橙皮苷衍生物的合成及其药理作用的研究
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摘要
橙皮苷是橙皮素的芸香糖苷,为二氢黄酮衍生物,主要存在甜橙及其他柑橘属的水果、叶和果皮中,橙皮苷具有广谱的生物活性,能抗癌、抗病毒、抗氧化、抗过敏、抗炎、降血压等。由于橙皮苷安全无毒副作用,以橙皮苷为先导化合物,通过计算机辅助药物设计进行结构修饰,开发新的活性物质,这一直是科学界研究的热点。本论文选择基于受体的药物设计方法,以ACE酶为受体,运用分子对接,设计与ACE酶受体相匹配的橙皮苷衍生物配体,然后对配体进行化学合成,开展体外ACE酶抑制活性的实验,验证分子对接的理论结果；同时,根据橙皮苷先导化合物具有的其他药理活性,还对橙皮苷衍生物开展了其他活性方面的研究。具体工作如下：
1.橙皮苷衍生物的合成及结构表征
以橙皮苷为先导化合物,通过酸水解和甲基化反应分别制备橙皮素、甲基橙皮苷、甲基橙皮素中间体,然后通过醚化和酯化反应得到橙皮素、甲基橙皮素的醚类及酯类物质,同时根据UV, IR,1H NMR, MS等图谱对目标化合物的结构进行确证。
2.橙皮素-7-烷基醚的抗菌作用
通过纸片法和二倍稀释法研究橙皮素-7-烷基醚对5种微生物菌株的抑制作用,菌株主要是细菌(G+：金黄色葡萄球菌、枯草芽孢杆菌；G-：大肠杆菌、变形杆菌)和真菌(白色念珠菌),结果表明,在药物浓度在400μg/mL时,橙皮素-7-烷基醚对白色念珠菌无抑制作用,但是对四种细菌具有显著的抑制效果,抑菌圈平均直径在1.5-3.9 mm；与橙皮苷和橙皮素相比,橙皮素-7-烷基醚对细菌的抑制能力都是随着烷基碳链的延长(Cn=12)而增强,其中,橙皮素-7-正十二烷基醚对金黄色葡萄球菌表现出最大抑制作用(MIC=6.25μg/mL)。
3.甲基橙皮素-7-烷基醚的抗氧化和抗炎作用
通过观察甲基橙皮素-7-烷基醚对体外超氧负离子自由基(02·-)和羟自由基(0H·)的清除能力、对小鼠体内巨噬细胞NO释放的抑制作用、对氟氏佐剂诱导的关节炎小鼠血清中丙二醛(MDA)和超氧化物歧化酶(SOD)浓度的影响,研究甲基橙皮素-7-烷基醚的抗氧化能力。同时通过考察衍生物对氟氏佐剂诱导的关节炎小鼠的足肿胀的抑制作用、对关节炎小鼠血清中COX-2、PGE2的影响和对醋酸致小鼠腹腔毛细管通透性的影响,研究甲基橙皮素-7-烷基醚的抗炎作用,结果得出甲基橙皮素-7-正辛基醚具有较好的抗氧化和抗炎能力。
4.甲基橙皮素-7-烷基醚对小鼠胃排空和小肠推进的作用
以小鼠胃内残留率和小肠推进率为指标,研究甲基橙皮素-7-烷基醚对阿托品所致小鼠胃排空和小肠推进抑制的拈抗作用,结果表明甲基橙皮苷对小鼠胃内残留率为39.9%,对小肠推进率为52.75%,拮抗作用显著。
5.橙皮苷衍生物对血管紧张素转化酶的抑制作用
以ACE酶为受体,将分子对接设计出的橙皮苷衍生物配体进行合成确证,然后通过ACE酶抑制实验,实际验证所合成化合物的抑制能力；同时,对所合成化合物的结构与降血压活性之间也进行了构效关系的研究,结果表明,橙皮苷对ACE酶的抑制活性,通过计算机分子对接技术预测评分得到的结果和实际测量的结果存在一定的误差。在橙皮素-7-烷基醚类衍生物中,橙皮素-7-正十六烷基醚表现出最强的抑制活性,对ACE酶的抑制率为50.96%；而甲基橙皮素-7-烷基醚类衍生物中,甲基橙皮素-7-正十二烷基醚抑制活性最强,抑制率为43.04%；在橙皮素7位醚类/酯类和甲基橙皮素7位醚类/酯类衍生物中,酯类化合物和引入含有苯基的醚类化合物对ACE酶的抑制率下降；甲基橙皮素-7-正丁基醚与甲基橙皮素-7-(1M-溴代)-正丁基醚两者的抑制率分别为37.47%和36.88%,表明在烷基链甲基端引入卤素,不能提高对ACE的抑制活性。这些结论与分子对接预测的结果基本一致。
Hesperidin, a rutinoside of hesperetin, is a dihydroflavonoid derivative. It is present in fruit, leaves and in the bark of orange and other citrus species. Hesperedin has shown a broad range of biological activities, including antitumor, antivirus, antioxidant, antiallergic, anti-inflammatory, hypotensive effects. As a result of its safety and non-toxic side effects, taking hesperidin as a lead compound to modificate its stucture by the method of computer-aided drug design for the development of some novel active substances, has become a hot topic in this field. In this study, the method of receptor-based drug design had been chosen, Angiotensin-converting enzyme (ACE) was selected as the receptor, hesperidin derivatives as the ligands to coupling with ACE-receptor by the technique of molecular docking. According to the pretest results, the hesperidin derivatives had been synthesized and their inhibitory activities on ACE in vitro were studied to confirm furtherly. At the same time, the other pharmacological effects of the derivatives had also been screened by the lead compound hesperidin owning. The special research was as follow:
1. Synthesis and structures confirmation of hesperidin derivatives
As a lead compound of hesperidin, hesperetin, methyl-hespereridin and methyl-hespereretin had been prepared by acid-catalyed hydrolysis and methylized reaction, and then by the esterified and etherified reaction, the ester and the ether derivatives of hesperetin and methyl-hespereretin had been synthesized. The spectral data of UV, IR, 1H NMR and MS confirmed the structures of the synthesized compounds.
2. Antimicrobial activities of hesperetin-7-alkyl ether
