芹菜素-钆配合物的合成及其抗小鼠高尿酸血症研究
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摘要
将芹菜素(AP)与钆(III)离子配位生成配合物,以期提高芹菜素抗高尿酸血症活性。以具有一定抗炎、抗痛风活性的芹菜素为配体,以稀土金属钆(III)离子为配位中心,设计合成芹菜素-钆配合物(AP-Gd)。采用紫外(UV)、红外(IR)、氢核磁共振(~1H-NMR)、电导法、 X射线光电子能谱(XPS)、差热-热重分析(TG-DTA)等技术对配合物的化学结构进行表征。考察配合物对酵母浸粉联合氧嗪酸钾诱导的高尿酸血症小鼠模型中尿酸、黄嘌呤氧化酶及超氧阴离子水平的影响。结果表明:芹菜素与钆(III)离子配位生成了配合物,配合物组成式为:[Gd(C_(15)H_9O_5)_2]·NO_3·3H_2O。芹菜素A环的5-OH和C环的4位C=O与钆(III)离子形成了配合物,且芹菜素与钆(III)离子的配位比为2。抗高尿酸症活性研究发现,芹菜素-钆配合物对高尿酸血症小鼠黄嘌呤氧化酶的抑制作用、清除超氧阴离子能力、降低血清尿酸水平及促进尿酸排泄能力均优于芹菜素,提示芹菜素与钆(III)离子配位后,所得配合物抗高尿酸血症活性增强。
The apigenin-gadolinium(AP-Gd) complex with apigenin(AP) and gadolinium(Gd)(III) ion was synthesized in order to improve its activity of anti-hyperuricemia. Based on the theory of traditional Chinese medicine coordination chemistry, AP-Gd complex was synthesized with AP possessed anti-inflammatory and anti-gout activity as ligand, and rare earth metal Gd(III) ion as coordination center. The chemical structure of the AP-Gd complex was characterized by UV, IR, ~1H-NMR, conductometry, XPS and TG-DTA. Effect of AP-Gd complex on uric acid(UA) level, xanthine oxidase(XOD) activity and superoxide anion(SOA) in hyperuricemia mice induced by yeast extract combined with potassium oxazinane was investigated respectively. The results showed that AP-Gd complex was coordinated through 5-OH and 4-C=O of apigenin with Gd(III) ion. The coordination ratio of AP to Gd(III) was 2. The composition of AP-Gd complex was [Gd(C_(15)H_9O_5)_2]·NO_3·3 H_2O. The study on the activity of anti-hyperuricemia found that AP-Gd complex was superior to AP in inhibiting XOD, removing SOA, reducing SUA and promoting UA excretion ability. Compared with apigenin, the AP-Gd complex increased the activity of anti-hyperuricemia after the coordination of apigenin and Gd(III) ion.
The apigenin-gadolinium(AP-Gd) complex with apigenin(AP) and gadolinium(Gd)(III) ion was synthesized in order to improve its activity of anti-hyperuricemia. Based on the theory of traditional Chinese medicine coordination chemistry, AP-Gd complex was synthesized with AP possessed anti-inflammatory and anti-gout activity as ligand, and rare earth metal Gd(III) ion as coordination center. The chemical structure of the AP-Gd complex was characterized by UV, IR, ~1H-NMR, conductometry, XPS and TG-DTA. Effect of AP-Gd complex on uric acid(UA) level, xanthine oxidase(XOD) activity and superoxide anion(SOA) in hyperuricemia mice induced by yeast extract combined with potassium oxazinane was investigated respectively. The results showed that AP-Gd complex was coordinated through 5-OH and 4-C=O of apigenin with Gd(III) ion. The coordination ratio of AP to Gd(III) was 2. The composition of AP-Gd complex was [Gd(C_(15)H_9O_5)_2]·NO_3·3 H_2O. The study on the activity of anti-hyperuricemia found that AP-Gd complex was superior to AP in inhibiting XOD, removing SOA, reducing SUA and promoting UA excretion ability. Compared with apigenin, the AP-Gd complex increased the activity of anti-hyperuricemia after the coordination of apigenin and Gd(III) ion.
引文
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[12] 阮琴, 申秀英, 饶和平, 王芳, 郑绍成, 徐晓虹, 俞世钢, 姜科声. 亚慢性Sm(NO_3)_3暴露对小鼠肝脏的影响 [J]. 中国稀土学报, 2017, 35(3): 383.Ruan Q, Shen X Y, Rao H P, Wang F, Zheng S C, Xu X H, Yu S G, Jiang K S. Effects of subchronic exposure of samarium nitrate on mice liver [J]. Journal of the Chinese Society of Rare Earths, 2017, 35(3): 383.
[13] 杨云裳, 陶莲春, 张应鹏, 孙世琪, 郭慧珅. 芹菜素镧配合物的结构表征及生物活性研究 [J]. 天然产物研究与开发, 2014, 26(9): 1402.Yang Y S, Tao L C, Zhang Y P, Sun S Q, Guo H S. Structure and biological activity of the La(III) complex with apigenin [J]. Natural Product Research and Development, 2014, 26(9): 1402.
