＝CH
2)，4.98-5.12(m，2H，-CH
2CH＝CH
2)，3.81-3.92(t，9H，-CH
3)，3.64(d，2H，-CH
2CH＝CH
2).
13CNMR(DMSO-d
6，75MHz)：161.12，159.74，158.32，152.41，141.78，135.30，131.45，126.04，122.42，117.17，115.66，115.20，113.70，107.24，104.53，99.05，56.05，55.69，26.78。
Synthesizing of embodiment 12:3-(2-chloro-phenyl-)-8-allyl group-ayapanin (6b)
With 3-(2-chloro-phenyl-)-8-allyl group-ayapanin 5b (0.624g, 2.0mmol) and Anhydrous potassium carbonate (0.552g 4.0mmol) joins among the new exsiccant DMF (20mL), adds methyl iodide (3.0mmol) after stirring 30min, continues to stir 6h.After reaction finishes, pour in the cold water white precipitate that suction filtration and washing are separated out into; Re-use column chromatography purification, with ETHYLE ACETATE and sherwood oil (1: 5, v/v) be eluent; Obtain white solid 3-(2-chloro-phenyl-)-8-allyl group-ayapanin 6b (0.606g, productive rate 93%).m.p.112-114℃.?
1H?NMR(300MHz，CDCl
3)：7.67(s，1H)，7.32-7.46(m，5H)，6.89(d，J＝8.7Hz，1H)，5.96-6.05(m，1H，-CH
2CH＝CH
2)，4.99-5.14(m，2H，-CH
2CH＝CH
2)，3.94(s，3H，-CH
3)，3.65(d，2H，-CH
2CH＝CH
2)。
Synthesizing of embodiment 13:3-(2, the 4-dihydroxy phenyl)-umbelliferone (7)
(0.298g 1.0mmol) joins in the mixed solution of acetate (2mL) and diacetyl oxide (2mL), stirs to add massfraction 45% hydroiodic acid HI (5mL) down with compound 2a.Under nitrogen protection, reflux 2h, cool to room temperature.Remove solvent under reduced pressure, add saturated sodium carbonate solution and transfer PH=6.Filtering and washing precipitation, purifies with column chromatography in dry back, and (v/v) be eluent at 1: 8, obtains pure cream-coloured powder 7, productive rate 50% with methyl alcohol and chloroform.m.p.144-146℃.
1H?NMR(300MHz，DMSO-d
6)：10.44(s，1H，-OH)，9.34(d，2H，-OH)，7.81(s，1H)，7.52(d，J＝8.4Hz，1H)，7.04(d，J＝8.4Hz，1H)，6.72-6.79(m，2H)，6.36(d，J＝2.4Hz，1H)，6.24-6.28(m，1H).
13C?NMR (DMSO-d
6，75MHz)：160.56，160.17，158.39，156.06，154.72，141.67，131.46，129.34，121.28，113.61，113.02，111.97，106.24，102.65，101.74。
Embodiment 14: whether assessment 3-aryl-8-allyl group-7-hydroxyl (methoxyl group) tonka bean camphor suppresses the activity of people source growth of cancer cells, utilizes the MTT method to measure its restraining effect to people source liver cancer cell, people source stomach cancer cell and the growth of people source cervical cancer cell.
Following angle and experimentation on animals from cytobiology confirms that The compounds of this invention 3-aryl-8-allyl group-7-hydroxyl (methoxyl group) tonka bean camphor has the effect of significant anticancer growth.
(1) cell cultures
With the DMEM substratum that contains the hot deactivation calf serum of 10% (v/v), 100U/mL penicillium mould and 100g/mL Streptomycin sulphate, cultivate SK-HEP-1 cell, HepG2 cell, HeLa cell, SGC7901 cell; Above-mentioned cell all places 37 ℃, the CO of volume(tric)fraction 5%
2Cultivate in the moist incubator.These 4 kinds of cells of taking the logarithm vegetative period are used for the MTT experiment.
(2) growth of cancer cells restraining effect
Above-mentioned cell is pressed 1 * 10
4Individual/hole is inoculated in 96 orifice plates, per 3 Kong Weiyi group; Behind DMEM culture medium culturing 24h, adding final concentration respectively is 0 μ g/ml, 1.3 μ g/ml; 3.2 μ g/ml, 6.5 μ g/ml, 13.0 μ g/ml; 26.0 the 3-aryl of μ g/ml and 65.1 μ g/ml-8-allyl group-7-hydroxyl (methoxyl group) tonka bean camphor; After continue cultivating tetrazolium bromide (MTT purchases the company in Sigma) that every hole behind the 72h adds 20 μ l, 5mg/ml again and hatching 4 hours, sucking-off nutrient solution gently; Every hole adds the crystallization of 150 μ l DMSO 99.8MIN.s (DMSO) dissolving first a ceremonial jade-ladle, used in libation again; Measure each hole absorbance value, calculation of half inhibitory concentration (IC in multi-functional ELIASA (TECAN GENios) 570nm wavelength
50Value).The result shows that 3-aryl-8-allyl group-7-hydroxyl (methoxyl group) tonka bean camphor all has significant inhibitory effect to people source liver cancer cell, people source stomach cancer cell and the growth of people source cervical cancer cell.