Antimicrobial activities of hesperetin-7-alkyl ether on 5 patheogenic microorga-nisms were studied with the methods of agar well diffusion and 2-fold serial dilution test.5 patheogenic microorganisms used for the antimicrobial assay were Gram-positive (G+) bacteria viz. Bacillus subtilis, Staphylococcus aureus, Gram-negative (G-) bacteria viz. Proteus vulgaris, Escherichia coli and a fungus viz. Candida albicans, respectively. The result indicated hesperetin-7-alkyl ether derivatives had the antibacterial effects none antifungal effects at the concentration of 400μg/mL. The average diameter of the inhi- bitory zone with 4 bacterial strains was from 1.5 to 3.9 mm. Compared with hesperidin and hesperetin, The antibacterial effects of hesperetin-7-alkyl ether derivatives were become stronger as the enlongating of the length of carbon chain (Cn= 12), hesperetin- 7-N-dodecyl ether showed the highest antibacterial activity (MIC= 6.25μg/mL) among all the compounds.
3. Antioxidant and anti-inflammatory effects of methyl-hespereretin-7-alkyl ether derivatives
The antioxidant activities of methyl-hespereretin-7-alkyl ether derivatives were studied with the in vitro screening effects on superoxide anion radical (O2·-) and hydroxyl radical (OH), the in vivo inhibitory effects on nitric oxide released by microphage, and the influence on the concentration of Malondialdehyde (MDA) and Superoxide dismutase (SOD) in the serum of Freund's complete adjuvant (FCA) induced arthritic mice. The anti-inflammatory activities of methyl-hespereretin-7-alkyl ether derivatives were studied with the inhibitory effects on FCA induced mouse paw edema, the influence on the concentration of COX-2, PGE2 in the serum of the arthritic mice and acetic acid induced capillary permeability in mice. The result showed methyl-hespereretin-7-n-octyl ether had good antioxidant and anti-inflammatory activities.
4. Influence of methyl-hespereretin-7-alkyl ether derivatives on the inhibitory effects of atropine sulfate-induced gastric emptying and small intestinal propulsive in mice
Gastric residual rate and small intestinal propulsive rate had served as the main parameters, the antagonistic action of methyl-hespereretin-7-n-octyl ether on the inhibitory effects of atropine sulfate-induced gastric emptying and small intestinal pro-pulsive in mice were studied, the conclusion indicated the gastric rate and small intes- tinal propulsive rate of methyl-hespereridin separately was 39.9% and 52.75%, methyl-hesperidin had the significantly antagonistic action.
5. Inhibitory effects of hesperidin derivatives on Angiotensin-converting enzyme
With ACE as the receptor, the ligands of hesperidin derivatives were synthesized under the method of molecular docking and their structures were confirmed, at the same time, the relationship between the structures of the synthesized compounds and the inhi-bitory activities on ACE had also been studied. The result had indicated that the inhibi-tory activities of hesperidin on ACE were different between the predict evaluation and the practical measurement, the inhibitory rate of hesperetin-7-n-hexadecyl ether and methyl-hespereretin-7-n-dodecyl ether on ACE individually was 50.96% and 43.04%, they had the significantly inhibitory effects on ACE. In hesperetin ether/ester derivatives and in methyl-hespereretin ether/ester derivatives, the conclusion also indicated ester derivatives and the introduction of phenyl group in ether could decrease the inhibitory effect on ACE. The inhibitory rate of methyl- hespereretin- 7-n-butyl ether and methyl-hespereretin-7-(1"-bromo)-N-butyl ether was 34.47% and 36.88%, respectively, it indicated that the introduction of halogen didn't improve the inhibitory activity on ACE, the result was correspondent with the prediction.
