CN1138571A - Shikimate compound - Google Patents
Shikimate compound Download PDFInfo
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- CN1138571A CN1138571A CN 96100318 CN96100318A CN1138571A CN 1138571 A CN1138571 A CN 1138571A CN 96100318 CN96100318 CN 96100318 CN 96100318 A CN96100318 A CN 96100318A CN 1138571 A CN1138571 A CN 1138571A
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Abstract
A new compound, sanshoketenes, is extracted from Uvaria grandiflora. Said compound has antitumor activity and contains more than 22 chemical radicals.
Description
The inventor separates the sub-ketenes of new compound Chinese pepper (formula I) that obtains from plant Chinese pepper (Uvaria grandiflora) have anti-tumor activity, 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
R wherein
1, R
2, R
3Can be identical or different, respectively be hydrogen (H), hydroxyl (OH), lipid acid ester group (O-CO-R '), aromatic acid ester group (O-CO-Ar), halogen (X), cyano group (CN), thiocyanogen (SCN), nitro (NO
2), nitrous acid ester group (ONO), alkane alkylsulfonyl (SO
2R '), fragrant alkylsulfonyl (SO
2Ar), alkoxyl group (OR '), fragrant oxygen base (OAr), amino (NH
2), imino-[NHR ' (Ar)], inferior amino [NR '
2(Ar)], sulfydryl (SH), alkane sulfuration base [SR ' (Ar)], carbonyl (=O), contain the oxygen triatomic ring with ortho position formation.
R
4For carbonyl (=O), hydrazone group (=N-NH-Ar) and the alkali metal sulfamate alkali (
).
The compounds of this invention can prepare as follows:
1. extraction separation, in plant Chinese pepper (Uvaria grandiflora) 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, prepare The compounds of this invention formula I
1
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 
2. extraction separation obtains known compound Pipoxide chlorohydrin (formula III) from plant, generate ketal (formula IV) with Pipoxide chlorohydrin as raw material and acetone reaction, hydrolysis obtains oxy-compound (formula V) under alkaline condition then.This oxy-compound reacts with Benzoyl chloride more then, make it to generate dibenzoic acid ester cpds (VI), this benzoic acid ester compounds generates carbonyl compound (formula VII) with the Manganse Dioxide reagent oxidation, uses this carbonyl compound of weak acid hydrolysis at last again, generates The compounds of this invention formula I
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 VIII), obtain 2-propine-1-alcohol (formula IX) through basic hydrolysis.
In second step, this compound and suitable divinyl addition generate 1 base methyl alcohol (formula X).
The 3rd the step, on go on foot product again with the NBS reagent react, generate two bromo compounds (formula XI), get trihydroxy-compound (formula XII) with basic hydrolysis.
In the 4th step, trihydroxy-compound and Benzoyl chloride reaction produce dibenzoic acid ester products (formula XIII), obtain carbonyl compound (formula XIV) 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 XV), 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 as follows
1. formula I of the present invention
2Compound can be by formula I
1Compound generates through basic hydrolysis.
2. formula I of the present invention
3Compound can be by formula I
2Compound and halogenating agent reaction generate.
Wherein X is F, Cl, Br, I.3. formula I of the present invention
4Compound can be by formula I
3Compound and R ' COO
-Reaction generates.
Wherein X is F, Cl, Br, I.
R ' is aliphatic group or aryl radical.4. formula I of the present invention
5Compound can be by formula I
1Compound and chlorination reaction generate.
5. formula I of the present invention
6Compound can be by 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 formula I
3Compound and alkyl sulfur compounds reaction generate.
Wherein X is F, Cl, and Br, I,
R ' is aliphatic group or aryl radical.7. formula I of the present invention
8Compound can be by formula I
3Compound and imine reaction generate.
Wherein X is F, Cl, and Br, I,
R ' is aliphatic group or aryl radical.8. formula I of the present invention
9Compound can be by formula I
3Compound and prussiate reaction generate.
Wherein X is F, Cl, Br, I.9. formula I of the present invention
10Compound can be by formula I
3Compound and nitroso-group reactant salt generate.
Wherein X is F, Cl, Br, I.
10. formula I of the present invention
11Compound can be by formula I
1Compound and phenylhydrazine reaction generate.
(11) formula I of the present invention
12Compound can be by 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 both do 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 both do 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, two medicines have 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 not regard the following example as limitation of the present invention.Embodiment 1 is from plant Chinese pepper (Uvaria grandiflora) extraction separation Compound 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, with sherwood oil-ether solvent system gradient elution, get The compounds of this invention I
13 (g).The compounds of this invention I
1, white, needle-shaped crystals.Mp155-156 ℃, be soluble in hot acetone, chloroform.[a]
D 20-126.5(c0.747，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; add 30 (mg) Manganse Dioxide oxidation of prepared fresh, produces 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).