(3) statistical procedures of data
Data are with mean number ± standard deviation (X ± S) utilize Sigma Plot to analyze among this paper.
Discussion of results
Experimental result shows: compound 5a, the 5b of the present invention's preparation have medium restraining effect for human liver cancer cell SK-HEP-1, its IC
50Be respectively 17.84 μ g/mL and 24.50 μ g/mL.It has moderate restraining effect, IC to liver cancer cell HepG2 for compound 5a, 5b
50Be respectively 21.74 μ g/mL and 19.56 μ g/mL.Compound 5a, 5b have good inhibitory effect to gastric carcinoma cells SGC-7901, and its IC50 is respectively 11.15 μ g/mL and 12.60 μ g/mL.For human cervical carcinoma cell HeLa, these several kinds of compounds all show good inhibitory effect except compound 7. Compound 5a, 5b and 6a, 6b have stronger inhibition effect, its IC to HeLa
50Difference 7.00 μ g/mL; 7.68 μ g/mL; 6.75 μ g/mL; 8.83 μ g/mL.The effect of compound 7 remains further to be developed.
In a word, above compound significantly suppresses all kinds of cancer cell multiplications, effective inducing cancer cell, comprises the cancer cell-apoptosis that highly shifts, and can do the medicine and the drug component of treatment cancer.
Claims (6)
1.3-aryl-8-allyl group-7-hydroxyl (methoxyl group) tonka bean camphor, its structural formula is as follows:
R wherein
1And R
2Identical, be methoxyl group; Or R
1Be chlorine, R
2Be hydrogen.
2. the application of the described 3-aryl of claim 1-8-allyl group-7-hydroxyl (methoxyl group) tonka bean camphor in the preparation antitumor drug.
3. the application of 3-aryl as claimed in claim 2-8-allyl group-7-hydroxyl (methoxyl group) tonka bean camphor in the preparation antitumor drug is characterized in that: the medicine that is used to prepare anti-liver cancer, cervical cancer or cancer of the stomach.
4. the application of 3-aryl as claimed in claim 2-8-allyl group-7-hydroxyl (methoxyl group) tonka bean camphor in the preparation antitumor drug; It is characterized in that: 3-aryl-8-allyl group-7-hydroxyl (methoxyl group) tonka bean camphor is used to prepare the pharmaceutical composition of anti-liver cancer, cervical cancer or cancer of the stomach as activeconstituents.
5. the application of 3-aryl as claimed in claim 4-8-allyl group-7-hydroxyl (methoxyl group) tonka bean camphor in the preparation antitumor drug; It is characterized in that: in pharmaceutical composition, by weight 3-aryl-8-allyl group-7-hydroxyl (methoxyl group) tonka bean camphor that contains 0.1%～99.5%.
6. the application of 3-aryl as claimed in claim 5-8-allyl group-7-hydroxyl (methoxyl group) tonka bean camphor in the preparation antitumor drug; It is characterized in that: in pharmaceutical composition, by weight 3-aryl-8-allyl group-7-hydroxyl (methoxyl group) tonka bean camphor that contains 10～90%.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000045165A1 (en) * | 1999-02-01 | 2000-08-03 | Cytovia, Inc. | Methods of identifying therapeutically effective antineoplastic agents with cultured cells having intact cell membranes and corresponding products |
| CN1890235A (en) * | 2003-09-15 | 2007-01-03 | 西格诺药品有限公司 | Benzopyranone compounds, compositions thereof, and methods of treatment therewith |
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2012
- 2012-05-03 CN CN2012101346737A patent/CN102675273A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000045165A1 (en) * | 1999-02-01 | 2000-08-03 | Cytovia, Inc. | Methods of identifying therapeutically effective antineoplastic agents with cultured cells having intact cell membranes and corresponding products |
| CN1890235A (en) * | 2003-09-15 | 2007-01-03 | 西格诺药品有限公司 | Benzopyranone compounds, compositions thereof, and methods of treatment therewith |
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| Title |
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| PIERO VALENTI，等: "Synthesis and antitumor activity of some analogues of flavone acetic acid", 《ANTI-CANCER DRUG DESIGN》 * |
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Application publication date: 20120919 |