1.橙皮苷衍生物的合成及结构表征
以橙皮苷为先导化合物,通过酸水解和甲基化反应分别制备橙皮素、甲基橙皮苷、甲基橙皮素中间体,然后通过醚化和酯化反应得到橙皮素、甲基橙皮素的醚类及酯类物质,同时根据UV, IR,1H NMR, MS等图谱对目标化合物的结构进行确证。
2.橙皮素-7-烷基醚的抗菌作用
通过纸片法和二倍稀释法研究橙皮素-7-烷基醚对5种微生物菌株的抑制作用,菌株主要是细菌(G+：金黄色葡萄球菌、枯草芽孢杆菌；G-：大肠杆菌、变形杆菌)和真菌(白色念珠菌),结果表明,在药物浓度在400μg/mL时,橙皮素-7-烷基醚对白色念珠菌无抑制作用,但是对四种细菌具有显著的抑制效果,抑菌圈平均直径在1.5-3.9 mm；与橙皮苷和橙皮素相比,橙皮素-7-烷基醚对细菌的抑制能力都是随着烷基碳链的延长(Cn=12)而增强,其中,橙皮素-7-正十二烷基醚对金黄色葡萄球菌表现出最大抑制作用(MIC=6.25μg/mL)。
3.甲基橙皮素-7-烷基醚的抗氧化和抗炎作用
通过观察甲基橙皮素-7-烷基醚对体外超氧负离子自由基(02·-)和羟自由基(0H·)的清除能力、对小鼠体内巨噬细胞NO释放的抑制作用、对氟氏佐剂诱导的关节炎小鼠血清中丙二醛(MDA)和超氧化物歧化酶(SOD)浓度的影响,研究甲基橙皮素-7-烷基醚的抗氧化能力。同时通过考察衍生物对氟氏佐剂诱导的关节炎小鼠的足肿胀的抑制作用、对关节炎小鼠血清中COX-2、PGE2的影响和对醋酸致小鼠腹腔毛细管通透性的影响,研究甲基橙皮素-7-烷基醚的抗炎作用,结果得出甲基橙皮素-7-正辛基醚具有较好的抗氧化和抗炎能力。
4.甲基橙皮素-7-烷基醚对小鼠胃排空和小肠推进的作用
以小鼠胃内残留率和小肠推进率为指标,研究甲基橙皮素-7-烷基醚对阿托品所致小鼠胃排空和小肠推进抑制的拈抗作用,结果表明甲基橙皮苷对小鼠胃内残留率为39.9%,对小肠推进率为52.75%,拮抗作用显著。
5.橙皮苷衍生物对血管紧张素转化酶的抑制作用
以ACE酶为受体,将分子对接设计出的橙皮苷衍生物配体进行合成确证,然后通过ACE酶抑制实验,实际验证所合成化合物的抑制能力；同时,对所合成化合物的结构与降血压活性之间也进行了构效关系的研究,结果表明,橙皮苷对ACE酶的抑制活性,通过计算机分子对接技术预测评分得到的结果和实际测量的结果存在一定的误差。在橙皮素-7-烷基醚类衍生物中,橙皮素-7-正十六烷基醚表现出最强的抑制活性,对ACE酶的抑制率为50.96%；而甲基橙皮素-7-烷基醚类衍生物中,甲基橙皮素-7-正十二烷基醚抑制活性最强,抑制率为43.04%；在橙皮素7位醚类/酯类和甲基橙皮素7位醚类/酯类衍生物中,酯类化合物和引入含有苯基的醚类化合物对ACE酶的抑制率下降；甲基橙皮素-7-正丁基醚与甲基橙皮素-7-(1M-溴代)-正丁基醚两者的抑制率分别为37.47%和36.88%,表明在烷基链甲基端引入卤素,不能提高对ACE的抑制活性。这些结论与分子对接预测的结果基本一致。
Hesperidin, a rutinoside of hesperetin, is a dihydroflavonoid derivative. It is present in fruit, leaves and in the bark of orange and other citrus species. Hesperedin has shown a broad range of biological activities, including antitumor, antivirus, antioxidant, antiallergic, anti-inflammatory, hypotensive effects. As a result of its safety and non-toxic side effects, taking hesperidin as a lead compound to modificate its stucture by the method of computer-aided drug design for the development of some novel active substances, has become a hot topic in this field. In this study, the method of receptor-based drug design had been chosen, Angiotensin-converting enzyme (ACE) was selected as the receptor, hesperidin derivatives as the ligands to coupling with ACE-receptor by the technique of molecular docking. According to the pretest results, the hesperidin derivatives had been synthesized and their inhibitory activities on ACE in vitro were studied to confirm furtherly. At the same time, the other pharmacological effects of the derivatives had also been screened by the lead compound hesperidin owning. The special research was as follow:
1. Synthesis and structures confirmation of hesperidin derivatives
As a lead compound of hesperidin, hesperetin, methyl-hespereridin and methyl-hespereretin had been prepared by acid-catalyed hydrolysis and methylized reaction, and then by the esterified and etherified reaction, the ester and the ether derivatives of hesperetin and methyl-hespereretin had been synthesized. The spectral data of UV, IR, 1H NMR and MS confirmed the structures of the synthesized compounds.
