新型低密度脂蛋白受体上调剂：异喹啉类衍生物的合成、构效关系及降脂作用
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摘要
我研究所发现并证实:我国传统中药单体小檗碱(俗称黄连素,berberine,简写BBR)是一个与他汀类药物不同、具有全新生物作用机制的降血脂天然药物,其分子式为C_(20)H_(18)NO_4Cl,分子量为371.5,结构式见图1。本论文以BBR为先导化合物,分别对其D环取代、C环及13位取代等进行结构修饰,设计合成了45个BBR类似物,并通过测定其上调低密度脂蛋白受体(LDLR)的表达活性,应用计算机辅助药物设计,得出了此类衍生物的最佳药效团模型,初步阐明了BBR的C和D环取代基上调LDLR活性的构效关系。
图1.BBR氯化物的结构式
(一)增加9-位和(或)10-位取代基的体积,即用OC_2H_5,OC_3H_7替代9-OCH_3和(或)10-OCH_3,所得衍生物M_2A_1、M_2B_1、M_2A_2、M_2B_2的活性均有不同程度的降低:去掉9-OCH_3,变换10-位取代基,10-OH衍生物93的活性与BBR相当,但拥有不同烷氧基的衍生物95、97、98的活性均降低;去掉10-OCH_3,9-位变为OH的衍生物83,活性也有所降低:而去掉9-OCH_3,10-OCH_3,所得衍生物SYD-3的活性大大降低。
(二)10-,11-位均为甲氧基的衍生物53,活性最好,是BBR的1.6倍;但将10-,11-位两个甲氧基用不同的取代基,如OH、CH_3、OC_H_5和OC_3H_7,同时替换或替换其中一个时,所得衍生物73、74、75、55、56、57、123和163活性均有不同程度的降低,甚至消失。
(三)相邻两个甲氧基是活性所必需的,但相邻三个甲氧基并不能增加活性,如9-,10-,11-,和10-,11-,12-三甲氧基取代产物63和173的活性均有所降低。
(四)C环的芳香体系是活性所必需的,将C环完全还原或不完全还原所得二氢衍生物181和四氢衍生物YD-4、THBBR、THY-53、THY-73、THY-93的活性均消失。
(五)C环13位为氢原子时活性最好,在BBR的13位引入不同的烷基和苯甲基,其活性均完全消失。
在合成的45个目标化合物中,53显示出很好的上调LDLR的活性,由此本课题对化合物53进行了深入的生物学研究。流式细胞实验结果证实,化合物53对LDLR蛋白的上调作用明显增强。Balb/c小鼠高脂模型实验结果表明,用BBR和53分别治疗(100 mg/kg,po)3周后,CHO分别下降12.1%和32.9%,LDL分别下降25%和50%;SD大鼠高脂模型实验结果表明,BBR和53(100 mg/kg,po)治疗30天后,CHO分别下降27.4%和38.5%,LDL分别下降28.9%和43.5%。53降低CHO和LDL的效果显著优于BBR(P＜0.01)。53在动物体内上调肝脏LDLRmRNA表达的作用是BBR的1.5倍,与体外结果一致。53组肝功能和肾功能的指标均保持在正常范围之内,表明53没有明显的肝肾毒性。
急性毒性实验结果表明,53的LD_(50)＞5000 mg/kg,在此剂量下小鼠大脑、心、肝、肾、肺和肠等脏器的病理切片均未见明显异常,表明其对各脏器没有明显的毒副作用。
53的活性强于BBR可以从三个方面解释:①计算机辅助设计结果表明,BBR分子中存在三个药效团,即疏水中心、阳离子中心和环芳香中心;而化合物53除此三个药效团之外,还在D环的11-OCH_3上增加一个氢键接受体,使之与靶蛋白的结合能力更强;②BBR分子中9-OCH_3的存在削弱了7-位氮正离子的电正性,而53分子中9-OCH_3移至11-位后,11-OCH_3对7-位氮正离子的作用减小或消失,使其电正性增强,从而进攻靶蛋白的能力亦增强;③53的水溶性增大,溶解度是BBR的4倍,可能改善了其体内吸收差的药代特性。
本课题共设计合成了45个目标化合物,其结构经MS、~1H NMR及IR等图谱确证无误。其中化合物53的降血脂活性高;毒性低、安全性好;机理与BBR相同而有别于他汀类药物;合成工艺成熟,操作简单,收率高。我们认为化合物53具有很好的应用前景,拟进行临床前研究。
By screening the pool of traditional Chinese herbs,we found in our previous studies that berberine(BBR) was a novel LDLR-up-regulator and cholesterol-lowering agent with a mechanism distinct from statins.BBR has definite chemical structure with a molecular weight of 371.5 and has a number of pharmacological activities.In the present study,we take BBR as a leading compound for the structure-activity relationship(SAR) analysis.By replacing the side chain of D ring with various substituents,alterrating the double bond of ring C and attaching different substitents at the 13-positon,45 new analogues were designed and synthesized.The LDLR- up-regulating activities of these compounds were determined and SAR of this group of chemical entities was elucidated accordingly.
