CN1062853C - Shikimate compound - Google Patents
Shikimate compound Download PDFInfo
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- CN1062853C CN1062853C CN96100318A CN96100318A CN1062853C CN 1062853 C CN1062853 C CN 1062853C CN 96100318 A CN96100318 A CN 96100318A CN 96100318 A CN96100318 A CN 96100318A CN 1062853 C CN1062853 C CN 1062853C
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- acid ester
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Abstract
The present invention relates to a shikimate compound. A novel compound Uvaria grandiflora ketene (a formula I) extracted from Uvaria grandiflora of a plant has antineoplastic activity. The structure of the compound of the present invention discloses in the specification, wherein R1, R2 and R3 can be identical or different, and R1, R2 and R3 are respectively hydrogen, hydroxyl, fatty acid ester groups, aromatic acid ester groups, halogen, cyano groups, sulphydryl, nitryl, nitrous acid ester groups, alkane sulfonyl, aromatic sulfonyl, aromatic oxo, amino groups, imino groups, secondary amino groups, sulphydryl, alkane vulcanization groups and carbonyl, and form a triatomic ring containing oxygen with an ortho-position. R4 is carbonyl, hydrazone groups and alkali metal sulphonate groups.
Description
The inventor has anti-tumor activity by separating the new compound that obtains green pepper (Uvaria grandifora) by green pepper ketenes (formula I) from plant, its characteristics have remarkable lethal effect to the multi-drug resistance tumor cell, can obviously strengthen the lethal effect of Zorubicin to the multi-drug resistance tumor cell.
The compounds of this invention has following structure
Wherein R1, R2, the R3 substituting group can be identical or different, hydrogen by name, hydroxyl, lipid acid ester group, the aromatic acid ester group, halogen, cyano group, thiocyanogen, nitro, nitrous acid ester group, alkane alkylsulfonyl, fragrant alkylsulfonyl, alkoxyl group, fragrant oxygen base, amino, imino-, inferior amino, sulfydryl, alkane sulfuration base, carbonyl contains the oxygen triatomic ring with ortho position formation;
R4 is a carbonyl, hydrazone group and alkali metal sulfamate alkali.
The compounds of this invention can prepare as follows: 1. extraction separation, and in plant Chinese pepper (Uvariagrandiflora) ethanol extract, sour insoluble part solvent elution, wherein the methylene dichloride part is got The compounds of this invention formula I through silica gel column chromatography
1
2. synthetic
A, from naturally occurring known compound, preparation The compounds of this invention formula I
1
Extraction separation obtains known compound Zeylenol (formula II) from plant, as raw material, generates The compounds of this invention formula I with freshly prepd Manganse Dioxide reagent react with Zeylenol
1
B. complete synthesis, prepare The compounds of this invention formula I from simple organic compound
1
The first step, raw material propine and NBS reagent react generate 1-bromo-2-propine (formula IV), obtain 2-propine-1-alcohol (formula V) through basic hydrolysis:
In second step, this compound and suitable divinyl addition generate 1 base methyl alcohol (formula VI):
The 3rd the step, on go on foot product again with the NBS reagent react, generate two bromo compounds (formula VII), get trihydroxy-compound (formula VIII) with basic hydrolysis;
In the 4th step, trihydroxy-compound and Benzoyl chloride reaction produce dibenzoic acid ester products (formula IX), obtain carbonyl compound (formula X) with the Manganse Dioxide oxidation again:
The 5th step went up and goes on foot product elder generation and 5% bromine carbon tetrachloride reaction, and the two keys in protection 2-position react with perosmic anhydride then, make another pair key be oxidized to cis glycol (formula III), at last with the chromite processing, made two key regeneration, and obtained compound formula I
1 
3. other compound of the present invention can prepare formula I 1. of the present invention as follows
2Compound can be by the formula I
1Compound generates through basic hydrolysis:
2. formula I of the present invention
3Compound can be by the formula I
2Compound and halogenating agent reaction generate:
Wherein X is F, Cl, Br, I formula I 3. of the present invention
4Compound can be by the formula I
3Compound and R ＇ COO
-Reaction generates:
Wherein X is F, Cl, Br, I
R ＇ is an aliphatic group or aryl radical formula I 4. of the present invention
5Compound can be by the formula I
1Compound and chlorination reaction generate:
5. formula I of the present invention
6Compound can be by the formula I
3Compound and sulfohydrate reaction generate:
Wherein X is F, Cl, Br, I formula I 6. of the present invention
7Compound, can be by the formula I
3Compound and alkyl sulfur compounds reaction generate:
Wherein X is F, Cl, Br, I
R ＇ is an aliphatic group or aryl radical formula I 7. of the present invention
8Compound can be by the formula I
3Compound and imine reaction generate:
Wherein X is F, Cl, Br, I
R ＇ is an aliphatic group or aryl radical formula I 8. of the present invention
9Compound can be by the formula I
3Compound and prussiate reaction generate:
Wherein X is F, Cl, Br, I formula I 9. of the present invention
10Compound can be by the formula I
3Compound and nitroso-group reactant salt generate:
Wherein X is F, Cl, Br, I formula I 10. of the present invention
11Compound can be by the formula I
1Compound and phenylhydrazine reaction generate:
(11) formula I of the present invention
12Compound can be by the formula I
1Compound and sodium bisulfite reaction generate.