[14] 张金超, 杨梦苏. 稀土配合物药物研究进展 [J]. 稀有金属, 2005, 29(6): 919.Zhang J C, Yang M S. Research progress on drugs of rare earth complexes [J]. Chinese Journal of Rare Metals, 2005, 29(6): 919.
[15] 刘燕, 周轶平, 罗敏, 李玛琳. 稀土配合物抗肿瘤活性研究进展 [J]. 中国稀土学报, 2014, 32(2): 143.Liu Y, Zhou Y P, Luo M, Li M L. Advances for antitumor activity of rare earth complexes [J]. Journal of the Chinese Society of Rare Earths, 2014, 32(2): 143.
[2] 王海娣, 刘艾林, 杜冠华. 芹菜素药理作用的研究进展 [J]. 中国新药杂志, 2008, 17(18): 1561.Wang H D, Liu A L, Du G H. New progress in the pharmacology of apigenin [J]. Chinese Journal of New Drugs, 2008, 17(18): 1561.
[3] 林丽文, 辛勤. 芹菜素药理作用的研究进展 [J]. 中国热带医学, 2012, 12(8): 1023.Lin L W, Xin Q. Progress in the research of pharmacology of apigenin [J]. China Tropical Medicine, 2012, 12(8): 1023.
[4] Sanjeev S, Sanjay G. Apigenin: A promising molecule for cancer prevention [J]. Pharm Res., 2010, 27: 962.
[5] Mrinmay C, Naren L, Banik, Ray S K. Sequential hTERT knockdown and apigenin treatment inhibited invasion and proliferation and induced apoptosis in human malignant neuroblastoma SK-N-DZ and SK-N-BE2 cells [J]. J. Mol. Neurosci., 2013, 51(1): 187.
[6] Benford M, Liang Y Y, Cynthia B W, Zhang X. Apigenin induces apoptosis and blocks growth of medroxyprogesterone acetate-depeGdent BT-474 xenograft tumors [J]. HORM CANC., 2012, 3(4): 160.
[7] Shukla S, Fu P F, Gupta S. Apigenin induces apoptosis by targeting inhibitor of apoptosis proteins and Ku70-Bax interaction in prostate cancer [J]. Apoptosis, 2014, 19(5): 883.
[8] Zhang X, Zhou C H, Zha X. Apigenin promotes osteogenic differentiation of human mesenchymal stem cells through JNK and p38 MAPK pathways [J]. Mol. Cell. Biochem., 2015, 407(1-2): 41.
[9] Kim J W, Kim C S, Hu Z Z, Han J Y, Kim S K, Yoo S K. Enhancement of pentobarbital-induced sleep by apigenin through chloride ion channel activation [J]. Arch Pharm Res., 2012, 35(2): 367.
[10] Zhang F, Li F C, Chen G. Neuroprotective effect of apigenin in rats after contusive spinal cord injury [J]. Neurol. Sci., 2014, 35(4): 583.
[11] 缪明星, 王星, 陆琰, 王欣. 芹菜素对氧嗪酸钾盐致高尿酸血症小鼠的降尿酸及肾保护作用机制研究 [J]. 中国药房, 2016, 27(34): 4794.Miao M X, Wang X, Lu Y, Wang X. Mechanism study on effects of apigenin on reducing uric acid and renal protection in oteracil potassium-induced hyperuricemia mice [J]. China Pharmacy, 2016, 27(34): 4794.
[12] 阮琴, 申秀英, 饶和平, 王芳, 郑绍成, 徐晓虹, 俞世钢, 姜科声. 亚慢性Sm(NO_3)_3暴露对小鼠肝脏的影响 [J]. 中国稀土学报, 2017, 35(3): 383.Ruan Q, Shen X Y, Rao H P, Wang F, Zheng S C, Xu X H, Yu S G, Jiang K S. Effects of subchronic exposure of samarium nitrate on mice liver [J]. Journal of the Chinese Society of Rare Earths, 2017, 35(3): 383.
[13] 杨云裳, 陶莲春, 张应鹏, 孙世琪, 郭慧珅. 芹菜素镧配合物的结构表征及生物活性研究 [J]. 天然产物研究与开发, 2014, 26(9): 1402.Yang Y S, Tao L C, Zhang Y P, Sun S Q, Guo H S. Structure and biological activity of the La(III) complex with apigenin [J]. Natural Product Research and Development, 2014, 26(9): 1402.
[14] 张金超, 杨梦苏. 稀土配合物药物研究进展 [J]. 稀有金属, 2005, 29(6): 919.Zhang J C, Yang M S. Research progress on drugs of rare earth complexes [J]. Chinese Journal of Rare Metals, 2005, 29(6): 919.
[15] 刘燕, 周轶平, 罗敏, 李玛琳. 稀土配合物抗肿瘤活性研究进展 [J]. 中国稀土学报, 2014, 32(2): 143.Liu Y, Zhou Y P, Luo M, Li M L. Advances for antitumor activity of rare earth complexes [J]. Journal of the Chinese Society of Rare Earths, 2014, 32(2): 143.