(1) By substituting 9-OCH_3 and/or 10-OCH_3 on D ring with OC_2H_5,OC_3H_7,the analogues with increasing volume of the side chain at the 9,10-positions had an activity lower than that of BBR.Removing 9-OCH_3,the analogue with 10-OH remained the activity,but substituting 10-OH with OCH_3,OC_2H_5 or OC_3H_7 made the acitity decreased partially.Removing 9-OCH_3 and 10-OCH_3 from the D ring made the activity decreased consumedly.
(2) The analogue with a dimethoxyl group at the 10,11-positions of D ring had the best activity of 1.6-fold of that of BBR.Substituting 10-OCH_3 and/or 11-OCH_3 with OH,CH_3, OC_2H_5 or OC_3H_7 made the acitity decreased consumedly or even deminished.This result indicated that a dimethoxyl structure in an ortho distribution afforded the optimal activity.
(3) Though an ortho dimethoxyl structure is essential for the activity,but increasing the number of the methoxyls at ring D did not enhance the activity,in fact,the analogues with 3 methoxyls at ring D had a regulating effect 60%of that in BBR.
(4) The aromatic system of ring C was essential;reducing one or two of the double bonds in the ring C made a complete loss of the activity.
(5) The hydrogen at 13-position was also essential;replacing the hydrogen with different alkoxyl or substituted benzyl group made the activity disappeared completely.
In vitro,LDLR mRNA expression was up-regulated by 8.5-fold with 53,which was the best analogue among the compounds.Besides,53 also increased LDLR protein expression on cell surface dramatically.So,we evaluated the cholesterol-lowering effect of 53 in vivo.First,hypercholesterolemic Balb/c mice were used.Our results showed that 100 mg/kg of BBR or 53 orally administrated twice a day for 3 weeks effectively lowered serum CHO levels by 12.1%and 32.9%,LDL by 25%and 50%,respectively. Then the cholesterol-lowering effect of 53 was evaluated in hypercholesterolemic SD rats.100 mg/kg of BBR or 53 orally administrated twice a day for 30 days lowered serum CHO by 27.4%and 38.5%,LDL by 28.9%and 43.5%,respectively.The CHO-and LDL-lowering activities of 53 were significantly higher than that of BBR in animals (P＜0.01).In the animal experiments,53 increased liver LDLR mRNA expression level to 1.5-fold of that of BBR,consistent with the results in vitro.In the two animal models, liver and kidney functions were not affected by 53.These results indicated that 53 has better cholesterol-lowering activity than BBR and does not have liver or kidney toxicities.
The acute toxicity experiment showed that the LD_(50) of 53 was far more than 5000 mg/kg in mice.The pathological examination of cerebrum,heart,liver,kidney,lung and intestine of the mice indicated that 53 does not have toxicity on these organs.
There could be at least three explaination for why 53 has better activity than BBR: Firstly,the results of Computer-assistant Drug Design showed that there were four active groups in these analogues:hydrogen-bonding acceptor,hydrophobic core,positive ion core and aromatic hydrophobic core.The molecule of BBR only mapped onto 3 active group sites of the modle,while 53 mapped well with all 4 active group sites.Secondly, 53 had an electropositivity in the 7-nitrogen ion more than that of BBR;the 7-N ion plays an important role in the interaction between the compound and the speculated target molecule.Thirdly,53 had a better water-solubility than BBR,which might increase its absorption in vivo.
