天然五环三萜及其衍生物抗心脑血管疾病的研究进展
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摘要
心脑血管疾病是我国成年人群首要致死病因,且发病率呈上升和年轻化趋势,运用中药治疗心脑血管疾病十分必要。天然产物是治疗心脑血管药物的重要来源。三萜类化合物是植物体内重要的次生代谢产物,具有广泛的生物活性,其中五环三萜类表现出明显的抗炎、抗肿瘤、抗病毒等药理作用。近年来,越来越多的研究集中在五环三萜类化合物抗心脑血管疾病领域,对其结构进行衍生化从而提升活性、改善药性的研究也越发深入。通过查阅国内外五环三萜类化合物及其衍生物近10年的文献专利报道,综述了齐墩果烷、乌苏烷、羽扇豆烷、木栓烷4种类型五环三萜类化合物及其衍生物抗心脑血管疾病的研究进展,为治疗心脑血管疾病药物的研发提供依据和参考。
Cardiovascular and cerebrovascular diseases are the leading cause of death among adult populations in China. The incidence and mortality rate shows an upward trend, and age of onset is younger trend. It is necessary to treat cardiovascular and cerebrovascular diseases with Chinese materia medica. Natural products have been the important and productive source of leading compounds for the development of anti-cardiovascular and cerebrovascular drugs. Naturally occurring triterpenoid saponins are generally plant-derived secondary metabolites with various valuable pharmacological properties. Pentacyclic triterpenoids of which show obvious anti-inflammatory, antitumor and antiviral effects. In recent years, increasing researches focused on the anticardiovascular and cerebrovascular mechanisms and modifications to improve the pharmacological activity and druggability of pentacyclic triterpenes. Based on previous studies, the literatures and patents of nearly 10 years on pentacyclic triterpenoids and their derivatives have been consulted. The research progress of anti-cardio-cerebrovascular activities of four types of compounds, oleanane, ursane, lupane, and friedelane, related to pentacyclic triterpenoids is reviewed, which provides a basis and reference for its further development and utilization in the treatment of cardiovascular and cerebrovascular diseases.
Cardiovascular and cerebrovascular diseases are the leading cause of death among adult populations in China. The incidence and mortality rate shows an upward trend, and age of onset is younger trend. It is necessary to treat cardiovascular and cerebrovascular diseases with Chinese materia medica. Natural products have been the important and productive source of leading compounds for the development of anti-cardiovascular and cerebrovascular drugs. Naturally occurring triterpenoid saponins are generally plant-derived secondary metabolites with various valuable pharmacological properties. Pentacyclic triterpenoids of which show obvious anti-inflammatory, antitumor and antiviral effects. In recent years, increasing researches focused on the anticardiovascular and cerebrovascular mechanisms and modifications to improve the pharmacological activity and druggability of pentacyclic triterpenes. Based on previous studies, the literatures and patents of nearly 10 years on pentacyclic triterpenoids and their derivatives have been consulted. The research progress of anti-cardio-cerebrovascular activities of four types of compounds, oleanane, ursane, lupane, and friedelane, related to pentacyclic triterpenoids is reviewed, which provides a basis and reference for its further development and utilization in the treatment of cardiovascular and cerebrovascular diseases.
引文
[1]王冬菊.心脑血管疾病流行概况及主要影响因素[J].预防医学论坛,2016,22(1):71-75.
[2]肖苏龙,王晗,王琪,等.基于五环三萜先导结构的抗病毒抑制剂研究进展[J].中国科学:化学,2015,45(9):865-883.
[3]王艺玮,徐盛涛,徐进宜.五环三萜羽扇豆烷型天然产物抗肿瘤活性研究进展[J].药学与临床研究,2017,25(4):336-342.
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[5]王军,张虹,谢凤杰,等.甘草酸预处理对大鼠心肌缺血再灌注损伤的保护作用及Bcl-2和Bax表达的影响[J].中国实验方剂学杂志,2018,24(6):126-132.
[6]赵瑞芳.熊果酸对大鼠心肌缺血再灌注损伤的保护作用[J].中国医药导报,2015,12(7):24-28.
[7]司林杰,许晶,易晨龙,等.积雪草酸抑制小鼠主动脉缩窄术后心肌肥厚形成[J].南京医科大学学报:自然科学版,2014,34(9):1168-1172.
[8]Der Sarkissian S,Cailhier J,Borie M,et al.Celastrol protects ischaemic myocardium through a heat shock response with up-regulation of haeme oxygenase-1[J].Br J Pharmacol,2015,171(23):5265-5279.
[9]赵全成,赫玉芳,南敏伦,等.救必应酸衍生物、合成方法及其在制备防治心血管疾病的药物中的应用:中国,CN102140126 A[P].2011-08-03.
