CN101230079A - 1,2-glycoside transderivative of oxazole compounds and preparation method thereof - Google Patents
1,2-glycoside transderivative of oxazole compounds and preparation method thereof Download PDFInfo
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- CN101230079A CN101230079A CNA2008100145081A CN200810014508A CN101230079A CN 101230079 A CN101230079 A CN 101230079A CN A2008100145081 A CNA2008100145081 A CN A2008100145081A CN 200810014508 A CN200810014508 A CN 200810014508A CN 101230079 A CN101230079 A CN 101230079A
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- glycosyl
- oxazole
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- oxazole compounds
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses 1, 2-anti form glucoside derivative of oxazole compound. During the preparation, 4-(3, 4, 5-trimethoxy phenyl)-5-(3-hydroxyl-4-methoxy phenyl oxazole is used as the acceptor of glycosyl, bromo sugar of D-glucose, D-galactose, L-arabinose, D-xylose, L-fucose or lactose with full acetyl protection, or trichlorine imine ester of L-rhamnose or D-mannose with full acetyl protection is adopted as the donator of glycosyl, glycosylation is performed with the catalysis of alkali and tetrabutyl ammonium bromide or lewis acid, to obtain glucoside derivative containing acetyl protecting group; and then the acetyl protecting group is removed by utilizing methyl alcohol and sodium methoxide, to obtain 1,2 anti-form glucoside derivative of oxazole compound. The preparation method is simple, highly effective and universal, the route is short, the water-solubility of the product is good, the bioavailability is high, thereby the glucoside derivative can be applied as antineoplastic medicine inhibiting microtubule assembly and selectively targeting tumor blood vessels.
Description
Technical field
The present invention relates to 1 of Yi Zhong oxazole compounds, 2-trans-glycoside and preparation method thereof.
Background technology
Lamellarins is that sponge, the Ascidian from the ocean separates the polyaromatic alkaloid compound of extended familys that obtain, and its constitutional features is that a pyrroles center is replaced by poly-hydroxy or Polymethoxylated phenyl ring.Studies show that Lamellarins has extremely strong cytotoxic activity to various tumor cell strains, but its synthetic complicacy makes its patent medicine become very difficult.
Antitumor drug Combretastatin A-4 (being called for short CA-4) is the diphenylethylene compounds of separating from the plant Combretum caffrum of South Africa, and it is to the ED of P3 88 cell strains
50Value is 0.0034 μ g/mL, and tubulin polymerization suppresses active IC
50Be 2-3 μ M.It has with 3,4 of cis-double bonds connection, the B ring that A ring that the 5-trimethoxy replaces and 3-hydroxyl 4-methoxyl group replace.CA-4 is a kind of new type antineoplastic medicine of many target spots, can effectively suppress the polymerization of tubulin, also is effective growth inhibitor for tumor vessels.But because CA-4 is water-soluble bad, cause the pharmacokinetics poor-performing, limited its application clinically; The easy isomery of cis-double bonds in the structure turns to the more stable trans double bond of thermodynamics in addition, thus active the reduction.Wang Le etc. utilizes heterocycles such as imidazoles, oxazole and pyrazoles to replace two keys to be connected A, B and encircles and obtained the CA-4 heterocyclic analogs, has solved the problem of CA-4 double-bond isomerization.CA-4 heterocyclic analogs Zhong De oxazole analogue 4-(3,4, the 5-trimethoxyphenyl)-5-(3-hydroxyl-4-p-methoxy-phenyl) oxazole [English name 4-(3,4,5-trimethoxyphenyl)-and 5-(3-hydroxy-4-methoxyphenyl) oxazole] tumour cell is had better inhibited activity, but still there are lipotropy height, water-soluble bad, the defective that bioavailability is low.
Summary of the invention
The purpose of this invention is to provide 1 of Yi Zhong oxazole compounds, 2-trans-glycoside derivative and preparation method thereof, can overcome nitrogenous polynuclear aromatic hydrocarbons compounds Lamellarins synthetic difficulty, and 1 of Gai oxazole compounds, 2-trans-glycoside derivative good water solubility, the bioavailability height can be as the antitumor drug that suppresses micropipe aggregation, selectivity target tumor blood vessel.