In this study,45 analogues were designed and synthesized.The physical and chemical information of these compounds have been confirmed by MS,~1H NMR and IR.All of these results indicated that 53 had a good cholestorel-lowering activity,unique mechanism of action different from that of statins,good safety and improved water-solubility.In addition,compound 53 could be synthesized successfully with a high yield via five steps.We consider the compound 53 a promising candidate for further preclinical investigation.
图1.BBR氯化物的结构式
(一)增加9-位和(或)10-位取代基的体积,即用OC_2H_5,OC_3H_7替代9-OCH_3和(或)10-OCH_3,所得衍生物M_2A_1、M_2B_1、M_2A_2、M_2B_2的活性均有不同程度的降低:去掉9-OCH_3,变换10-位取代基,10-OH衍生物93的活性与BBR相当,但拥有不同烷氧基的衍生物95、97、98的活性均降低;去掉10-OCH_3,9-位变为OH的衍生物83,活性也有所降低:而去掉9-OCH_3,10-OCH_3,所得衍生物SYD-3的活性大大降低。
(二)10-,11-位均为甲氧基的衍生物53,活性最好,是BBR的1.6倍;但将10-,11-位两个甲氧基用不同的取代基,如OH、CH_3、OC_H_5和OC_3H_7,同时替换或替换其中一个时,所得衍生物73、74、75、55、56、57、123和163活性均有不同程度的降低,甚至消失。
(三)相邻两个甲氧基是活性所必需的,但相邻三个甲氧基并不能增加活性,如9-,10-,11-,和10-,11-,12-三甲氧基取代产物63和173的活性均有所降低。
(四)C环的芳香体系是活性所必需的,将C环完全还原或不完全还原所得二氢衍生物181和四氢衍生物YD-4、THBBR、THY-53、THY-73、THY-93的活性均消失。
(五)C环13位为氢原子时活性最好,在BBR的13位引入不同的烷基和苯甲基,其活性均完全消失。
在合成的45个目标化合物中,53显示出很好的上调LDLR的活性,由此本课题对化合物53进行了深入的生物学研究。流式细胞实验结果证实,化合物53对LDLR蛋白的上调作用明显增强。Balb/c小鼠高脂模型实验结果表明,用BBR和53分别治疗(100 mg/kg,po)3周后,CHO分别下降12.1%和32.9%,LDL分别下降25%和50%;SD大鼠高脂模型实验结果表明,BBR和53(100 mg/kg,po)治疗30天后,CHO分别下降27.4%和38.5%,LDL分别下降28.9%和43.5%。53降低CHO和LDL的效果显著优于BBR(P＜0.01)。53在动物体内上调肝脏LDLRmRNA表达的作用是BBR的1.5倍,与体外结果一致。53组肝功能和肾功能的指标均保持在正常范围之内,表明53没有明显的肝肾毒性。
急性毒性实验结果表明,53的LD_(50)＞5000 mg/kg,在此剂量下小鼠大脑、心、肝、肾、肺和肠等脏器的病理切片均未见明显异常,表明其对各脏器没有明显的毒副作用。
53的活性强于BBR可以从三个方面解释:①计算机辅助设计结果表明,BBR分子中存在三个药效团,即疏水中心、阳离子中心和环芳香中心;而化合物53除此三个药效团之外,还在D环的11-OCH_3上增加一个氢键接受体,使之与靶蛋白的结合能力更强;②BBR分子中9-OCH_3的存在削弱了7-位氮正离子的电正性,而53分子中9-OCH_3移至11-位后,11-OCH_3对7-位氮正离子的作用减小或消失,使其电正性增强,从而进攻靶蛋白的能力亦增强;③53的水溶性增大,溶解度是BBR的4倍,可能改善了其体内吸收差的药代特性。
本课题共设计合成了45个目标化合物,其结构经MS、~1H NMR及IR等图谱确证无误。其中化合物53的降血脂活性高;毒性低、安全性好;机理与BBR相同而有别于他汀类药物;合成工艺成熟,操作简单,收率高。我们认为化合物53具有很好的应用前景,拟进行临床前研究。
By screening the pool of traditional Chinese herbs,we found in our previous studies that berberine(BBR) was a novel LDLR-up-regulator and cholesterol-lowering agent with a mechanism distinct from statins.BBR has definite chemical structure with a molecular weight of 371.5 and has a number of pharmacological activities.In the present study,we take BBR as a leading compound for the structure-activity relationship(SAR) analysis.By replacing the side chain of D ring with various substituents,alterrating the double bond of ring C and attaching different substitents at the 13-positon,45 new analogues were designed and synthesized.The LDLR- up-regulating activities of these compounds were determined and SAR of this group of chemical entities was elucidated accordingly.
