反相高效液相法快速预测化合物亲脂性的研究
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摘要
目的:任梦鹤同学的硕士研究论文已经分别在XTerra RP 18,YMC- Pack ODS-A色谱柱上的对11个中性及两性化合物的保留因子(logk)进行了研究,建立了logkw值与logP_(oct)值线性回归方程,并且运用LSER(线性溶剂自由能关系)法分析并证明了化合物在XTerra RP 18柱的保留机制与在正辛醇/水系统中的分配机制是一致的,XTerra RP 18柱比YMC-Pack ODS-A更适合用来快速的预测化合物的亲脂性参数logP_(oct)值。在此基础上,用XTerra RP 18进一步测定了35个结构及性质多样化的化合物(包括中性、两性、酸性及碱性)在反相高效液相色谱(RP-HPLC)上的保留因子logk,并外推出甲醇含量为0的流动相中的logkw值。同时,对测得logkw值与这些化合物亲脂性参数logP_(oct)值的进行了相关性分析,探索以XTerra RP 18柱快速测定结构及性质多样化的化合物(尤其是碱性化合物)亲脂性的方法的可行性及其测定范围。
方法:采用RP-HPLC法测定了结构及性质多样化的化合物集合在XTerra RP 18色谱柱上的保留因子(logk),并外推出logkw值。建立logkw值与logP_(oct)值线性回归方程。将前期研究的11种化合物的logkw值代入线性方程,计算出logPpre值,并与logP_(oct)值比较。
结果:35个中性、两性、酸性和碱性化合物的logP_(oct)值与logkw值的线性方程: logP_(oct) =0.8964(±0.219)logkw+0.1805(±0.201) n=35, r~2=0.9471, F=322中性及两性化合物logkw值和logP_(oct)值的线性方程: logP_(oct)=0.8151(±0.172)logkw +0.5466(±0.142) n=9, r~2= 0.9832, F=410酸性化合物logkw值和logP_(oct)值的线性方程: logP_(oct) =1.0153(±0.340)logkw-0.0882(±0.352) n=10, r~2=0.9634, F=211碱性化合物logkw值和logP_(oct)值的线性方程:logP_(oct) =0.9428(±0.376)logkw-0.0.0925(±0.0.360) n=16, r~2=0.9706, F=462所有46个化合物(本论文选择的35个化合物加上在任梦鹤硕士论文中的11个化合物)的的测定结果,建立的logkw值和logP_(oct)值的线性方程如下: logP_(oct)=0.8596(±0.213)logkw+0.3448(±0.189) n=46, r~2=0.9356, F=639
结论:XTerra RP 18柱在本实验条件下所测定中性、两性、酸性及碱性化合物的logkw值与正辛醇/水系统中的分配系数logP_(oct)值之间存在线性关系(r~2=0.9471),用35个化合物所建立的线性方程计算前期研究的11个化合物的logPpre值与logP_(oct)值无显著性差异。XTerra RP 18柱可用来预测结构及性质多样化的化合物的亲脂性参数logP_(oct)值,尤其是用于对碱性化合物的亲脂性预测。
Objective: A set of 11 model solutes and drugs were selected to determine their extrapolated logkw of the retention factor logk by Reversed-Phase High-Performance Liquid Chromatography (RP-HPLC)in two different stationary phases(XTerra RP 18,YMC- Pack ODS-A). Compared the correlations of extrapolation capacity factors logkw and the lipophilicity partition coefficients (logP_(oct)) in two stationary phases. The previous experiments analyzed by a method based on linear solvation-energy relationships (LSERs) had already demonstrated that the retention mechanism of the compounds on the XTerra RP 18 stationary phase was similar to the mechanisms of the solutes’partition in octanol/water system. And the polar embedded ligands phase XTerra RP 18 phase was more suitable for the rapidly determining lipophilicity. On this basis, a set 35 compounds and drugs of various structures and properties (neutral, amphoteric, acid and basic compounds) were selected to determine their extrapolated logkw of the retention factor logk by the XTerra RP 18 stationary phase to explore the feasibility and range of determining method of the the XTerra RP 18 stationary phase.
