The Preparations And Applications Of Novel β-Cyclodextrin Derivatives

It has attracted significant interest of utilizing the cone-shaped cyclodextrins(CDs, includingα,β,γ-CD etc),which possesses a hydrophobic cavity and a hydrophilic outside,in artificial enzymes,molecule recognition,food,commodity,pharmacy, chemical industry,agriculture and other field.As the largest scale industrial production of cyclodextrins,β-CD has been winning more and more applications and developments for it's low price and high performance.However,the inherent defects of naturalβ-CD restrict its practical applications.For instance,the lacks of chromophores and auxochromes would limit the UV-Fluorescence analysis application ofβ-CD in supramolecular chemistry(Host-Guest interaction).In addition,β-cyclodextrin is lack of effective functional point of enzymes.To increase its Pattern Recognization(PR) ability for a enzyme simulation,theβ-cyclodextrin should be modified to become functionalβ-cyclodextrin derivatives by introducing certain functional groups.Moreover,poor water-solubility also restricts the application ofβ-CD.In order to expending its application,it is necessary to modifyβ-cyclodextrin properly.The main content of the paper was showed as follows:1.Oligo lactic acid modifiedβ-cyclodextrin derivatives:synthesis and application in drug complex and capillary electrophoresis.It has been a research focus on the poly lactic acid(PLA) drug carrier system for the biocompatibility and biodegradability of PLA.Combining oligo lactic acid andβ-cyclodextrin may get a useful pharmaceutic material.Based on the ring-opening polymerization of 3,6-dimethyl-1,4-dioxane-2,5-dione (lactide),newβ-cyclodextrin derivative was gotten by modification of oligo lactic acid group onβ-cyclodextrin.The new water soluble and biodegradableβ-cyclodextrin derivative shows as follow:6-oligo(D,L-lactic acid)-β-Cyclodextrin (6-OLA-β-CD),6-oligo(D-lactic acid)-β-Cyclodextrin(6-ODLA-β-CD),6-oligo (L-lactic acid)-β-Cyclodextrin(6-OLLA-β-CD),Oligo(lactic acid)-2-hydroxypropyl-β-Cyclodextrin (OLA-2-HP-β-CD),Oligo(lactic acid)-2-hydroxyethyl-β-Cyclodextrin (OLA-2-HE-β-CD).Based on the finding that the modified OLA side chain could degrade off from the cyclodextrin when being dissolved in water,the dynamic degradability controlled releasing system was put forward.The dynamic degradability controlled releasing system combine the specialty of cyclodextrin drug releasing system and PLA drug releasing system.When amoxicillin,simvastatin,lovastatin were employed to test the dynamic degradability controlled releasing system,it was found that the abscission of the OLA side chain can significantly influence the releasing ratio of amoxicillin complex(inclusion stability constant K reduces from 2.4×10⁵ to 137.3M^-1).The reason for this phenomenon was studied by DSC,FT-IR,¹H NMR.The possible reason may be the OLA side chain can give one force just like hydrogen bond with the guest drug molecular,which in macroscopic view manifested as the increased inclusion stability constant.In the drug stability and solubilization experiments,it was found that amoxicillin, simvastatin and lovastatin could effectively be solubilized and stabilized by 6-OLA-β-CD.However,ozagrel could effectively be stabilized by OLA-2-HP-β-CD. Phase solubility method was applied to study the inclusion of 6-OLA-β-CD (molecular weight=1637) andα-naphthylacetic acid.The stoichiometry of 6-OLA-β-CD andα-naphthylacetic acid was 1:1,and the inclusion stability constant K=177.67M^-1The 6-OLA-β-CD was used as chiral selectors in capillary electrophoresis for the separation of chlorpheniramine,propranolol,ketotifen.The separation of Ketotifen achieved good results,6-OLA-β-CD(mw=1637) achieved Rs=6.5 and 6-OLA-β-CD (mw=1307) achieved Rs=3.2.High molecular weight 6-OLA-β-CD shows better separation effect,compared with the low molecular weight 6-OLA-β-CD.The force between N atoms of chiral drugs and OLA side group may play an important role.2.Synthesis and thermal stability study ofβ-cyclodextrin ester derivetivesAmong the cyclodextrin derivatives,ester derivatives play an important role. Compared to ordinary ester compounds,the cyclodextrin esters has a unique cavity structure,it is possible