新型大豆素苯磺酸酯的细胞吸收利用与构性关系研究
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摘要
为了提高大豆素衍生物的抗动脉粥样硬化等功效,利用药动团变换原理对大豆素进行结构修饰,合成了大豆素磺酸酯衍生物(D1、D2)。采用HPLC和软件Chem Axon对目标衍生物的药学性质进行考察和计算,利用人主动脉血管平滑肌细胞HAVSMCs和HPLC考察大豆素及其衍生物的吸收利用率。结果表明:大豆素(DD)、衍生物D1、D2在主动脉血管平滑肌细胞吸收率最大,分别为20. 3%、29. 4%和71. 7%,最大吸收率表现为D2> D1> DD。构性关系研究表明,药物的吸收利用与药物的理化性质密切相关,只有脂溶性和水溶性适宜,药物的细胞吸收利用才会得以提高。
To improve the effect of daidzein inhibiting the atherosclerosis,its structure was modified using the principle ofpharmacokinetic group and its sulfonate derivatives(D1,D2) were synthesized. The pharmacological properties of the targetderivatives were investigated by HPLC and Chem Axon. The absorptivity of daidzein and its derivatives were investigated byHAVSMCs and HPLC. The results showed that absorptivity on HAVSMCs of DD,its derivatives D1,D2 were maxmum with20. 3% 、29. 4% and 71. 7% respectively and the maximum absorptivity were D2 > D1 > DD. The study on relationship ofstructure and properties showed that the absorption and utilization of drugs were closely related to the physicochemical proper-ties of the drugs,and the absorption and utilization of the drugs on cells were optimal only with moderate liposolubility and wa-ter solubility.
To improve the effect of daidzein inhibiting the atherosclerosis,its structure was modified using the principle ofpharmacokinetic group and its sulfonate derivatives(D1,D2) were synthesized. The pharmacological properties of the targetderivatives were investigated by HPLC and Chem Axon. The absorptivity of daidzein and its derivatives were investigated byHAVSMCs and HPLC. The results showed that absorptivity on HAVSMCs of DD,its derivatives D1,D2 were maxmum with20. 3% 、29. 4% and 71. 7% respectively and the maximum absorptivity were D2 > D1 > DD. The study on relationship ofstructure and properties showed that the absorption and utilization of drugs were closely related to the physicochemical proper-ties of the drugs,and the absorption and utilization of the drugs on cells were optimal only with moderate liposolubility and wa-ter solubility.
引文
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[2] Antonella G,Imperatrice C,Angela C,et al. Antioxidant activityinduced by main polyphenols present in edible artichoke heads:Influence of in vitro gastro-intestinal digestion[J]. Journal ofFunctional Foods,2014,10:456-464.
[3] Peng Y,Shi Y N,Zhang H,et al. Anti-inflammatory and anti-ox-idative activities of daidzein and its sulfonic acid ester derivatives[J]. Journal of Functional Foods,2017,35:635-640.
[4] Dong X,Xu W Q,Sikes R,et al. Combination of low dose ofgenistein and daidzein has synergistic preventive effects on isogenichuman prostate cancer cells when compared with individual soyisoflavone[J]. Food Chemistry,2013,141:1923-1933.
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[6]韩晓乐,滕晓涵,许怡,等.大豆苷元防治心脑血管疾病的研究进展[J].国际药学研究杂志,2017,44(12):1093-1124.(Han X L,Teng X H,Xu Y,et al. Prevention and treatment ofcardio-cerebrovascular diseases by daidzein:Research advances[J]. Journal International Pharmacy Research,2017,44(12):1093-1124.)
[7]黎晓,刘瑞珍,林彧夫,等.大豆苷元通过抑制炎症反应对大鼠脑缺血再灌注损伤保护作用的研究[J].时珍国医国药,2014,25(1):6-8.(Li X,Liu R Z,Lin Y F,et al. The protec-tive effects of daidzein on cerebral ischemia-reperfusion injurythrough inhibition inflammatory response[J]. Lishizhen Medicineand Materia Medica,2014,25(1):6-8.)