Method: XTerra RP 18 stationary phase was applied to determine the 35 compounds’logk and extrapolated to 100% H2O (phosphate buffer)logkw and established the linear regression equation of logkw and logP_(oct) by the sas JMP6.0 to discuss the the feasibility and range of determining method of the the XTerra RP 18 stationary phase. Calculated the previous 11 compouds’logPpre by introduce the logkw into the linear regression equation and analyzed the logPpre and logP_(oct) by SPSS.
Results: The linear regression equation of logkw value and logP_(oct) value of neutral, amphoteric, acid and basic compounds: logP_(oct) =0.8964(±0.219)logkw+0.1805(±0.201) n=35, r~2=0.9471, F=322
The linear regression equation of logkw value and logP_(oct) value of neutral and amphoteric compounds: logP_(oct)=0.8151(±0.172)logkw +0.5466(±0.142) n=9, r~2= 0.9832, F=410 The linear regression equation of logkw value and logP_(oct) value of acid compounds: logP_(oct) =1.0153(±0.340)logkw-0.0882(±0.352) n=10, r~2=0.9634, F=211 The linear regression equation of logkw value and logP_(oct) value of basic compounds: logP_(oct) =0.9428(±0.376)logkw-0.0.0925(±0.0.360) n=16, r~2=0.9706, F=462 Calculated the previous 11 compouds’logPpre value by introduce the logkw into the linear regression equation and analyzed the logPpre and logP_(oct) by SPSS. There was no significant difference between logP_(oct) value and logPpre value.
Conclusion: The good correlation between the logkw and log Poct of the set of 35 neutral, amphoteric, acid and basic compounds indicated that the XTerra RP 18 stationary phase was appropriate to predict the log Poct of compounds of various structures and properties. And there was no significant difference between logP_(oct) value and logPpre value.
方法:采用RP-HPLC法测定了结构及性质多样化的化合物集合在XTerra RP 18色谱柱上的保留因子(logk),并外推出logkw值。建立logkw值与logP_(oct)值线性回归方程。将前期研究的11种化合物的logkw值代入线性方程,计算出logPpre值,并与logP_(oct)值比较。
结果:35个中性、两性、酸性和碱性化合物的logP_(oct)值与logkw值的线性方程: logP_(oct) =0.8964(±0.219)logkw+0.1805(±0.201) n=35, r~2=0.9471, F=322中性及两性化合物logkw值和logP_(oct)值的线性方程: logP_(oct)=0.8151(±0.172)logkw +0.5466(±0.142) n=9, r~2= 0.9832, F=410酸性化合物logkw值和logP_(oct)值的线性方程: logP_(oct) =1.0153(±0.340)logkw-0.0882(±0.352) n=10, r~2=0.9634, F=211碱性化合物logkw值和logP_(oct)值的线性方程:logP_(oct) =0.9428(±0.376)logkw-0.0.0925(±0.0.360) n=16, r~2=0.9706, F=462所有46个化合物(本论文选择的35个化合物加上在任梦鹤硕士论文中的11个化合物)的的测定结果,建立的logkw值和logP_(oct)值的线性方程如下: logP_(oct)=0.8596(±0.213)logkw+0.3448(±0.189) n=46, r~2=0.9356, F=639
结论:XTerra RP 18柱在本实验条件下所测定中性、两性、酸性及碱性化合物的logkw值与正辛醇/水系统中的分配系数logP_(oct)值之间存在线性关系(r~2=0.9471),用35个化合物所建立的线性方程计算前期研究的11个化合物的logPpre值与logP_(oct)值无显著性差异。XTerra RP 18柱可用来预测结构及性质多样化的化合物的亲脂性参数logP_(oct)值,尤其是用于对碱性化合物的亲脂性预测。
Objective: A set of 11 model solutes and drugs were selected to determine their extrapolated logkw of the retention factor logk by Reversed-Phase High-Performance Liquid Chromatography (RP-HPLC)in two different stationary phases(XTerra RP 18,YMC- Pack ODS-A). Compared the correlations of extrapolation capacity factors logkw and the lipophilicity partition coefficients (logP_(oct)) in two stationary phases. The previous experiments analyzed by a method based on linear solvation-energy relationships (LSERs) had already demonstrated that the retention mechanism of the compounds on the XTerra RP 18 stationary phase was similar to the mechanisms of the solutes’partition in octanol/water system. And the polar embedded ligands phase XTerra RP 18 phase was more suitable for the rapidly determining lipophilicity. On this basis, a set 35 compounds and drugs of various structures and properties (neutral, amphoteric, acid and basic compounds) were selected to determine their extrapolated logkw of the retention factor logk by the XTerra RP 18 stationary phase to explore the feasibility and range of determining method of the the XTerra RP 18 stationary phase.