1 of Yi Zhong oxazole compounds, 2-trans-glycoside derivative is characterized in that its structural formula is as follows:
R=CH in the formula
2During OH, glycosyl part is D-glucose, D-semi-lactosi or D-seminose; During R=H, glycosyl part is L-arabinose or D-wood sugar; R=CH
3The time, glycosyl part is L-rhamnosyl or L-Fucose; R=C
6H
11O
6The time, glycosyl part is a lactose.
1 of Shang Shu oxazole compounds, the preparation method of 2 trans-glycoside derivatives, it is characterized in that with 4-(3,4, the 5-trimethoxyphenyl)-(3-hydroxyl-4-p-methoxy-phenyl) oxazole is a glycosyl acceptor to 5-, bromo sugar with D-glucose, D-semi-lactosi, L-arabinose, D-wood sugar, L-Fucose or the lactose of full acetyl protection, or be glycosyl donor with the L-rhamnosyl of full acetyl protection or three chlorimide esters of D-seminose, at alkali and Tetrabutyl amonium bromide or under lewis acidic catalysis, carry out glycosylation reaction, obtain containing the glycosides derivatives of acetyl protection base; Utilize methyl alcohol and sodium methylate to remove the ethanoyl protecting group then, De is Dao 1,2 trans-glycoside derivative of oxazole compounds.
1 of De oxazole compounds of the present invention, the good water solubility of 2-trans-glycoside derivative can be improved the bioavailability of guide's thing and the target tumor vascular of raising drug molecule; The preparation method is easy, and route is shorter, and condition is easy to control, has improved combined coefficient greatly.
Embodiment
Simple in structure and have the Lamellarin 1C and a CA-4 De oxazole analogue 4-(3 of remarkable anti-tumor activity, 4, the 5-trimethoxyphenyl)-and 5-(3-hydroxyl-4-p-methoxy-phenyl) oxazole structurally has-the skeleton similarity of Ding, and the oxazole analogue of CA-4 is equivalent to the pyrrole ring with oxazole ring displacement Lamellarin frame center.Therefore the present invention simulates Lamellarins as lead compound with CA-4 De oxazole analogue, carry out structural modification, prepare the high-activity compound that suppresses micropipe aggregation, has selectivity target inner skin cell function, obtain existing tumor vessel in the body is had the microtubule association class antitumor drug of the novel structure of tangible destruction on this basis.
The present invention utilizes glycosylation that lead compound is modified, and it is water-soluble to improving, the target of bioavailability and raising drug molecule has meaning preferably.
1. the preparation of the D-glucose of oxazole compounds, D-semi-lactosi, L-arabinose, D-wood sugar, L-Fucose, lactose glycosides derivatives, its concrete steps are as follows:
4-(3 with 0.6mmol, 4, the 5-trimethoxyphenyl)-(the Tetrabutyl amonium bromide phase-transfer catalyst of 3-hydroxyl-4-p-methoxy-phenyl) oxazole glycosyl acceptor and 0.6mmol is dissolved in the chloroform of 30mL 5-, the 30mL aqueous solution that adds 4.2mmol alkali then stirs adding 0.96mmol bromo sugar glycosyl donor after 10 minutes, is warming up to 40 ℃, reacted 6 hours, with the dilution of 30mL chloroform, use 30mL deionized water, the water washing of 30mL saturated common salt successively, use anhydrous Na
2SO
4Drying is filtered, and concentrates, and obtains containing the glycosides derivatives solid of acetyl protection base through silica gel column chromatography.This solid is dissolved in 20mL methyl alcohol, and the adding sodium methylate transfers to pH 8-9 and removes the ethanoyl protecting group, reacts about 30 minutes; with the resin cation (R.C.) neutralization, filter, concentrate; silica gel column chromatography obtains glycosides derivatives, is 1,2 trans-glycoside derivative of De oxazole compounds of the present invention.