[8] Knapp A N,Stout J M,Grisley E D,et al. Effects of subcutaneousdaidzein on recovery of function in the rat after ischemic stroke[J]. FASEB Journal,2013,27(7):1093-1093.
[9] Ysuda T,Kano Y,Saito K,et al. Urinary and biliary metabolitesof daidzin and daidzein in rats[J]. Biological&PharmaceuticalBulletin,1994,17(10):1369-1374.
[10]徐海燕,苏芳铭,蒋唤,等.大鼠体内大豆苷元及其代谢物分布影响因素研究[J].沈阳药科大学学报,2017,34(9):768-775.(Xu H Y,Su F M,Jiang H,et al. Influences of dosing fre-quency and gender of animals on the plasma distribution of daid-zein and its metabolites in rats[J]. Journal of Shenyang Pharma-ceutical University,2017,34(9):768-775.)
[11] Kulling S E,Honig D M,Metzler M. Oxidative metabolism of thesoy isoflavones daidzein and genistein in humans in vitro and in vi-vo[J]. Journal of Agricultural and Food Chemistry,2001,49(6):3024-3033.
[12]仇峰.大豆苷元及其前体药物的药物动力学研究[D].沈阳:沈阳药科大学,2005.(Chou F. Pharmacokinetics of daidzeinand its precursors[D]. Shenyang:Shenyang Pharmaceutical Uni-versity,2005.)
[13]彭游,钟婵娟.植物雌激素大豆苷元的药物动力学研究进展[J].安徽农业科学,2011,39(7):3796-3797.(Peng Y,Zhong C J. Research progress in pharmacok inetics of phytoestro-gen daidzein[J]. Journal of Anhui Agricultural Science,2011,39(7):3796-3797.)
[14]彭游,邓泽元,叶兴琳.异黄酮衍生物的设计、合成与抗肿瘤活性[J].天然产物研究与开发,2009,21:796-799.(Peng Y,Deng Z Y,Ye X L. Design,synthesis and anticancer activity ofisofavone derivatives[J]. Natural Products Research and Develop-ment,2009,21:796-799.)
[15]彭游.植物黄酮的微波辅助提取,苯磺酸酯修饰与药物动力学研究[D].南昌:南昌大学,2009.(Peng Y. Extraction of fla-vones with microwave radiation,benzensulfonate modification andpharmacokinetics experiments[D]. Nanchang:Nanchang Univer-sity,2009.)
[16]黄春勇,彭游,柏杨,等.大豆异黄酮苯磺酸酯的微波合成与药学性质研究[J].九江学院学报(自然科学版),2017(2):11-15.(Huang C Y,Peng Y,Bai Y,et al. Study on microwavesynthesis and pharmaceutical properties of soybean isoflavone ben-zene sulfonic acid ester[J]. Journal of Jiujiang University(Natu-ral Science Edition),2017(2):11-15.)
[17] van de Waterbeemd H,Lennernas H,Artursson P.药物生物利用度[M].何仲贵,钟大放,等译.北京:化工出版社,2007:18-21.(van de Waterbeemd H,Lennernas H,Artursson P. Drugbioavailability[M]. He Z G,Zhong D F,et al. translated. Bei-jing:Chemical Industry Press,2007:18-21.)
[18] Borghetti G S,Pinto A P,Lula I S,et al. Daidzein/cyclodextrin/hydrophilic polymer ternary systems[J]. Drug Development andIndustrial Pharmacy,2011,37(8):886-893.
[19]姜铁夫,康万军,杜妙,等.葛根黄豆苷元衍生物的合成及理化性质研究[J].解放军药学学报,2006,22(3):228-230.(Jiang T F,Kang W J,Tu M,et al. Synthesis and study of daid-zeiderivative DZ18[J]. Pharmacy Journal of Chinese PLA,2006,22(3):228-230.)