Pharmaceutical composition of the present invention contains formula I compound of the present invention and the pharmaceutically acceptable carrier or the thinner of significant quantity.Preferred carrier comprises: a lot.
The pharmacologically active of The compounds of this invention can be proved by following Bioexperiment:
(1) nucleosides with labelled with radioisotope detects, and medicine contacts 5 minutes in advance with tumour cell, and insulation is 30 seconds behind the nucleosides of adding mark, determines that The compounds of this invention has remarkable restraining effect to the nucleoside transporting of tumour cell.In the ehrlich's ascite cell detected result, The compounds of this invention is 9ug/ml to the IC50 (concentration that suppresses transhipment 50%) of thymidine transhipment, and the IC50 that uridine is transported is 12ug/ml (accompanying drawing 1)
(2) vitro culture human cancer cell, detect with mtt assay (observing medicine) the tumor cell proliferation inhibition effect, medicine and cancer cells duration of contact are 72 hours, studies show that The compounds of this invention has remarkable effect to the propagation of cancer cells, the IC50 of oral cavity squamous cell carcinoma KB cell (anticancer propagation 50% concentration) is 0.9ug/ml (accompanying drawing 2), is 2.6ug/ml (accompanying drawing 3) to the IC50 of mammary cancer MCF-7 cell.
(3) vitro culture human cancer cell detects with mtt assay, uses multi-medicine resistance cell and non-resistance cell to compare simultaneously.Studies have shown that The compounds of this invention has remarkable restraining effect equally to the multi-drug resistance tumor cell, do not see cross-resistance, the IC50 of The compounds of this invention oral cavity squamous cell carcinoma KB cell and KB/VCR cell (multi-medicine resistance cell) is respectively 0.9ug/ml and 1.0ug/ml, and the rain person does not have significant difference (accompanying drawing 2).The compounds of this invention is respectively 2.6ug/m and 2.2ug/ml to the IC50 of mammary cancer MCF-7 cell and MCF-7/ADM cell, and the rain person does not have significant difference (accompanying drawing 3).
(4) vitro culture human cancer cell detects with mtt assay, and by drug interaction coefficient (Coeffi-cient of drug interaction. is called for short CDI) judged result, CDI＜1 expression rain medicine has synergy, CDI＜0.7, and expression is synergy significantly.Use mammary cancer MCF-7 cell research result, The compounds of this invention can obviously strengthen the anti-tumor activity of Zorubicin, CDI＜0.7 (accompanying drawing 4).Use the breast cancer cell MCF-7/ADM of multi-medicine resistance, The compounds of this invention also can strengthen the anti-tumor activity of Zorubicin, and CDI＜0.7 (accompanying drawing 5), this shows, for the multi-drug resistance tumor cell, the same synergism that shows for antitumor drug of The compounds of this invention.
(5) animal vivo test at kunming mouse subcutaneous vaccination sarcoma 180 cell, begins to irritate stomach and gives The compounds of this invention after 24 hours, 1 time every other day, totally 5 times, press tumor weight and calculate inhibiting rate.Result of study, The compounds of this invention dosage 500mg/Kg and 1000mg/Kg are respectively 32% (P＜0.05) and 37% (P＜0.05) (subordinate list 1) to the inhibiting rate of sarcoma 180, studies show that The compounds of this invention has certain curative effect to tumour.