Bromo sugar glycosyl donor described in the above-mentioned reaction is full acetyl bromide for glucose, full acetyl bromide for semi-lactosi, full acetyl bromide for pectinose, full acetyl bromide for wood sugar, full acetyl bromide for Fucose or full acetyl bromide for lactose.Described alkali is sodium hydroxide or Anhydrous potassium carbonate.The mol ratio of described glycosyl acceptor, glycosyl donor, alkali and phase-transfer catalyst is 1.0-1.5: 1.0-2.0: 7.0-11.0: 1.0-1.5.
2. the preparation of the L-rhamnosyl of oxazole compounds and D-seminose glycosides derivatives, its concrete steps are as follows:
4-(3,4, the 5-trimethoxyphenyl)-5-(3-hydroxyl-4-p-methoxy-phenyl) oxazole glycosyl acceptor and new activatory 50mg4 molecular sieve adding 10mL exsiccant CH with 0.1mmol
2Cl
2, stirred 20 minutes under the room temperature, change-40 ℃ of low-temp reaction devices over to, stirred 15 minutes, drip the 0.1mmol lewis acid catalyst, slowly drip the CH of three chlorimide ester glycosyl donors of the full acetyl sugar of 1.3mmol then
2Cl
2Solution ,-40 ℃ were reacted 1 hour, with triethylamine cancellation reaction, filtration, concentrating under reduced pressure, obtained containing the glycosides derivatives solid of acetyl protection base through silica gel column chromatography.This solid is dissolved in 20mL methyl alcohol; the adding sodium methylate transfers to pH8-9 and removes the ethanoyl protecting group; reacted about 20 minutes; TLC detects to the reaction end, with the resin cation (R.C.) neutralization, filters; concentrate; obtain white solid through silica gel column chromatography, be 1,2 trans-glycoside derivative of De oxazole compounds of the present invention.
Three chlorimide ester glycosyl donors of the full acetyl sugar described in the above-mentioned reaction are three chlorimide esters of full acetyl rhamnosyl or three chlorimide esters of full acetylated mannan sugar.Described Lewis acid is trifluoromethanesulfonic acid (TfOH) or trimethyl silicane triflate (TMSOTf) or boron trifluoride-ether.The mol ratio of described glycosyl acceptor, glycosyl donor, lewis acid catalyst is 1-1.5: 1.0-1.5: 0.5-1.0
1 of the De oxazole compounds of the present invention that above-mentioned reaction obtains, the structural formula of 2-trans-glycoside derivative is:
R=CH in the formula
2During OH, glycosyl part is D-glucose, D-semi-lactosi or D-seminose; During structure R=H, glycosyl part is L-arabinose or D-wood sugar; R=CH
3The time, glycosyl part is L-rhamnosyl or L-Fucose; R=C
6H
11O
6The time, glycosyl part is a lactose.
1 of this invention Yi Zhong oxazole compounds, 2-trans-glycoside derivative has good water solubility, biological utilisation Spend high advantage, can carry out as the antineoplastic that suppresses micropipe aggregation, selective target tumor blood vessel Use.
Claims (4)
1. 1 of Yi Zhong oxazole compounds, 2-trans-glycoside derivative is characterized in that its structural formula is as follows:
R=CH in the formula
2During OH, glycosyl part is D-glucose, D-semi-lactosi or D-seminose; During R=H, glycosyl part is L-arabinose or D-wood sugar; R=CH
3The time, glycosyl part is L-rhamnosyl or L-Fucose; R=C
6H
11O
6The time, glycosyl part is a lactose.
2. 1 of claim 1 Suo Shu De oxazole compounds, the preparation method of 2 trans-glycoside derivatives, it is characterized in that with 4-(3,4, the 5-trimethoxyphenyl)-(3-hydroxyl-4-p-methoxy-phenyl) oxazole is a glycosyl acceptor to 5-, D-glucose with full acetyl protection, the D-semi-lactosi, L-arabinose, the D-wood sugar, the bromo sugar of L-Fucose or lactose, or be glycosyl donor with the L-rhamnosyl of full acetyl protection or three chlorimide esters of D-seminose, at alkali and Tetrabutyl amonium bromide or under lewis acidic catalysis, carry out glycosylation reaction, obtain containing the glycosides derivatives of acetyl protection base; Utilize methyl alcohol-sodium methylate to remove the ethanoyl protecting group then, De is Dao 1,2 trans-glycoside derivative of oxazole compounds.
