葛根素4′-位和7-位衍生物的合成及其抗缺氧活性
|
摘要
以葛根素为起始原料,经醚化反应制备中间体4′-O-(3-溴丙基)葛根素(3)和7-O-(3-溴丙基)葛根素(4),3和4分别经胺化反应合成葛根素衍生物4′-O-[3-(4-吗啉基)丙基]葛根素(1)和7-O-[3-(4-吗啉基)丙基]葛根素(2),其结构经~1H NMR、~(13)C NMR、 HR-MS(ESI-TOF)和NOE表征,其中4和2为新化合物。通过小鼠常压抗缺氧实验对葛根素及1和2的活性进行评价,结果显示葛根素、1和2灌胃给药对缺氧小鼠存活时间的延长率分别为24.43%、 10.62%、 28.63%,化合物2的抗缺氧活性与葛根素相当,化合物1则较葛根素弱。
Intermediates 4′-O-(3-bromopropyl) puerarin(3) and 7-O-(3-bromopropyl) puerarin(4), were synthesized from puerarin by etherification. The target compounds 4′-O-[3-(4-morpholinyl) propyl] puerarin(1) and 7-O-[3-(4-morpholinyl) propyl] puerarin(2) were synthesized by amination of 3 and 4, respectively. 4 and 2 were new compounds, the structures were characterized by ~1H NMR, ~(13)C NMR, HR-MS(ESI-TOF) and NOE. The activities of puerarin, 1 and 2 were evaluated by the normobaric anti-hypoxia test in mice, and their prolongation rates of mice survival time by gavage were 24.43%, 10.62% and 28.63%, respectively. The anti-hypoxia activity of Compound 2 was similar to Puerarin, and Compound 1 was weaker than Puerarin.
Intermediates 4′-O-(3-bromopropyl) puerarin(3) and 7-O-(3-bromopropyl) puerarin(4), were synthesized from puerarin by etherification. The target compounds 4′-O-[3-(4-morpholinyl) propyl] puerarin(1) and 7-O-[3-(4-morpholinyl) propyl] puerarin(2) were synthesized by amination of 3 and 4, respectively. 4 and 2 were new compounds, the structures were characterized by ~1H NMR, ~(13)C NMR, HR-MS(ESI-TOF) and NOE. The activities of puerarin, 1 and 2 were evaluated by the normobaric anti-hypoxia test in mice, and their prolongation rates of mice survival time by gavage were 24.43%, 10.62% and 28.63%, respectively. The anti-hypoxia activity of Compound 2 was similar to Puerarin, and Compound 1 was weaker than Puerarin.
引文
[1] WEI S Y, CHEN Y, YU X U. Progress on the pharmacological research of puerarin:A review[J].Chin J Nat Med,2014,12(6):407-414.
[2] FENG Z Q, WANG Y Y, GUO Z R, et al. The synthesis of puerarin derivatives and their protective effect on the myocardial ischemia and reperfusion injury[J].Asian Nat Prod Res,2010,12(10):843-850.
[3] 黄晓巍,张丹丹,王晋冀,等. 葛根化学成分及药理作用[J].吉林中医药,2018,38(1):87-89
[4] JIANG B, LIU J H, BAO Y M, et al. Hydrogen peroxide-induced apoptosis in PC12 cells and the protective effect of Puerarin[J].Cell Bio Int,2003,27(12):1025-1031.
[5] 陈龙菊,吴建清,吴太鼎,等. 葛根素保护双氧水诱导的SH-SY5Y细胞凋亡[J].中国药理学通报,2018,34(3):343-347.
[6] 张首国,王林,朱晓伟,等. 葛根素衍生物的合成及抗缺氧活性研究[J].中国药物化学杂志,2008,18(02):90-95.
[7] 张首国. 葛根素及其衍生物的合成与初步活性研究[D].北京:中国人民解放军军事医学科学院,2005.
[8] 邹驰,樊光辉,刘长清,等. 天麻素对模拟高原缺氧小鼠的保护作用[J].华南国防医学杂志,2017,31(8):501-503.
[9] 郭密,韦倩,张仲君,等. 中药葛根素抗缺氧及抗氧化的药效学研究[J].解放军保健医学杂志,2007,9(2):104-106.
[10] CUI Y, TAO Y, JIANG L, et al. Antihypoxic activities of constituents from Arenaria kansuensis[J].Phytomedicine,2018,38:175-182.
[11] DONG Y, HU S, LIU C, et al. Purification of polysaccharides from Cordycepsmilitaris and their antihypoxic effect[J].Mol Med Rep,2015,11(2):1312-1317.
[12] ZHANG C X, DAI Z R. Anti-hypoxia activity of a polysaccharide extracted from the Sipunculusnudus L[J]. Int J Biol Macromol,2011,49(4):523-526.