The following example is illustrated more clearly in the present invention, should regard the following example as limitation of the present invention.Embodiment 1 is from plant Chinese pepper (Uvaria grandiflora) extraction separation chemical compounds I
18.5 kilograms in plant Chinese pepper (Uvaria grandiflora) branches and leaves, soak three times (70000 * 3ml) with 95% ethanol temperature, the extracting solution concentrating under reduced pressure gets half-dried medicinal extract 140 (g), grind bubble 5 times (200 * 5ml) with 2%HCl, wherein sour insoluble part, be adsorbed on 1 kilogram of silica gel, use the solvent refluxing wash-out, methylene dichloride wash-out part 34 (g), be adsorbed on 40 (g) silica gel through silica gel column layer (silica gel of 50 times of amounts) repeatedly, take off with sherwood oil-gradient Xian of ether solvent system, get the The compounds of this invention I
13 (g).
The The compounds of this invention I
1, white, needle-shaped crystals.Mp155-156 ℃, be soluble in hot acetone, chloroform.[a]
D 20-126.5(c?0.747,CHCl
3).UV(CHCl
3)nm：224，268。CD(CH
3CN)nm：324(+),240(-),226(-).IR(KBr)cm
-1： 3405,3030,2945,1710,1700,1690,1600,1580,1495,
1450,1275,1105,1100,710。EI-MS?m/e?(％)：?260(2.6),219(1.1),201(1.8),188(2.6),163(1.8),
138(3.2),123(3.3),110(2.6),105(100),97(20.8),
77(20.2).FAB-MS： 383(M+H),405(M+Na).
1H-NMR(CDCl
3)ppm：4.36(1H,dd,J=4.2,1.2,H-2),5.94(1H,td,J=4.2,1.0,H-3),6.93(1H,ddd,J=10.0,4.0?1.2,H-4),6.30(1H,dd,J=10.0,0.9,H-5),4.82(1H,d.J=11.6,H-7),4.58(1H,d,J=11.6,H-7＇),8.00(2H,m，H-6′,2＇),7.91(2H，m,H-2″,6″)，7.38(4H,m，H-3＇,5＇,3″,5″),7.52(2H,m,H-4＇,4″)。
13C-NMR?ppm：77.2(C-1), 71.7(C-2)， 69.4(C-3), 142.7(C-4),128.6(C-5), 196.6(C-6)， 65.3(C-7), 129.1(C-1＇),129.6(C-2＇,6＇)，?128.6(C-3＇，5＇)， 133.7(C-4＇), 165.4(C-7＇),128.8(1″), 129.7(C-2″,，6″)，?128.4(C-3″,5″),?133.4(C-4″),166.2(C-7″).
Embodiment 2 is dissolved in known compound zeylenol (name of document) 100 (mg) in the methyl alcohol, 30 (mg) Manganse Dioxide oxidation that adds prepared fresh, produce The compounds of this invention formula I 142 (mg), by identical method, with the oxidation of zeylenol derivative, obtain other formula I compound of the present invention.Embodiment 3 pharmacy
Prescription:
Active compound formula I 5.0 of the present invention (g),
Microcrystalline Cellulose 0.5 (g),
Starch 5.0 (g),
Magnesium Stearate 0.1 (g).
Medicine is sieved, remove big and smaller particles, add Microcrystalline Cellulose, Magnesium Stearate and starch and mix, drying, after sieve, i.e. compressing tablet.Every contains active drug 50 of the present invention (mg).
Dosage number of animals body weight changes heavy (g) inhibiting rate of knurl
(mg/kg) beginning/end (g) mean ± SD (g)
D6 500 10/10 +3.5 2.16±0.67 32*
D6 1000 10/10 +9.4 1.67±11.08 37*
* P＜0.05 D
6Represent the sub-ketenes of Chinese pepper (formula I
1).(following identical)
Claims (5)
1. the compound shown in the formula I or its pharmacy acceptable salt or ester,
Wherein R1, R2, the R3 substituting group can be identical or different, hydrogen by name, hydroxyl, lipid acid ester group, the aromatic acid ester group, halogen, cyano group, thiocyanogen, nitro, nitrous acid ester group, alkane alkylsulfonyl, fragrant alkylsulfonyl, alkoxyl group, fragrant oxygen base, amino, imino-, inferior amino, sulfydryl, alkane sulfuration base, carbonyl contains the oxygen triatomic ring with ortho position formation;
R4 is a carbonyl, hydrazone group and alkali metal sulfamate alkali.
