有机锡抗癌化合物的合成、质量标准及初步吸收动力学研究
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摘要
近年来有机金属类抗癌化合物的研究引起了国内外的广泛关注,其中有机锡类配合物作为一种典型的金属类化合物在抗癌化合物的设计合成领域占有重要的地位。本课题组前期已对有机锡类抗癌化合物进行了深入系统的研究,提出了以有生物活性的O⌒O型螯合配体(配体与锡原子形成五员螯合环或六员螯合环)来合成单核R_2SnL_2型和双核[R_2SnL]_2O型(R为烃基;L为异羟肟酸)的新型抗癌化合物的设计构思。
本文以苯环上引入不同电性取代基的苯甲酰异羟肟酸衍生物为配体,共合成了6个有机锡化合物,采用IR,~1H NMR,~(13)C NMR,~(119)Sn NMR和单晶X-Ray.进行了结构表征。在研究[二-(对氯苯甲酰异羟肟酸)-二正丁基合锡](DBDCT)结构特征与理化性质关系的基础上,建立了DBDCT原料药的质量标准,并建立了血浆样品的液-液萃取预处理方法及RP-HPLC血药浓度测定方法,进行了DBDCT在大鼠体内的初步吸收动力学探讨。
第一部分为有机锡抗癌化合物的合成及其抗肿瘤活性研究。以在对位引入不同电性取代基的苯甲酰异羟肟酸衍生物为配体合成了6个有机锡化合物,并进行了结构表征,同时对其中两个化合物进行了单晶X-Ray分析。此外,在体外活性筛选的基础上,对其中活性较强的配合物2(DBDCT)还进行了体内抗肿瘤活性试验,结果表明配合物2显示出较强的体内抗肿瘤活性。
第二部分在研究DBDCT结构特征与理化性质关系的基础上,建立了DBDCT原料药的质量控制方法。首次选用具有分离分析双重功能的HPLC法对DBDCT这一有机金属类抗癌化合物进行含量测定和有关物质检查。具体方法采用Diamonsil C_(18)柱(250×4.6mm,5μm),甲醇-水(40:60,用TFA调节pH至3.0)为流动相,检测波长为236nm。在此色谱条件下,DBDCT在2.0-80.0μg/ml范围内,其浓度与峰面积呈良好的线性关系(r=0.9997),检出限为8ng(S/N=3),精密度试验RSD=1.56%(n=5),重复性试验RSD为1.47%(n=6)。本研究工作为DBDCT原料药质量控制提供了准确可行的分析方法。
本课题进行了DBDCT在大鼠体内的初步吸收动力学研究,建立了血浆样品的液-液萃取预处理方法,通过色谱条件筛选,采用甲醇-水(30:70,用TFA调节pH至3.0)为流动相的RP-HPLC法,在236nm处测定大鼠血浆中DBDCT浓度。在此色谱条件下DBDCT在0.1-25.0μg/ml浓度范围内与其峰面积线性关系良好(r=0.9998),检测限为9ng(S/N=3);提取回收率＞85%,日内和日间精密度的RSD均＜10.0%,本文采用该方法对6只大鼠进行了单剂量注射DBDCT后的初步吸收动力学研究。试验结果表明,大鼠单剂量尾静脉注射DBDCT后,分布及消除速度快,其体内过程符合二室模型。
In recent years the research of anticancer organometallic compounds attracts widespread attention in the world.As typical organometallic compounds,organotin compounds in cancer research still occupy an important position.As for this,our group put forwords a new design guideline and a series of diorganotin complexes formulated as R_2SnL_2 and[R_2Sn(L)]_2O with the the O⌒O type-ligands which have biological activities have been prepared.
Six new dibutyltin complexes were prepared when dibutyltin dichloride reacted with the benzoyl hydroxamic acids which have different substituted group in the para-position with different electricity.These complexes were characterized by IR,~1H NMR,~(13)C NMR and ~(119)Sn NMR.Single crystal R-ray analysis was also been used to determined the structure for compound 2 and 5.Based on its physical and chemical properties,the quality standard of DBDCT,an antitumor compound with novel structure was established.The primilary absorption pharmacokinetics of DBDCT in rats was investigated in this study.Liquid-liquid extraction method was chosen to pretreat plasma samples before RP-HPLC analysis of DBDCT in plasma samples.