[20]邓颖慧,苏丽娜,庞艳华,等.大豆苷元与氨基修饰β-环糊精包合物的制备、表征及水溶性[J].分析化学,2017,45(5):648-653.(Deng Y H,Su L N,Pang Y H,et al. Preparation,characterization and water solubility of inclusion complexes of daid-zein with amino-modifiedβ-Cyclodextrins[J]. Chinese Journal ofAnalytical Chemistry,2017,45(5):648-653.)
[21]张尊听,刘谦光,郁开北,等.单甲基化大豆苷元磺酸盐的合成、晶体结构及活性研究[J].化学学报,2002,60:1846-1853.(Zhang Z T,Liu Q G,Yu K B,et al. Synthesis,crystalstructure and biological activity of monomethylated daidzein sulfon-ates[J]. Acta Chimica Sinica,2002,60:1846-1853.)
[22]彭游,邓泽元.高效液相色谱法对新型大豆异黄酮磺酸酯的前药研究[J].药物分析杂志,2011,31(5):810-815.(PengY,Deng Z Y. HPLC studies for prodrug of isoflavones sulphonicacid ester[J]. Chinese Journal of Pharnaceutical Analysis,2011,31(5):810-815.)
[2] Antonella G,Imperatrice C,Angela C,et al. Antioxidant activityinduced by main polyphenols present in edible artichoke heads:Influence of in vitro gastro-intestinal digestion[J]. Journal ofFunctional Foods,2014,10:456-464.
[3] Peng Y,Shi Y N,Zhang H,et al. Anti-inflammatory and anti-ox-idative activities of daidzein and its sulfonic acid ester derivatives[J]. Journal of Functional Foods,2017,35:635-640.
[4] Dong X,Xu W Q,Sikes R,et al. Combination of low dose ofgenistein and daidzein has synergistic preventive effects on isogenichuman prostate cancer cells when compared with individual soyisoflavone[J]. Food Chemistry,2013,141:1923-1933.
[5]黄进,罗琼,李晓莉,等.大豆异黄酮的降血糖活性研究[J].食品科学,2004,25(1):166-170.(Huang J,Luo Q,Li X L,et al. Hyperglycemia lowering effect of soybean isoflavone(SI)onalloxan-induced diabetic mice[J]. Food Science,2004,25(1):166-170.)
[6]韩晓乐,滕晓涵,许怡,等.大豆苷元防治心脑血管疾病的研究进展[J].国际药学研究杂志,2017,44(12):1093-1124.(Han X L,Teng X H,Xu Y,et al. Prevention and treatment ofcardio-cerebrovascular diseases by daidzein:Research advances[J]. Journal International Pharmacy Research,2017,44(12):1093-1124.)
[7]黎晓,刘瑞珍,林彧夫,等.大豆苷元通过抑制炎症反应对大鼠脑缺血再灌注损伤保护作用的研究[J].时珍国医国药,2014,25(1):6-8.(Li X,Liu R Z,Lin Y F,et al. The protec-tive effects of daidzein on cerebral ischemia-reperfusion injurythrough inhibition inflammatory response[J]. Lishizhen Medicineand Materia Medica,2014,25(1):6-8.)
[8] Knapp A N,Stout J M,Grisley E D,et al. Effects of subcutaneousdaidzein on recovery of function in the rat after ischemic stroke[J]. FASEB Journal,2013,27(7):1093-1093.
[9] Ysuda T,Kano Y,Saito K,et al. Urinary and biliary metabolitesof daidzin and daidzein in rats[J]. Biological&PharmaceuticalBulletin,1994,17(10):1369-1374.
[10]徐海燕,苏芳铭,蒋唤,等.大鼠体内大豆苷元及其代谢物分布影响因素研究[J].沈阳药科大学学报,2017,34(9):768-775.(Xu H Y,Su F M,Jiang H,et al. Influences of dosing fre-quency and gender of animals on the plasma distribution of daid-zein and its metabolites in rats[J]. Journal of Shenyang Pharma-ceutical University,2017,34(9):768-775.)
[11] Kulling S E,Honig D M,Metzler M. Oxidative metabolism of thesoy isoflavones daidzein and genistein in humans in vitro and in vi-vo[J]. Journal of Agricultural and Food Chemistry,2001,49(6):3024-3033.