[10]Tian Y,Sun Z,Wang W,et al.Semisynthesis and biological evaluation of oleanolic acid 3-O-β-D-glucuronopyranoside derivatives for protecting H9c2cardiomyoblasts against H2O2-induced injury[J].Molecules,2018,doi:10.3390/molecules23010044.
[11]郑磊,付帮泽,解华,等.甘草酸和甘草次酸对H9c2鼠心肌细胞活性氧水平的影响[J].中西医结合心脑血管病杂志,2016,14(1):21-25.
[12]Pan Y,Zhou F H,Song Z H,et al.Oleanolic acid protects against pathogenesis of atherosclerosis,possibly via FXR-mediated angiotensin(Ang)-(1-7)upregulation[J].Ritorno Al Numero,2018,doi:10.1016/j.biopha.2017.11.151.
[13]Niels H B,Nicolaj C H,Rosalia R R,et al.Antiatherogenic effects of oleanolic acid in apolipoprotein E knockout mice[J].Eur J Pharmacol,2011,670(2/3):519-526.
[14]Tzakos A G,Kontogianni V G,Tsoumani M,et al.Exploration of the antiplatelet activity profile of betulinic acid on human platelets[J].J Agric Food Chem,2012,60(28):6977-6983.
[15]高倩,吴佩,何疆,等.青蒿素和桦木酸阻断脂多糖诱导小鼠血管新生及组织增殖[J].中国药学杂志,2015,50(4):330-338.
[16]顾磊.雷公藤红素对抗动脉粥样硬化的作用及机制研究[D].南京:南京医科大学,2013.
[17]齐炼文,李萍,张蕾.常春藤皂苷元及其糖苷在制备治疗冠心病的药物中的应用:中国,CN107875156A[P].2018-04-06.
[18]孙宏斌,张丽颖,柳军.熊果烷型五环三萜氨基酸衍生物、其制备方法及其医药用途:中国,CN101337984[P].2009-01-07.
[19]王策.积雪草苷对心肌梗死大鼠转化生长因子-β1、I和III型胶原表达的影响[J].中国老年学杂志,2016,36(23):5799-5802.
[20]王策.积雪草苷对心梗大鼠心肌纤维化影响的实验研究[J].中国生化药物杂志,2014,34(8):19-22.
[21]Martín R,Carvalho-Tavares J,Hernández M,et al.Beneficial actions of oleanolic acid in an experimental model of multiple sclerosis:A potential therapeutic role[J].Biochem Pharmacol,2010,79(2):198-208.
[22]刘秀娟,韩雨薇,李晓明.齐墩果酸通过抑制NF-κB/ICAM-1信号通路减轻大鼠蛛网膜下腔出血后早期脑损伤的研究[J].中国现代应用药学,2017,34(9):1225-1228.
[23]齐炼文,李萍.常春藤皂苷元及其糖苷在制备防治脑卒中的药物中的应用:中国,CN107875157A[P].2018-04-06.
[24]Zhang T,Su J,Wang K,et al.Ursolic acid reduces oxidative stress to alleviate early brain injury following experimental subarachnoid hemorrhage[J].Neurosci Lett,2014,579(13):12-17.
[25]Lu Q,Xia N,Xu H,et al.Betulinic acid protects against cerebral ischemia-reperfusion injury in mice by reducing oxidative and nitrosative stress[J].Nitric Oxide,2011,24(3):132-138.
[26]Yoon J J,Lee Y J,Kim J S,et al.Protective role of betulinic acid on TNF-α-induced cell adhesion molecules in vascular endothelial cells[J].Biochem Biophys Res Commun,2010,391(1):96-101.
[27]王文娟,任欢欢,韩吉春,等.积雪草苷对缺血再灌注损伤的保护作用及其机制的研究[J].石河子大学学报:自然科学版,2015,33(5):593-598.
[28]Li L,Zhang X,Cui L,et al.Ursolic acid promotes the neuroprotection by activating Nrf2 pathway after cerebral ischemia in mice[J].Brain Res Rev,2013,1497(6):32-39.
[29]Qian Y,Guan T,Tang X,et al.Astrocytic glutamate transporter-dependent neuroprotection against glutamate toxicity:An in vitro study of maslinic acid[J].Eur JPharmacol,2011,651(1/3):59-65.
[30]Qian Y,Huang M,Guan T,et al.Maslinic acid promotes synaptogenesis and axon growth via Akt/GSK-3βactivation in cerebral ischemia model[J].Eur JPharmacol,2015,764:298-305.
[31]张朝弘,刘丹彦.雷公藤红素后处理对大鼠局灶性脑缺血再灌注损伤后脑组织NF-κB及TNF-α、IL-1β的影响[J].重庆医科大学学报,2015,40(1):37-41.