Method: XTerra RP 18 stationary phase was applied to determine the 35 compounds’logk and extrapolated to 100% H2O (phosphate buffer)logkw and established the linear regression equation of logkw and logP_(oct) by the sas JMP6.0 to discuss the the feasibility and range of determining method of the the XTerra RP 18 stationary phase. Calculated the previous 11 compouds’logPpre by introduce the logkw into the linear regression equation and analyzed the logPpre and logP_(oct) by SPSS.
Results: The linear regression equation of logkw value and logP_(oct) value of neutral, amphoteric, acid and basic compounds: logP_(oct) =0.8964(±0.219)logkw+0.1805(±0.201) n=35, r~2=0.9471, F=322
The linear regression equation of logkw value and logP_(oct) value of neutral and amphoteric compounds: logP_(oct)=0.8151(±0.172)logkw +0.5466(±0.142) n=9, r~2= 0.9832, F=410 The linear regression equation of logkw value and logP_(oct) value of acid compounds: logP_(oct) =1.0153(±0.340)logkw-0.0882(±0.352) n=10, r~2=0.9634, F=211 The linear regression equation of logkw value and logP_(oct) value of basic compounds: logP_(oct) =0.9428(±0.376)logkw-0.0.0925(±0.0.360) n=16, r~2=0.9706, F=462 Calculated the previous 11 compouds’logPpre value by introduce the logkw into the linear regression equation and analyzed the logPpre and logP_(oct) by SPSS. There was no significant difference between logP_(oct) value and logPpre value.
Conclusion: The good correlation between the logkw and log Poct of the set of 35 neutral, amphoteric, acid and basic compounds indicated that the XTerra RP 18 stationary phase was appropriate to predict the log Poct of compounds of various structures and properties. And there was no significant difference between logP_(oct) value and logPpre value.
引文
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[2] Xiangli Liu, Hiroshi Chuman. Determination of solute lipophilicity by reversed-phase high–performance liquid chromatography(RP-HPLC) [J]. The Journal of Medical Investe- gation,2005,52Suppl :293-294.
[3] Z. Mrkvickova, P.Kovar?kova, S. Bal?kova,J. Klimes.Determination of lipophilicity of novel potential antituberculotic agents using HPLC on monolithic stationary phase and theoretical calculations[J]. J Pharm Biomed Anal (2008), doi:10.1016/ j.jpba. 2007.12.040.
[4] K. Valko, J. Chromatogr. A 1037 (2004): 299–310.
[5] OECD Guidelines for the Testing of Chemicals, Test No. 107; Organisation for Economic Co-operation and Development (OECD): Paris, 1995.
[6] Danielsson, L.-G.; Zhang, Y.-H. TrAC, Trends Anal. Chem. 1996, 15, VIII.
[7] Sangster, J. Octanol-water Partition Coefficients: Fundamentals and Physical Chemistry; Wiley: New York, 1997.
[8] Liu.X, G.Bouchard, H.Girault,et al. Partition Coefficients of Ionizable Compounds in o-Nitrophenyl Octyl Ether/Water Measured by the Potentiometric Method[J]. Anal. Chem, 2003, 75: 7036-7039.
[9] Roman Kaliszan, Antoni Nasal and Micha Jan Markuszewski. New approaches to hromatographic determination of lipophilicity of xenobiotics[J]. Analytical and Bioanalytical Chemistry, 2003, 377: 803-811.
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