(1) By substituting 9-OCH_3 and/or 10-OCH_3 on D ring with OC_2H_5,OC_3H_7,the analogues with increasing volume of the side chain at the 9,10-positions had an activity lower than that of BBR.Removing 9-OCH_3,the analogue with 10-OH remained the activity,but substituting 10-OH with OCH_3,OC_2H_5 or OC_3H_7 made the acitity decreased partially.Removing 9-OCH_3 and 10-OCH_3 from the D ring made the activity decreased consumedly.
(2) The analogue with a dimethoxyl group at the 10,11-positions of D ring had the best activity of 1.6-fold of that of BBR.Substituting 10-OCH_3 and/or 11-OCH_3 with OH,CH_3, OC_2H_5 or OC_3H_7 made the acitity decreased consumedly or even deminished.This result indicated that a dimethoxyl structure in an ortho distribution afforded the optimal activity.
(3) Though an ortho dimethoxyl structure is essential for the activity,but increasing the number of the methoxyls at ring D did not enhance the activity,in fact,the analogues with 3 methoxyls at ring D had a regulating effect 60%of that in BBR.
(4) The aromatic system of ring C was essential;reducing one or two of the double bonds in the ring C made a complete loss of the activity.
(5) The hydrogen at 13-position was also essential;replacing the hydrogen with different alkoxyl or substituted benzyl group made the activity disappeared completely.
In vitro,LDLR mRNA expression was up-regulated by 8.5-fold with 53,which was the best analogue among the compounds.Besides,53 also increased LDLR protein expression on cell surface dramatically.So,we evaluated the cholesterol-lowering effect of 53 in vivo.First,hypercholesterolemic Balb/c mice were used.Our results showed that 100 mg/kg of BBR or 53 orally administrated twice a day for 3 weeks effectively lowered serum CHO levels by 12.1%and 32.9%,LDL by 25%and 50%,respectively. Then the cholesterol-lowering effect of 53 was evaluated in hypercholesterolemic SD rats.100 mg/kg of BBR or 53 orally administrated twice a day for 30 days lowered serum CHO by 27.4%and 38.5%,LDL by 28.9%and 43.5%,respectively.The CHO-and LDL-lowering activities of 53 were significantly higher than that of BBR in animals (P＜0.01).In the animal experiments,53 increased liver LDLR mRNA expression level to 1.5-fold of that of BBR,consistent with the results in vitro.In the two animal models, liver and kidney functions were not affected by 53.These results indicated that 53 has better cholesterol-lowering activity than BBR and does not have liver or kidney toxicities.
The acute toxicity experiment showed that the LD_(50) of 53 was far more than 5000 mg/kg in mice.The pathological examination of cerebrum,heart,liver,kidney,lung and intestine of the mice indicated that 53 does not have toxicity on these organs.
There could be at least three explaination for why 53 has better activity than BBR: Firstly,the results of Computer-assistant Drug Design showed that there were four active groups in these analogues:hydrogen-bonding acceptor,hydrophobic core,positive ion core and aromatic hydrophobic core.The molecule of BBR only mapped onto 3 active group sites of the modle,while 53 mapped well with all 4 active group sites.Secondly, 53 had an electropositivity in the 7-nitrogen ion more than that of BBR;the 7-N ion plays an important role in the interaction between the compound and the speculated target molecule.Thirdly,53 had a better water-solubility than BBR,which might increase its absorption in vivo.
In this study,45 analogues were designed and synthesized.The physical and chemical information of these compounds have been confirmed by MS,~1H NMR and IR.All of these results indicated that 53 had a good cholestorel-lowering activity,unique mechanism of action different from that of statins,good safety and improved water-solubility.In addition,compound 53 could be synthesized successfully with a high yield via five steps.We consider the compound 53 a promising candidate for further preclinical investigation.
引文
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