[32]杨雪莲,孙鑑,江梅,等.雷公藤红素对大鼠局灶性脑缺血再灌注损伤的作用[J].上海医学,2014,37(2):152-156.
[33]赵维民,章海燕,王红敏,等.咖啡酰基取代的五环三萜类衍生物及其用途:中国,CN103342729A[P].2013-10-09.
[34]Martín R,Cordova C,San Román J A,et al.Oleanolic acid modulates the immune-inflammatory response in mice with experimental autoimmune myocarditis and protects from cardiac injury.Therapeutic implications for the human disease[J].J Mol Cell Cardiol,2014,72(1):250-262.
[35]Ieong C,Sun H,Wang Q,et al.Glycyrrhizin suppresses the expressions of HMGB1 and ameliorates inflammative effect after acute subarachnoid hemorrhage in rat model[J].J Clin Neurosci,2017,doi:10.1016/j.jocn.2017.10.034.
[36]Wang X T,Gong Y,Zhou B,et al.Ursolic acid ameliorates oxidative stress,inflammation and fibrosis indiabetic cardiomyopathy rats[J].Biomed Pharmacother,2017,doi:10.1016/j.biopha.2017.11.032.
[37]Zhang H,Song Y,Zhang Z.Glycyrrhizin administration ameliorates coxsackievirus B3-induced myocarditis in mice[J].Am J Med Sci,2012,344(3):206-210.
[38]罗剑,李珍,荆吉,等.白桦脂酸衍生物在制备抑制T细胞分化的药物中的应用:中国,CN104337819A[P].2015-02-11.
[2]肖苏龙,王晗,王琪,等.基于五环三萜先导结构的抗病毒抑制剂研究进展[J].中国科学:化学,2015,45(9):865-883.
[3]王艺玮,徐盛涛,徐进宜.五环三萜羽扇豆烷型天然产物抗肿瘤活性研究进展[J].药学与临床研究,2017,25(4):336-342.
[4]Kim H Y,Cho K W,Kang D G,et al.Oleanolic acid increases plasma ANP levels via an accentuation of cardiac ANP synthesis and secretion in rats[J].Eur JPharmacol,2013,710(1/3):73-79.
[5]王军,张虹,谢凤杰,等.甘草酸预处理对大鼠心肌缺血再灌注损伤的保护作用及Bcl-2和Bax表达的影响[J].中国实验方剂学杂志,2018,24(6):126-132.
[6]赵瑞芳.熊果酸对大鼠心肌缺血再灌注损伤的保护作用[J].中国医药导报,2015,12(7):24-28.
[7]司林杰,许晶,易晨龙,等.积雪草酸抑制小鼠主动脉缩窄术后心肌肥厚形成[J].南京医科大学学报:自然科学版,2014,34(9):1168-1172.
[8]Der Sarkissian S,Cailhier J,Borie M,et al.Celastrol protects ischaemic myocardium through a heat shock response with up-regulation of haeme oxygenase-1[J].Br J Pharmacol,2015,171(23):5265-5279.
[9]赵全成,赫玉芳,南敏伦,等.救必应酸衍生物、合成方法及其在制备防治心血管疾病的药物中的应用:中国,CN102140126 A[P].2011-08-03.
[10]Tian Y,Sun Z,Wang W,et al.Semisynthesis and biological evaluation of oleanolic acid 3-O-β-D-glucuronopyranoside derivatives for protecting H9c2cardiomyoblasts against H2O2-induced injury[J].Molecules,2018,doi:10.3390/molecules23010044.
[11]郑磊,付帮泽,解华,等.甘草酸和甘草次酸对H9c2鼠心肌细胞活性氧水平的影响[J].中西医结合心脑血管病杂志,2016,14(1):21-25.
[12]Pan Y,Zhou F H,Song Z H,et al.Oleanolic acid protects against pathogenesis of atherosclerosis,possibly via FXR-mediated angiotensin(Ang)-(1-7)upregulation[J].Ritorno Al Numero,2018,doi:10.1016/j.biopha.2017.11.151.
[13]Niels H B,Nicolaj C H,Rosalia R R,et al.Antiatherogenic effects of oleanolic acid in apolipoprotein E knockout mice[J].Eur J Pharmacol,2011,670(2/3):519-526.
[14]Tzakos A G,Kontogianni V G,Tsoumani M,et al.Exploration of the antiplatelet activity profile of betulinic acid on human platelets[J].J Agric Food Chem,2012,60(28):6977-6983.
[15]高倩,吴佩,何疆,等.青蒿素和桦木酸阻断脂多糖诱导小鼠血管新生及组织增殖[J].中国药学杂志,2015,50(4):330-338.
[16]顾磊.雷公藤红素对抗动脉粥样硬化的作用及机制研究[D].南京:南京医科大学,2013.