3. as the preparation method of 1,2 trans-glycoside derivative of claim 2 Suo Shu De oxazole compounds, it is characterized in that described alkali is sodium hydroxide or Anhydrous potassium carbonate; The mol ratio of described glycosyl acceptor, glycosyl donor, alkali and Tetrabutyl amonium bromide is 1.0-1.5: 1.0-2.0: 7.0-11.0: 1.0-1.5.
4. as the preparation method of 1,2 trans-glycoside derivative of claim 2 Suo Shu De oxazole compounds, it is characterized in that described Lewis acid is trifluoromethanesulfonic acid (TfOH) or trimethyl silicane triflate (TMSOTf) or boron trifluoride-ether; Described glycosyl acceptor, glycosyl donor, lewis acidic mol ratio are 1: 1.0-1.5: 0.5-1.0.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011073112A3 (en) * | 2009-12-14 | 2011-09-09 | University Of Basel | Mannose derivatives as antagonists of bacterial adhesion |
| CN102863472A (en) * | 2012-10-15 | 2013-01-09 | 中国海洋大学 | Combretastatin A-4 analogue, preparation method of combretastatin A-4 analogue and application of combretastatin A-4 analogue in preparing anti-tumor drugs |
| JP2014523885A (en) * | 2011-07-05 | 2014-09-18 | 南京聖和薬業有限公司 | Tumor targeting drug combretastatin A4 derivative |
| CN112300232A (en) * | 2020-11-03 | 2021-02-02 | 浙江大学 | Lamelarin D glycosylated derivative and preparation and application thereof |
-
2008
- 2008-01-29 CN CNA2008100145081A patent/CN101230079A/en active Pending
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102753562B (en) * | 2009-12-14 | 2015-11-25 | 巴塞尔大学 | As the mannose derivative of bacterial adhesion antagonist |
| CN102753562A (en) * | 2009-12-14 | 2012-10-24 | 巴塞尔大学 | Mannose derivatives as antagonists of bacterial adhesion |
| JP2013513637A (en) * | 2009-12-14 | 2013-04-22 | ユニバーシティ・オブ・バーゼル | Mannose derivatives as antagonists of bacterial adhesion |
| EP2604619A2 (en) * | 2009-12-14 | 2013-06-19 | University of Basel | Mannose derivatives as antagonists of bacterial adhesion |
| EP2604619A3 (en) * | 2009-12-14 | 2014-01-22 | University of Basel | Mannose derivatives as antagonists of bacterial adhesion |
| WO2011073112A3 (en) * | 2009-12-14 | 2011-09-09 | University Of Basel | Mannose derivatives as antagonists of bacterial adhesion |
| EP2960247A1 (en) * | 2009-12-14 | 2015-12-30 | University of Basel | Phenyl-alpha-d-mannosides for use in the treatment of bacterial infections caused by escherichia coli |
| JP2014523885A (en) * | 2011-07-05 | 2014-09-18 | 南京聖和薬業有限公司 | Tumor targeting drug combretastatin A4 derivative |
| US9139574B2 (en) | 2011-07-05 | 2015-09-22 | Nanjing Sanhome Pharmaceutical Co., Ltd. | Tumor targeted drug combretastatin A4 derivative |
| CN102863472A (en) * | 2012-10-15 | 2013-01-09 | 中国海洋大学 | Combretastatin A-4 analogue, preparation method of combretastatin A-4 analogue and application of combretastatin A-4 analogue in preparing anti-tumor drugs |
| CN102863472B (en) * | 2012-10-15 | 2015-05-13 | 中国海洋大学 | Combretastatin A-4 analogue, preparation method of combretastatin A-4 analogue and application of combretastatin A-4 analogue in preparing anti-tumor drugs |
| CN112300232A (en) * | 2020-11-03 | 2021-02-02 | 浙江大学 | Lamelarin D glycosylated derivative and preparation and application thereof |
| CN112300232B (en) * | 2020-11-03 | 2021-11-09 | 浙江大学 | Lamelarin D glycosylated derivative and preparation and application thereof |
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Open date: 20080730 |