摘要
超分子体是指在一定条件下,在主体分子的空间结构中全部或部分包入客体分子后,形成的一类高级结构。环糊精(CD)具有内疏水、外亲水的独特分子结构,其特有的疏水空腔能够选择性包合各种客体分子,形成稳定的包合物,从而使客体分子的药学性能得到改善;近年来,环糊精被广泛应用于医药、分析、食品、环境等多个领域。
本文采用β-环糊精、羟丙基-β-环糊精及环糊精硫酸酯作为主体,选取水溶性差的抗癌药物作为客体分子进行了分子识别研究,并进行了药物包合实验。
实验分为三个部分:(一)以5-氟尿嘧啶为客体,研究了四种环糊精(β-CD、HP-β-CD、6-β-CDS、2-β-CDS)在水溶液中对客体的分子识别性能,采用紫外-可见光光谱法测定了其包合稳定常数及包合比,结果表明:主体分子与客体分子形成了摩尔比为1:1的包合物;主客体分子的包合稳定性与取代基团、取代基的疏水性有关;环糊精硫酸酯对客体分子的包合作用最强,且2-β-CDS对客体分子的包合常数大于6-β-CDS。并制备了环糊精.氟尿嘧啶包合物,通过IR、DSC分析推断了其包合模型。(二)以姜黄素为客体,研究了五种环糊精(β-CD、HP-β-CD、6-β-CD、2-β-CD、β-CDS)在pH=2的柠檬酸缓冲溶液系统中对客体的包合和增溶作用。采用等摩尔比法测定包合比,紫外分光光度法研究增溶作用,荧光分光光度法研究荧光增强作用。结果表明:主体分子与客体分子形成了摩尔比为1:1的包合物;HP-β-CD对姜黄素的增溶效果最显著,β-CDS的增溶效果仅次于HP-β-CD;五种环糊精均能通过包合作用增加姜黄素的荧光强度,其中HP-β-CD与β-CDS的包合作用最强,当他们浓度达到3×10~(-2)M时,荧光增强倍数可到17和19倍;五种环糊精与姜黄素的包合常数K分别为129,397680,15562,52054,79956。(三)以多西紫杉醇为客体,应用圆二色谱研究水溶液中五种环糊精和多西紫杉醇的相互作用;并采用冷冻干燥法制备固体包合物,IR、DSC对包合物进行鉴定;同时对包合过程中相关的热力学参数进行考察。结果表明:多西紫杉醇与β-CD相互作用时其圆二色正性带和负性带强度增加最大,常温下五种环糊精与多西紫杉醇的包合常数K分别为521,147,65,179,467;制备环糊精-多西紫杉醇包合物,通过IR、DSC分析推断了包合模型;相溶解度法测定了热力学参数ΔG和ΔH均为负值,ΔS为负值,说明在恒温和恒压下,包合过程是一个能自发进行的放热过程。
Supermolecular is formed by host and guest molecular when a guest molecular is fully or partly included in the host molecular.Cyclodextrins(CD),have suitable molecular size and excellent biocompatibility,due to the unique structure with hydrophobic central cavity,they can selectively bind different guest molecules to form inclusion complexes.When the drug is included into the cavity of the cyclodextrin molecule,some interactions will happen and thus the pharmaceutical properties will be improved.Thus cyclodextrins have been widely used in many different fields,such as pharmaceutics,analytics,food and environment,etc in recent years.
In this paper,the use ofβ-cyclodextrin,hydroxypropyl-β-cyclodextrin and different substituted sulfated cyclodextrins as host molecules was investigated.The complexes of the cyclodextrins mentioned above with several poor water-soluble anti-cancer drugs were prepared and identified,and their molecular recognition behaviors were studied using several methods.
The experiments included the following three parts:
1.The molecular recognition behaviors between 5-fluorouracil and the following host moleculesβ-CD,HP-β-CD,6-β-CDS,2-β-CDS were studied.UV-Vis method was used to calculate the stability constants and inclusion ratio.The results showed that inclusion complexes were formed between the host and guest molecules with the molar ratios of 1:1;the stability of inclusion complexes was related to substituted functions and the hydrophobicity of the substituted functions;β-CDS showed the best complexation ability with the guest molecules,and the complexation constant of 2S-β-CD on the guest molecules was higher than that of 6-β-CD.The inclusion complexes of cyclodextrins with 5-fluorouracil were also characterized by IR,DSC.
2.The inclusion and solubility improvement of Curcumin with five cyclodextrins (β-CD,HP-β-CD,6-β-CDS,2-β-CDS,β-CDS)were studied in citrate buffer solution (pH=2).The solubility improvement of curcumin with the five cyclodextrins mentioned above was studied in saturated solutions.The fluoresence spectrophotometric titrations had been performed in buffer solution(pH=2.0),and the complexes stability constants(K)formed by the five cyclodextrins with curcumin were also calculated.The results showed that:all host molecules and guest molecule formed inclusion complex with the molar ratios of 1:1;The solubility of curcumin is improved in the five cyclodextrins solutions,in which HP-β-CD is the best,β-CDS was after HP-β-CD;The fluorescence intensity of curcumin was also improved in the five cyclodextrins solutions,in which HP-β-CD andβ-CDS are better.The fluoresence enhancement factors are up to 17 and 19 when their concentrations are 3×10~(-2)M.Inclusion constant K formed by cyclodextrins with cureumin is 129,397680, 15562,52054,79956 respectively.
3.Interactions between different concentration of cyclodextrins and docetaxel were studied using circular dichroism spectra in water.The inclusion compounds were prepared with lyophilization technique.The measurements of the inclusion molar ratio of the host to guest molecules,apparent complexation constants,the thermodynamic parameters and the identication of the inclusion complex were carded out by the methods such as continuous variation method,UV absorption spectroscopy,phase solubility diagram,differential scanning calorimeter(DSC)and infrared spectra(IR) methods,respectively.The circular dichroism results showed that the positive and negative band of docetaxel had the biggest increase in strength when docetaxel interacted withβ-CD.Inclusion constant K formed by cyclodextrins with docetaxel is 521,147,65,179,467 respectively at room temperature.The inclusion complexes of cyclodextrins with docetaxel were characterized by IR,DSC.Thermodynamic parametersΔG、ΔH are negative,ΔS is negative determinated by phase solubility method,these showed that the inclusion process was exothermic spontaneously.
引文
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