that the cavity inclusion generates additional tension to the ester bond,which influences the stability of the ester.Meanwhile cyclodextrin can simulate ester hydrolase,which also may have an impact on itself.Up to now,there is no research focused on the stability of cyclodextrin ester.The new synthesized cyclodextrin ester shows as follows:6-O-monomethyl -maleate-β-cyclodextrin,2-O-(4-hydroxybutyrate)-β-cyclodextrin,Ethylene-diamine -tetraacetic-β-cyclodextrin,nitrilo triacetate-β-cyclodextrin,6-O-pivalyl-β-cyclodextrin, 6-O-xanthogen-β-cyclodextrin,6-O-dodecyloxyhdroxyphosphoryl-β-cyclodextrin, 6-O-tetradecyloxyhdroxyphosphoryl-β-cyclodextrin,6-O-cetyloxy -hdroxyphosphoryl-β-cyclodextrin,6-O-octadecyl oxyhdroxyphosphoryl-β-cyclodextrin.By DSC/TG analysis,the thermal stabilities of 6-O-monomethylmaleate-β-cyclodextrin, 2-O-(4-hydroxybutyrate)-β-cyclodextrin,Ethylenediaminetetraacetic-β-cyclodextrin, nitrilo triacetate-β-cyclodextrin,6-O-pivalyl-β-cyclodextrin,6-O-xanthogen-β-cyclodextrin, 6-O-dodecyloxyhdroxyphosphoryl-β-cyclodextrin,6-O-tetradecyl oxyhdroxyphosphoryl-β-cyclodextrin,6-O-cetyloxyhdroxyphosphoryl-β-cyclodextrin, 6-O-octadecyl oxyhdroxyphosphoryl-β-cyclodextrin,6-OLA-β-CD, OLA-HP-β-CD,6-OLLA-β-CD,mono-(3-O-benzoyl)-β-cyclodextrin and mono-(6-O-benzoyl)-β-cyclodextrin were studied.DSC/TGA analysis found that the modification location of substituents lead to different thermal stability.In the DSC/TGA curve,mono-(3-O-benzoyl)-β-cyclodextrin loss weight at 176℃and mono-(6-O-benzoyl)-β-cyclodextrin at 274℃.3.Thermal-conversable capped cyclodextrin based on reversible Diels-Alder reactionThe existence of the cap is of great significance in cyclodextrin supramolecular system.The introduction of the cap can bring different hydrophilic or hydrophobic site,which can improved solubility in certain solvents.The existence of cap can limit the free rotation of included molecular,which can changed inclusion ability to certain moleculars.Also the caps complexed with metal ions can analog metalloenzyme or active site for catalysis of phosphorus or nitrogen ligand. Using anhydride amidolysis reaction,a reversible group based on Diels-Alder reaction is introduced to cyclodextrin,which provides a new controlled cyclodextrin inclusion system.Two new capped cyclodextrin derivatives were prepared by reacting Ethylenediamine-β-cyclodextrin with furan/maleic anhydride cycloaddition product and anthracene/maleic anhydride cycloaddition product.DSC/TGA tests indicate anthraquinone/maleic anhydride cycloaddition cappedβ-cyclodextrin could lose anthracene structure at 135-191℃,which influence the inclusion with guest molecular of benzoic acid.4.New dendritic cyclodextrin derivatives:synthesis and microspheroidization for drug carrierIn a convenient way,the new dendritic cyclodextrin derivatives,which have cone-shaped cavity and long dendritic functional group,were synthesized through the semi-solid state reaction.The derivatives were successfully microspheridizated by emulsion solvent evaporation technique.In the static lossing experiments of I₂,the result shows that modified dendritic peripheral could significantly slow down the release of I₂ molecules in inclusion complex,and by changing the ratio of long and short chain can achieve different release speed.When the reaction materials octadecanol:alcohol= 1:1,the release of I₂ is the slowest,only 1/250β-CD which under the same conditions.5.β-cyclodextrin catalyst in organic synthesisCyclodextrin can form reversible inclusion complex with hydrophobic organic molecules,which can increasing solubility of hydrophobic molecules in water,so that the organic reactions can be carried out in the water that friendly to the environment. Meanwhile,the cavity is in rich of electron,which also can affect the electrical properties the guest molecular.Hydroxyl group on the rim of the cavity can form hydrogen bond with special molecular,which will activate some organic reactions.In the experiment of styrene epoxidation by H₂O₂,the results shows that the catalytic effects are carboxymethyl-β-cyclodextrin＞β-cyclodextrin sulfonate(high DS)＞β-cyclodextrin sulfonate(low DS)＞β-cyclodextrin,Sulfuric acid,acetic acid. The results indicate thatβ-cyclodextrin derivative with