2. the compound of claim 1,
Wherein R1 is the lipid acid ester group, the aromatic acid ester group;
R2 is a hydroxyl, lipid acid ester group, aromatic acid ester group, sulfydryl;
R3 is a hydroxyl, lipid acid ester group, aromatic acid ester group, sulfydryl, halogen;
R4 is a carbonyl, hydrazone group, alkali metal sulfamate alkali.
3. the compound of claim 1,
Wherein R1 is the phenylformic acid ester group, and R2 is a hydroxyl,
R3 is a hydroxyl, and R4 is a carbonyl.
4. the preparation method of formula I compound, comprising:
(1) formula I
1Compound can be as follows, and extraction separation obtains from plant:
The sour insoluble part of the sub-ethanol extract of plant Chinese pepper is washed glue with solvent, and wherein the methylene dichloride part is got The compounds of this invention formula I through silica gel column chromatography
1
(2) formula I
1Compound, can synthesize as follows:
A, formula II compound and freshly prepd Manganse Dioxide reagent react generate compound formula I
1
B, formula III compound and chromite reaction generate compound formula I
1 
(3) formula I
2Compound can be by the formula I
1Compound generates through basic hydrolysis:
(4) formula I
3Compound can be by the formula I
2Compound and halogenating agent reaction generate:
Wherein X is F, Cl, Br, I
(5) formula I
4Compound can be by the formula I
3Compound and R ＇ COO
-Reaction generates:
(6) formula I
5Compound can be by the formula I
3Compound and chlorination reaction generate:
(7) formula I
6Compound can be by the formula I
3Compound and oxysulfide reaction generate:
Wherein X is F, Cl, Br, I
(8) formula I
7Compound can be by the formula I
3Compound and alkyl sulfur compounds reaction generate:
Wherein X is F, Cl, Br, I
R ＇ is aliphatic group or aryl radical
(9) formula I
1Compound can be by the formula I
3Compound and imine reaction generate;
Wherein X is F, Cl, Br, I
R ＇ is aliphatic group or aryl radical
(10) formula I
9Compound can be by the formula I
3Compound and prussiate reaction generate;
Wherein X is F, Cl, Br, I
(11) formula I
10Compound can be by the formula I
3Compound and nitroso-group reactant salt generate;
Wherein X is F, Cl, Br, I
(12) formula I
11Compound can be by the formula I
1Compound and phenylhydrazine reaction generate;
(13) formula I
12Compound can be by the formula I
1Compound and sodium bisulfite reaction generate.
5. pharmaceutical composition wherein contains the formula I compound of significant quantity, with pharmaceutically acceptable carrier or thinner.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN96100318A CN1062853C (en) | 1996-01-19 | 1996-01-19 | Shikimate compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN96100318A CN1062853C (en) | 1996-01-19 | 1996-01-19 | Shikimate compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1138571A CN1138571A (en) | 1996-12-25 |
| CN1062853C true CN1062853C (en) | 2001-03-07 |
Family
ID=5116525
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96100318A Expired - Fee Related CN1062853C (en) | 1996-01-19 | 1996-01-19 | Shikimate compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1062853C (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101723930B (en) * | 2009-12-02 | 2013-07-24 | 中国科学院上海药物研究所 | Shikimic acid compound and preparation method and application thereof |
| CN105687180B (en) * | 2015-12-11 | 2018-06-12 | 中国药科大学 | One kind has 1.7 inhibitor of sodium-ion channel of analgesic activity |
| CN113662964A (en) * | 2020-05-13 | 2021-11-19 | 中国医学科学院药用植物研究所 | Medicine for treating tumor |
| CN113261568B (en) * | 2021-04-21 | 2022-04-08 | 海南大学 | Zanthoxylum piperitum plant source bactericide and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4661516A (en) * | 1983-06-20 | 1987-04-28 | Research Corporation | Diaminocyclohexane platinum complexes |
| US4758588A (en) * | 1983-06-20 | 1988-07-19 | Research Corporation Technologies | Diaminocyclohexane platinum complexes |
-
1996
- 1996-01-19 CN CN96100318A patent/CN1062853C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4661516A (en) * | 1983-06-20 | 1987-04-28 | Research Corporation | Diaminocyclohexane platinum complexes |
| US4758588A (en) * | 1983-06-20 | 1988-07-19 | Research Corporation Technologies | Diaminocyclohexane platinum complexes |
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| Publication number | Publication date |
|---|---|
| CN1138571A (en) | 1996-12-25 |
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