[12]仇峰.大豆苷元及其前体药物的药物动力学研究[D].沈阳:沈阳药科大学,2005.(Chou F. Pharmacokinetics of daidzeinand its precursors[D]. Shenyang:Shenyang Pharmaceutical Uni-versity,2005.)
[13]彭游,钟婵娟.植物雌激素大豆苷元的药物动力学研究进展[J].安徽农业科学,2011,39(7):3796-3797.(Peng Y,Zhong C J. Research progress in pharmacok inetics of phytoestro-gen daidzein[J]. Journal of Anhui Agricultural Science,2011,39(7):3796-3797.)
[14]彭游,邓泽元,叶兴琳.异黄酮衍生物的设计、合成与抗肿瘤活性[J].天然产物研究与开发,2009,21:796-799.(Peng Y,Deng Z Y,Ye X L. Design,synthesis and anticancer activity ofisofavone derivatives[J]. Natural Products Research and Develop-ment,2009,21:796-799.)
[15]彭游.植物黄酮的微波辅助提取,苯磺酸酯修饰与药物动力学研究[D].南昌:南昌大学,2009.(Peng Y. Extraction of fla-vones with microwave radiation,benzensulfonate modification andpharmacokinetics experiments[D]. Nanchang:Nanchang Univer-sity,2009.)
[16]黄春勇,彭游,柏杨,等.大豆异黄酮苯磺酸酯的微波合成与药学性质研究[J].九江学院学报(自然科学版),2017(2):11-15.(Huang C Y,Peng Y,Bai Y,et al. Study on microwavesynthesis and pharmaceutical properties of soybean isoflavone ben-zene sulfonic acid ester[J]. Journal of Jiujiang University(Natu-ral Science Edition),2017(2):11-15.)
[17] van de Waterbeemd H,Lennernas H,Artursson P.药物生物利用度[M].何仲贵,钟大放,等译.北京:化工出版社,2007:18-21.(van de Waterbeemd H,Lennernas H,Artursson P. Drugbioavailability[M]. He Z G,Zhong D F,et al. translated. Bei-jing:Chemical Industry Press,2007:18-21.)
[18] Borghetti G S,Pinto A P,Lula I S,et al. Daidzein/cyclodextrin/hydrophilic polymer ternary systems[J]. Drug Development andIndustrial Pharmacy,2011,37(8):886-893.
[19]姜铁夫,康万军,杜妙,等.葛根黄豆苷元衍生物的合成及理化性质研究[J].解放军药学学报,2006,22(3):228-230.(Jiang T F,Kang W J,Tu M,et al. Synthesis and study of daid-zeiderivative DZ18[J]. Pharmacy Journal of Chinese PLA,2006,22(3):228-230.)
[20]邓颖慧,苏丽娜,庞艳华,等.大豆苷元与氨基修饰β-环糊精包合物的制备、表征及水溶性[J].分析化学,2017,45(5):648-653.(Deng Y H,Su L N,Pang Y H,et al. Preparation,characterization and water solubility of inclusion complexes of daid-zein with amino-modifiedβ-Cyclodextrins[J]. Chinese Journal ofAnalytical Chemistry,2017,45(5):648-653.)
[21]张尊听,刘谦光,郁开北,等.单甲基化大豆苷元磺酸盐的合成、晶体结构及活性研究[J].化学学报,2002,60:1846-1853.(Zhang Z T,Liu Q G,Yu K B,et al. Synthesis,crystalstructure and biological activity of monomethylated daidzein sulfon-ates[J]. Acta Chimica Sinica,2002,60:1846-1853.)
[22]彭游,邓泽元.高效液相色谱法对新型大豆异黄酮磺酸酯的前药研究[J].药物分析杂志,2011,31(5):810-815.(PengY,Deng Z Y. HPLC studies for prodrug of isoflavones sulphonicacid ester[J]. Chinese Journal of Pharnaceutical Analysis,2011,31(5):810-815.)