carboxyl functional groups can serve as a phase transfer catalyst;on the other hand carboxyl functional groups can serve as a reaction catalyst,which catalytic effect is better thanβ-cyclodextrin, sulfuric acid,acetic acid.The use ofβ-cyclodextrin can make oximation of acetylacetone happened without sulfuric acid and at high temperature.Cyclodextrin catalysis has different catalytic mechanism,compared with traditional acid catalysis.Cyclodextrin can transfer organic molecular to water,and the electronic cavity can activate the reacting point of acetylacetone.The addition reaction of acrylonitrile and water can be achieved in roomtemperature by KI and cyclodextrin,the introduction of cyclodextrin as a phase transfer catalyst increases solubility of acrylonitrile in water.And at the same time theβ-CD cavity may also be involved in the activation of the reaction.Main innovations of the thesis:(1) A new fine water-soluble and biodegradableβ-cyclodextrin derivatives, oligo(lactic acid) group modifiedβ-cyclodextrin were synthesized:6-OLA-β-CD (mw=1236,n=0.8,x=1.7),6-OLA-β-CD(mw=1339,n=1.219,x=2.325),6-OLA-β-CD (mw=1469,n=1.68,x=2.76) 6-OLA-β-CD(mw=1637,n=1.55,x=4.48),6-ODLA-β-CD(mw=1297), 6-OLLA-β-CD(mw=1309),OLA-HP-β-CD(x=1.4),OLA -HP-β-CD(x=10.3),OLA-HE-β-CD.(2) For the first time,the dynamic degradation controlled release model,which combined the traditional cyclodextrin release with PLA release,is put forwards.And this model achieved controlled release of amoxicillin,simvastatin,lovastatin.The degradation of PLA side chain had a clear impact on the inclusion of amoxicillin. Meanwhile,6-OLA-β-CD can effectively solubilize and stabilize amoxicillin, simvastatin,lovastatin.OLA-HP-β-CD can effectively stabilize ozagrel.(3) The 6-OLA-β-CD was used as chiral selectors in capillary electrophoresis for the separation of chlorpheniramine,propranolol,ketotifen.The separation of Ketotifen achieved fine results,6-OLA-β-CD(mw=1637) achieved Rs=6.5 and 6-OLA-β-CD(mw=1307) achieved Rs=3.2.It is found that high molecular weight 6-OLA-β-CD shows better separation effect,compared with the low molecular weight 6-OLA-β-CD.(4) The new cyclodextrin ester were synthesized:6-O-monomethyl-maleate-β-cyclodextrin, 2-O-(4-hydroxybutyrate)-β-cyclodextrin,Ethylenediaminetetraacetic-β-cyclodextrin, nitrilo triacetate-β-cyclodextrin,6-O-pivalyl-β-cyclodextrin,6-O-xanthogen-β-cyclodextrin, 6-O-dodecyloxyhdroxyphosphoryl-β-cyclodextrin,6-O -tetradecyloxyhdroxyphosphoryl-β-cyclodextrin,6-O-cetyloxyhdroxy-phosphoryl-β-cyclodextrin, 6-O-octadecyl oxyhdroxyphosphoryl-β-cyclodextrin.(5) DSC/TGA analysis found that the modification location of substituents lead to different thermal stability.In the DSC/TGA curve,mono-(3-O-benzoyl) -β-cyclodextrin loss weight at 176℃and mono-(6-O-benzoyl)-β-cyclodextrin at 274℃.(6) Two new capped cyclodextrin derivatives were prepared by reacting Ethylenediamin-β-cyclodextrin with furan/maleic anhydride cycloaddition product and anthracene/maleic anhydride cycloaddition product.DSC/TGA tests indicate anthraquinone/maleic anhydride cycloaddition cappedβ-cyclodextrin could lose anthracene structure at 135-191℃,which will influence the inclusion with guest molecular.(7) In a convenient way,the new dendritic cyclodextrin derivatives,which have cone-shaped cavity and long dendritic functional group,were synthesized through the semi-solid state reaction.In the static lossing experiments of I₂,the result shows that modified dendritic peripheral can significantly slow down the release of I₂ molecules in inclusion complex,and by changing the ratio of long and short chain can achieve different release speed.When the reaction materials octadecanol:alcohol=1:1,the release of I₂ is the slowest,only 1/250β-CD which under the same conditions.(8) In the experiment of styrene epoxidation by H₂O₂,the results shows that the catalytic effects are carboxymethyl-β-cyclodextrin＞β-cyclodextrin sulfonate(high DS)＞β-cyclodextrin sulfonate(low DS)＞β-cyclodextrin,Sulfuric acid,acetic acid.(9) The use ofβ-cyclodextrin can make oximation of acetylacetone happened without sulfuric acid and at high temperature. (10) The addition reaction of acrylonitrile and water can be achieved in roomtemperature by KI and cyclodextrin.