[13] YUAN J W, CHEN X L, QU L B. A Novel Conformation Investigation on Newly Synthesized Compound of Diethyl Puerarin-7-yl Phosphate[J].Chin J Struct Chem,2006,25(1):78-84.
[14] 尹兵. 几种药物给药途径的选择与临床应用[J].中国医院药学杂志,1992,(4):174-175.
[15] 李盛姿. 浅谈药物剂型及给药途径对临床疗效的影响[J].中国现代药物应用,2013,7(21):168-169.
[16] 周玖瑶,曾南. 药理学实验[M].北京:中国医药科技出版社,2015.
[17] 薛秀清,黄光荣. ADR的发生与给药途径[J].中国中医药现代远程教育, 2010,08(20):124-125.
[18] 刘凤,赵子文,于小玲,等. 不同机体代谢状况对缺氧耐受性影响的实验研究[J].滨州医学院学报,2000,(5):427-428.
[19] 邢树文. 小鼠缺氧耐受性影响因素的研究[J].环境与健康杂志,2011,28(4):314-317.
[20] 吴燕红,苏子仁,陈建南,等. 从小鼠体内血药浓度时间曲线与组织分布特征评价葛根素的给药途径[J].中药新药与临床药理,2005,16(2):112-115.
[21] 张甘良,汪钊,鄢洪德. 生物类黄酮化合物的结构与生物活性的关系[J].生物学杂志,2005,22(1):4-7.
[2] FENG Z Q, WANG Y Y, GUO Z R, et al. The synthesis of puerarin derivatives and their protective effect on the myocardial ischemia and reperfusion injury[J].Asian Nat Prod Res,2010,12(10):843-850.
[3] 黄晓巍,张丹丹,王晋冀,等. 葛根化学成分及药理作用[J].吉林中医药,2018,38(1):87-89
[4] JIANG B, LIU J H, BAO Y M, et al. Hydrogen peroxide-induced apoptosis in PC12 cells and the protective effect of Puerarin[J].Cell Bio Int,2003,27(12):1025-1031.
[5] 陈龙菊,吴建清,吴太鼎,等. 葛根素保护双氧水诱导的SH-SY5Y细胞凋亡[J].中国药理学通报,2018,34(3):343-347.
[6] 张首国,王林,朱晓伟,等. 葛根素衍生物的合成及抗缺氧活性研究[J].中国药物化学杂志,2008,18(02):90-95.
[7] 张首国. 葛根素及其衍生物的合成与初步活性研究[D].北京:中国人民解放军军事医学科学院,2005.
[8] 邹驰,樊光辉,刘长清,等. 天麻素对模拟高原缺氧小鼠的保护作用[J].华南国防医学杂志,2017,31(8):501-503.
[9] 郭密,韦倩,张仲君,等. 中药葛根素抗缺氧及抗氧化的药效学研究[J].解放军保健医学杂志,2007,9(2):104-106.
[10] CUI Y, TAO Y, JIANG L, et al. Antihypoxic activities of constituents from Arenaria kansuensis[J].Phytomedicine,2018,38:175-182.
[11] DONG Y, HU S, LIU C, et al. Purification of polysaccharides from Cordycepsmilitaris and their antihypoxic effect[J].Mol Med Rep,2015,11(2):1312-1317.
[12] ZHANG C X, DAI Z R. Anti-hypoxia activity of a polysaccharide extracted from the Sipunculusnudus L[J]. Int J Biol Macromol,2011,49(4):523-526.
[13] YUAN J W, CHEN X L, QU L B. A Novel Conformation Investigation on Newly Synthesized Compound of Diethyl Puerarin-7-yl Phosphate[J].Chin J Struct Chem,2006,25(1):78-84.
[14] 尹兵. 几种药物给药途径的选择与临床应用[J].中国医院药学杂志,1992,(4):174-175.
[15] 李盛姿. 浅谈药物剂型及给药途径对临床疗效的影响[J].中国现代药物应用,2013,7(21):168-169.
[16] 周玖瑶,曾南. 药理学实验[M].北京:中国医药科技出版社,2015.
[17] 薛秀清,黄光荣. ADR的发生与给药途径[J].中国中医药现代远程教育, 2010,08(20):124-125.
[18] 刘凤,赵子文,于小玲,等. 不同机体代谢状况对缺氧耐受性影响的实验研究[J].滨州医学院学报,2000,(5):427-428.
[19] 邢树文. 小鼠缺氧耐受性影响因素的研究[J].环境与健康杂志,2011,28(4):314-317.
[20] 吴燕红,苏子仁,陈建南,等. 从小鼠体内血药浓度时间曲线与组织分布特征评价葛根素的给药途径[J].中药新药与临床药理,2005,16(2):112-115.
[21] 张甘良,汪钊,鄢洪德. 生物类黄酮化合物的结构与生物活性的关系[J].生物学杂志,2005,22(1):4-7.