In the first section the synthesis and antitumor activity study of the new complexes were described.When dibutyltin dichloride reacted with the benzoyl hydroxamic acid with different electricity,six new complexes were got which had been characterized by IR,~1H NMR,~(13)C NMR and ~(119)Sn NMR.Single crystal x-ray analysis was also been carried out for the compound 2 and 5.The x-ray diffraction analysis showed that tin atom is five-coordinated forming trigonal bipyramidal structure.In addition,the anti-tumor activity test in vitro showed compound 2 has strong cytotoxicity.
The chemical identification,determination of general and related substance and assaying were determinated for DBDCT based on its structure,physical and chemical property,and its quality standard was established.A RP-HPLC method was developed for the deterimnation of the content of the sample and drug-related impurities.DBDCT and its related substance were separated on the Diamonsil C_(18)column(250×4.6mm,5μm)with methanol-water(40:60 with TFA to adjust pH 3.0)as the mobile phase and detected at 236nm.The calibration curve was linear(r=0.9997)within the range of 2.0-80.0μg/ml for DBDCT} the detection limit was 8ng(S/N=3),the analysis precision RSD was1.56%(n=5)the repeatability precision RSD was 1.47%(n=6),and the limit of drug-related impurities was 1.0%.This method was simple. accurate and suitable for the quality control for DBDCT.
The primilary absorption pHarmacokinetics of DBDCT in rats was investigated in this study. Liquid-liquid extraction method was chosen to pretreat plasma samples before RP-HPLC analysis.DBDCT was separated on C_(18)column with(250×4.6mm 5μm)methanol-water(30:70 with TFA to adjust pH 3.0)as the mobile phase.By RP-HPLC and detect at 236nm.The calibration curve was linear(r＞0.9997)within the range of 0.1-25.0μg/ml for DBDCT.The detection limit was 9ng(S/N=3).The analytical recovery was more than 85%.Both of the intra-day and inter-day precision were less than 10.0%.The reliability of this method is high enough to perform quantitative analysis of DBDCT in plasma samples.The pharmacokinetics study of DBDCT was performed in 6 healthy rats via injection with single dosage by the established analytical method.The experimental data showed that the concentration-time curve of DBDCT in rat plasma could be fitted to two-compartment model.It was also proved that DBDCT was eliminated quickly in blood.
本文以苯环上引入不同电性取代基的苯甲酰异羟肟酸衍生物为配体,共合成了6个有机锡化合物,采用IR,~1H NMR,~(13)C NMR,~(119)Sn NMR和单晶X-Ray.进行了结构表征。在研究[二-(对氯苯甲酰异羟肟酸)-二正丁基合锡](DBDCT)结构特征与理化性质关系的基础上,建立了DBDCT原料药的质量标准,并建立了血浆样品的液-液萃取预处理方法及RP-HPLC血药浓度测定方法,进行了DBDCT在大鼠体内的初步吸收动力学探讨。
第一部分为有机锡抗癌化合物的合成及其抗肿瘤活性研究。以在对位引入不同电性取代基的苯甲酰异羟肟酸衍生物为配体合成了6个有机锡化合物,并进行了结构表征,同时对其中两个化合物进行了单晶X-Ray分析。此外,在体外活性筛选的基础上,对其中活性较强的配合物2(DBDCT)还进行了体内抗肿瘤活性试验,结果表明配合物2显示出较强的体内抗肿瘤活性。
第二部分在研究DBDCT结构特征与理化性质关系的基础上,建立了DBDCT原料药的质量控制方法。首次选用具有分离分析双重功能的HPLC法对DBDCT这一有机金属类抗癌化合物进行含量测定和有关物质检查。具体方法采用Diamonsil C_(18)柱(250×4.6mm,5μm),甲醇-水(40:60,用TFA调节pH至3.0)为流动相,检测波长为236nm。在此色谱条件下,DBDCT在2.0-80.0μg/ml范围内,其浓度与峰面积呈良好的线性关系(r=0.9997),检出限为8ng(S/N=3),精密度试验RSD=1.56%(n=5),重复性试验RSD为1.47%(n=6)。本研究工作为DBDCT原料药质量控制提供了准确可行的分析方法。
本课题进行了DBDCT在大鼠体内的初步吸收动力学研究,建立了血浆样品的液-液萃取预处理方法,通过色谱条件筛选,采用甲醇-水(30:70,用TFA调节pH至3.0)为流动相的RP-HPLC法,在236nm处测定大鼠血浆中DBDCT浓度。在此色谱条件下DBDCT在0.1-25.0μg/ml浓度范围内与其峰面积线性关系良好(r=0.9998),检测限为9ng(S/N=3);提取回收率＞85%,日内和日间精密度的RSD均＜10.0%,本文采用该方法对6只大鼠进行了单剂量注射DBDCT后的初步吸收动力学研究。试验结果表明,大鼠单剂量尾静脉注射DBDCT后,分布及消除速度快,其体内过程符合二室模型。
In recent years the research of anticancer organometallic compounds attracts widespread attention in the world.As typical organometallic compounds,organotin compounds in cancer research still occupy an important position.As for this,our group put forwords a new design guideline and a series of diorganotin complexes formulated as R_2SnL_2 and[R_2Sn(L)]_2O with the the O⌒O type-ligands which have biological activities have been prepared.