[17]齐炼文,李萍,张蕾.常春藤皂苷元及其糖苷在制备治疗冠心病的药物中的应用:中国,CN107875156A[P].2018-04-06.
[18]孙宏斌,张丽颖,柳军.熊果烷型五环三萜氨基酸衍生物、其制备方法及其医药用途:中国,CN101337984[P].2009-01-07.
[19]王策.积雪草苷对心肌梗死大鼠转化生长因子-β1、I和III型胶原表达的影响[J].中国老年学杂志,2016,36(23):5799-5802.
[20]王策.积雪草苷对心梗大鼠心肌纤维化影响的实验研究[J].中国生化药物杂志,2014,34(8):19-22.
[21]Martín R,Carvalho-Tavares J,Hernández M,et al.Beneficial actions of oleanolic acid in an experimental model of multiple sclerosis:A potential therapeutic role[J].Biochem Pharmacol,2010,79(2):198-208.
[22]刘秀娟,韩雨薇,李晓明.齐墩果酸通过抑制NF-κB/ICAM-1信号通路减轻大鼠蛛网膜下腔出血后早期脑损伤的研究[J].中国现代应用药学,2017,34(9):1225-1228.
[23]齐炼文,李萍.常春藤皂苷元及其糖苷在制备防治脑卒中的药物中的应用:中国,CN107875157A[P].2018-04-06.
[24]Zhang T,Su J,Wang K,et al.Ursolic acid reduces oxidative stress to alleviate early brain injury following experimental subarachnoid hemorrhage[J].Neurosci Lett,2014,579(13):12-17.
[25]Lu Q,Xia N,Xu H,et al.Betulinic acid protects against cerebral ischemia-reperfusion injury in mice by reducing oxidative and nitrosative stress[J].Nitric Oxide,2011,24(3):132-138.
[26]Yoon J J,Lee Y J,Kim J S,et al.Protective role of betulinic acid on TNF-α-induced cell adhesion molecules in vascular endothelial cells[J].Biochem Biophys Res Commun,2010,391(1):96-101.
[27]王文娟,任欢欢,韩吉春,等.积雪草苷对缺血再灌注损伤的保护作用及其机制的研究[J].石河子大学学报:自然科学版,2015,33(5):593-598.
[28]Li L,Zhang X,Cui L,et al.Ursolic acid promotes the neuroprotection by activating Nrf2 pathway after cerebral ischemia in mice[J].Brain Res Rev,2013,1497(6):32-39.
[29]Qian Y,Guan T,Tang X,et al.Astrocytic glutamate transporter-dependent neuroprotection against glutamate toxicity:An in vitro study of maslinic acid[J].Eur JPharmacol,2011,651(1/3):59-65.
[30]Qian Y,Huang M,Guan T,et al.Maslinic acid promotes synaptogenesis and axon growth via Akt/GSK-3βactivation in cerebral ischemia model[J].Eur JPharmacol,2015,764:298-305.
[31]张朝弘,刘丹彦.雷公藤红素后处理对大鼠局灶性脑缺血再灌注损伤后脑组织NF-κB及TNF-α、IL-1β的影响[J].重庆医科大学学报,2015,40(1):37-41.
[32]杨雪莲,孙鑑,江梅,等.雷公藤红素对大鼠局灶性脑缺血再灌注损伤的作用[J].上海医学,2014,37(2):152-156.
[33]赵维民,章海燕,王红敏,等.咖啡酰基取代的五环三萜类衍生物及其用途:中国,CN103342729A[P].2013-10-09.
[34]Martín R,Cordova C,San Román J A,et al.Oleanolic acid modulates the immune-inflammatory response in mice with experimental autoimmune myocarditis and protects from cardiac injury.Therapeutic implications for the human disease[J].J Mol Cell Cardiol,2014,72(1):250-262.
[35]Ieong C,Sun H,Wang Q,et al.Glycyrrhizin suppresses the expressions of HMGB1 and ameliorates inflammative effect after acute subarachnoid hemorrhage in rat model[J].J Clin Neurosci,2017,doi:10.1016/j.jocn.2017.10.034.
[36]Wang X T,Gong Y,Zhou B,et al.Ursolic acid ameliorates oxidative stress,inflammation and fibrosis indiabetic cardiomyopathy rats[J].Biomed Pharmacother,2017,doi:10.1016/j.biopha.2017.11.032.
[37]Zhang H,Song Y,Zhang Z.Glycyrrhizin administration ameliorates coxsackievirus B3-induced myocarditis in mice[J].Am J Med Sci,2012,344(3):206-210.
[38]罗剑,李珍,荆吉,等.白桦脂酸衍生物在制备抑制T细胞分化的药物中的应用:中国,CN104337819A[P].2015-02-11.