2. Antimicrobial activities of hesperetin-7-alkyl ether
Antimicrobial activities of hesperetin-7-alkyl ether on 5 patheogenic microorga-nisms were studied with the methods of agar well diffusion and 2-fold serial dilution test.5 patheogenic microorganisms used for the antimicrobial assay were Gram-positive (G+) bacteria viz. Bacillus subtilis, Staphylococcus aureus, Gram-negative (G-) bacteria viz. Proteus vulgaris, Escherichia coli and a fungus viz. Candida albicans, respectively. The result indicated hesperetin-7-alkyl ether derivatives had the antibacterial effects none antifungal effects at the concentration of 400μg/mL. The average diameter of the inhi- bitory zone with 4 bacterial strains was from 1.5 to 3.9 mm. Compared with hesperidin and hesperetin, The antibacterial effects of hesperetin-7-alkyl ether derivatives were become stronger as the enlongating of the length of carbon chain (Cn= 12), hesperetin- 7-N-dodecyl ether showed the highest antibacterial activity (MIC= 6.25μg/mL) among all the compounds.
3. Antioxidant and anti-inflammatory effects of methyl-hespereretin-7-alkyl ether derivatives
The antioxidant activities of methyl-hespereretin-7-alkyl ether derivatives were studied with the in vitro screening effects on superoxide anion radical (O2·-) and hydroxyl radical (OH), the in vivo inhibitory effects on nitric oxide released by microphage, and the influence on the concentration of Malondialdehyde (MDA) and Superoxide dismutase (SOD) in the serum of Freund's complete adjuvant (FCA) induced arthritic mice. The anti-inflammatory activities of methyl-hespereretin-7-alkyl ether derivatives were studied with the inhibitory effects on FCA induced mouse paw edema, the influence on the concentration of COX-2, PGE2 in the serum of the arthritic mice and acetic acid induced capillary permeability in mice. The result showed methyl-hespereretin-7-n-octyl ether had good antioxidant and anti-inflammatory activities.
4. Influence of methyl-hespereretin-7-alkyl ether derivatives on the inhibitory effects of atropine sulfate-induced gastric emptying and small intestinal propulsive in mice
Gastric residual rate and small intestinal propulsive rate had served as the main parameters, the antagonistic action of methyl-hespereretin-7-n-octyl ether on the inhibitory effects of atropine sulfate-induced gastric emptying and small intestinal pro-pulsive in mice were studied, the conclusion indicated the gastric rate and small intes- tinal propulsive rate of methyl-hespereridin separately was 39.9% and 52.75%, methyl-hesperidin had the significantly antagonistic action.
5. Inhibitory effects of hesperidin derivatives on Angiotensin-converting enzyme
With ACE as the receptor, the ligands of hesperidin derivatives were synthesized under the method of molecular docking and their structures were confirmed, at the same time, the relationship between the structures of the synthesized compounds and the inhi-bitory activities on ACE had also been studied. The result had indicated that the inhibi-tory activities of hesperidin on ACE were different between the predict evaluation and the practical measurement, the inhibitory rate of hesperetin-7-n-hexadecyl ether and methyl-hespereretin-7-n-dodecyl ether on ACE individually was 50.96% and 43.04%, they had the significantly inhibitory effects on ACE. In hesperetin ether/ester derivatives and in methyl-hespereretin ether/ester derivatives, the conclusion also indicated ester derivatives and the introduction of phenyl group in ether could decrease the inhibitory effect on ACE. The inhibitory rate of methyl- hespereretin- 7-n-butyl ether and methyl-hespereretin-7-(1"-bromo)-N-butyl ether was 34.47% and 36.88%, respectively, it indicated that the introduction of halogen didn't improve the inhibitory activity on ACE, the result was correspondent with the prediction.
引文
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