Six new dibutyltin complexes were prepared when dibutyltin dichloride reacted with the benzoyl hydroxamic acids which have different substituted group in the para-position with different electricity.These complexes were characterized by IR,~1H NMR,~(13)C NMR and ~(119)Sn NMR.Single crystal R-ray analysis was also been used to determined the structure for compound 2 and 5.Based on its physical and chemical properties,the quality standard of DBDCT,an antitumor compound with novel structure was established.The primilary absorption pharmacokinetics of DBDCT in rats was investigated in this study.Liquid-liquid extraction method was chosen to pretreat plasma samples before RP-HPLC analysis of DBDCT in plasma samples.
In the first section the synthesis and antitumor activity study of the new complexes were described.When dibutyltin dichloride reacted with the benzoyl hydroxamic acid with different electricity,six new complexes were got which had been characterized by IR,~1H NMR,~(13)C NMR and ~(119)Sn NMR.Single crystal x-ray analysis was also been carried out for the compound 2 and 5.The x-ray diffraction analysis showed that tin atom is five-coordinated forming trigonal bipyramidal structure.In addition,the anti-tumor activity test in vitro showed compound 2 has strong cytotoxicity.
The chemical identification,determination of general and related substance and assaying were determinated for DBDCT based on its structure,physical and chemical property,and its quality standard was established.A RP-HPLC method was developed for the deterimnation of the content of the sample and drug-related impurities.DBDCT and its related substance were separated on the Diamonsil C_(18)column(250×4.6mm,5μm)with methanol-water(40:60 with TFA to adjust pH 3.0)as the mobile phase and detected at 236nm.The calibration curve was linear(r=0.9997)within the range of 2.0-80.0μg/ml for DBDCT} the detection limit was 8ng(S/N=3),the analysis precision RSD was1.56%(n=5)the repeatability precision RSD was 1.47%(n=6),and the limit of drug-related impurities was 1.0%.This method was simple. accurate and suitable for the quality control for DBDCT.
The primilary absorption pHarmacokinetics of DBDCT in rats was investigated in this study. Liquid-liquid extraction method was chosen to pretreat plasma samples before RP-HPLC analysis.DBDCT was separated on C_(18)column with(250×4.6mm 5μm)methanol-water(30:70 with TFA to adjust pH 3.0)as the mobile phase.By RP-HPLC and detect at 236nm.The calibration curve was linear(r＞0.9997)within the range of 0.1-25.0μg/ml for DBDCT.The detection limit was 9ng(S/N=3).The analytical recovery was more than 85%.Both of the intra-day and inter-day precision were less than 10.0%.The reliability of this method is high enough to perform quantitative analysis of DBDCT in plasma samples.The pharmacokinetics study of DBDCT was performed in 6 healthy rats via injection with single dosage by the established analytical method.The experimental data showed that the concentration-time curve of DBDCT in rat plasma could be fitted to two-compartment model.It was also proved that DBDCT was eliminated quickly in blood.
引文
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