The dosage number of animals not heavily changes heavy (g) inhibiting rate of knurl
(mg/kg) beginning/finish, (g) mean ± SD, (g) contrast 10/10+4.1 3.17 ± 0.47 D6 500 10/10+3.5 2.16 ± 0.67 32* contrast, 10/10+9.4 2.67 ± 0.92 D6,1,000 10/10+9.4 1.6711.08 37*
*P＜0.05 D
6Represent (4R,5S,6S)-4-(benzoyloxy)-6-[(benzoyloxy)methyl (formula I1). (following identical)
Claims (6)
1. the compound shown in the formula I or its pharmacy acceptable salt or ester,
Substituent R wherein
1, R
2, R
3Can be identical or different, respectively be hydrogen (H), hydroxyl (OH), lipid acid ester group (O-CO-R '), aromatic acid ester group (O-CO-Ar), halogen (X), cyano group (CN), thiocyanogen (SCN), nitro (NO
2), nitrous acid ester group (ONO), alkane alkylsulfonyl (SO
2R '), fragrant alkylsulfonyl (SO
2Ar), alkoxyl group (OR ').Fragrance oxygen base (OAr), amino (NH
2), imino-[NHR ' (Ar)], inferior amino [NR '
2(Ar)], sulfydryl (SH), alkane sulfuration base [SR ' (Ar)], carbonyl (=O), contain the oxygen triatomic ring with ortho position formation;
R
4For carbonyl (=O), hydrazone group (=N-NH-Ar) and the 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 chemical combination of claim 1, wherein R1 is the phenylformic acid ester group, 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:
With the sour insoluble part solvent elution of plant Chinese pepper (Uvaria grandiflora) ethanol extract, 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 acetone react production IV compound, and hydrolysis obtains formula V compound under alkaline condition then.This compound reacts with Benzoyl chloride more then, makes it production VI compound, this compound Manganse Dioxide reagent oxidation, and production VII compound is used weak acid hydrolyzing type VII compound at last again, generates The compounds of this invention formula I
1 C. formula VIII compound and chromite reaction generates compound formula I
1 (3) formula I
2Compound can be by formula I
1Compound generates through basic hydrolysis;
(4) formula I
3Compound can be by formula I
2Compound and halogenating agent reaction generate;
Wherein X is F, Cl, Br, I (5) formula I
4Compound can be by formula I
3Compound and R ' COO
-Reaction generates;
Wherein X is F, Cl, Br, I
R ' is aliphatic group or aryl radical (6) formula I
5Compound can be by formula I
1Compound and chlorination reaction generate;
(7) formula I
6Compound can be by formula I
3Compound and sulfohydrate reaction generate;
Wherein X is F, Cl, Br, I (8) formula I
7Compound can be by formula I
3Compound and alkyl sulfur compounds reaction generate;
Wherein X is F, Cl, and Br, I,
R ' is aliphatic group or aryl radical (9) formula I
8Compound can be by formula I
3Compound and imine reaction generate;
Wherein X is F, Cl, and Br, I,
R ' is aliphatic group or aryl radical
(10) formula I
9Compound can be by formula I
3Compound and prussiate reaction generate;
Wherein X is F, Cl, Br, I
(11) formula I
10Compound can be by formula I
3Compound and nitroso-group reactant salt generate;
Wherein X is F, Cl, Br, I
(12) formula I
11Compound can be by formula I
1Compound and phenylhydrazine reaction generate;
(13) formula I
12Compound can be by 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.
6. the method for formula I compounds for treating people or mammalian tumor cell is comprising the formula I compound that uses significant quantity to the patient.
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 true CN1138571A (en) | 1996-12-25 |
| CN1062853C 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) |
Cited By (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 |
| CN105687180A (en) * | 2015-12-11 | 2016-06-22 | 中国药科大学 | Sodium ion channel 1.7 inhibitor with analgesic effect |
| CN113261568A (en) * | 2021-04-21 | 2021-08-17 | 海南大学 | Zanthoxylum piperitum plant source bactericide and preparation method and application thereof |
| 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 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4758588A (en) * | 1983-06-20 | 1988-07-19 | Research Corporation Technologies | Diaminocyclohexane platinum complexes |
| US4661516A (en) * | 1983-06-20 | 1987-04-28 | Research Corporation | Diaminocyclohexane platinum complexes |
-
1996
- 1996-01-19 CN CN96100318A patent/CN1062853C/en not_active Expired - Fee Related
Cited By (6)
| 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 |
| CN105687180A (en) * | 2015-12-11 | 2016-06-22 | 中国药科大学 | Sodium ion channel 1.7 inhibitor with analgesic effect |
| 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 |
| CN113261568A (en) * | 2021-04-21 | 2021-08-17 | 海南大学 | Zanthoxylum piperitum plant source bactericide and preparation method and application thereof |
| WO2022222382A1 (en) * | 2021-04-21 | 2022-10-27 | 海南大学 | Uvaria grandiflora plant-derived fungicide, preparation method therefor, and application thereof |
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| Publication number | Publication date |
|---|---|
| CN1062853C (en) | 2001-03-07 |
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