白杨素Mannich碱衍生物的合成及抗高尿酸血症活性
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摘要
目的设计并合成新型具有抗高尿酸活性的白杨素Mannich碱衍生物。方法以天然产物白杨素为起始原料,与不同含氟有机物进行胺甲基化反应,合成系列白杨素Mannich碱衍生物。采用氯化硝基四氮唑蓝比色法测定目标化合物在体外对黄嘌呤氧化酶的抑制活性,并研究其在昆明种小鼠的体内抗高尿酸活性。结果与结论合成了10个未见文献报道的新化合物,目标化合物的结构经核磁共振氢谱和碳谱、电子轰击质谱(EI-MS)确证。体外活性实验显示,大多数含氟白杨素衍生物都具有较好的黄嘌呤氧化酶抑制作用,且体内抗高尿酸作用显著,在40 mg·kg~(-1)剂量时白杨素衍生物1a、1b、1c、1e、1f、1i和1j抗高尿酸效果最好,可使昆明种小鼠的血清尿酸值接近正常水平。
Chrysin has been reported to have various bioactivities,especially antioxidant activities.Some studies have showed that bioavailability and pharmacological properties could be improved by modification.In this paper,ten novel Mannich base derivatives of chrysin were synthesized via ammonia methylation reaction.All the compounds are not reported in literature.The structures of the novel compounds were assigned by ~1H-NMR,~(13)C-NMR and EI-MS.The inhibitory activity on the xanthine oxidase(XO) of chrysin and its derivatives were evaluated by nitro-tetrazolium chloride blue colorimetry(NBT).In the target compounds,1 b and 1 e possessed the more potent XO inhibitory activities at high doses,87.54% and 87.62% respectively.The anti-hyperuricemia activities of these novel compounds were measured in mice model of hyperuricemia induced by potassium oxonate.The results of primary pharmacological tests in vivo showed that 1 a,1 b,1 c,1 e,1 f,1 i,and 1 j possessed the more potent anti-hyperuricemia activity than chrysin at high doses,even equivalent to allopurinol.The novel compounds showed better anti-hyperuricemia activities than the lead compound.■
Chrysin has been reported to have various bioactivities,especially antioxidant activities.Some studies have showed that bioavailability and pharmacological properties could be improved by modification.In this paper,ten novel Mannich base derivatives of chrysin were synthesized via ammonia methylation reaction.All the compounds are not reported in literature.The structures of the novel compounds were assigned by ~1H-NMR,~(13)C-NMR and EI-MS.The inhibitory activity on the xanthine oxidase(XO) of chrysin and its derivatives were evaluated by nitro-tetrazolium chloride blue colorimetry(NBT).In the target compounds,1 b and 1 e possessed the more potent XO inhibitory activities at high doses,87.54% and 87.62% respectively.The anti-hyperuricemia activities of these novel compounds were measured in mice model of hyperuricemia induced by potassium oxonate.The results of primary pharmacological tests in vivo showed that 1 a,1 b,1 c,1 e,1 f,1 i,and 1 j possessed the more potent anti-hyperuricemia activity than chrysin at high doses,even equivalent to allopurinol.The novel compounds showed better anti-hyperuricemia activities than the lead compound.■
引文
[1] LIU Y M,SONG X D,HE J,et al.Synthetic derivatives of chrysin and their biological activities[J].Med Chem Res,2014,23(2):555-563.
[2] 臧路平,刘志刚,吴新荣.高尿酸血症发病机制及其药物治疗研究进展[J].医药导报,2011,30(1):69-73.
[3] GLIOZZI M,MALARA N,MUSCOLI S,et al.The treatment of hyperuricemia[J].Int J Cardiol,2016,213(1):23-27.
[4] TSUJI P A,WINN R N,WALLE T.Accumulation and metabolism of the anticancer flavonoid 5,7-di-methoxyflavone compared to its unmethylated analog chrysin in the Atlantic killifish[J].Chem Biol Interact,2006,164(1/2):85-92.
[5] TOREL J,CILLARD J,CILLARD P.Antioxidant activity of flavonoids and reactivity with peroxy[J].Phytochemistry,1986,25(2):383-385.
[6] 王秋亚,王烨娟,高锦红.白杨素衍生物的合成及生理活性研究进展[J].化学研究,2011,22(1):96-103.
[7] ZHENG X,MENG W D,XU Y Y,et al.Synthesis and anticancer effect of chrysin derivatives[J].Bioorg Med Chem Lett,2003,13(5):881-884.
[8] 胡昆,王炜,任杰.白杨素Mannich碱衍生物的合成及其抗癌活性[J].沈阳药科大学学报,2010,27(6):449-452.
[9] 陈光亮,徐叔云.高尿酸血症研究进展[J].中国药理学通报,2003,19(10):1088-1092.
[10] 仲崇琳,杨美林,全哲山,等.白杨素衍生物及其制备在治疗高尿酸血症中的研究:中国,201610256522.7[P].2017-03-15.
[11] SOWNDHARARAJAN K,JOSEPH J M,RAJENDRAKUMARAN D.In vitro xanthine oxidase inhibitory activity of methanol extracts of Erythrina indica Lam.leaves and stem bark[J].Asian Pac J Trop Biomed,2012,2(3):1415-1417.
[12] HU Q H,ZHU J X,JI J,et al.Fructus gardenia extract ameliorates oxonate-induced hyperuricemia with renal dysfunction in mice by regulating organic ion transporters and mOIT3[J].Molecules,2013,18(8):8976-8993.
[13] WU X H,RUAN J L,ZHANG J,et al.Pallidifloside D,a saponin glycoside constituent from Smilax riparia,resist to hyperuricemia based on URAT1 and GLUT9 in hyperuricemic mice[J].J Ethnopharmacol,2014,157(17):201-205.
[14] ZHENG X,ZHAO F F,LIU Y M,et al.Synthesis and preliminary biological evalution of chrysin deri-vatives as potential anticancer drugs[J].Med Chem,2010,6(1):6-8.
[2] 臧路平,刘志刚,吴新荣.高尿酸血症发病机制及其药物治疗研究进展[J].医药导报,2011,30(1):69-73.
[3] GLIOZZI M,MALARA N,MUSCOLI S,et al.The treatment of hyperuricemia[J].Int J Cardiol,2016,213(1):23-27.
[4] TSUJI P A,WINN R N,WALLE T.Accumulation and metabolism of the anticancer flavonoid 5,7-di-methoxyflavone compared to its unmethylated analog chrysin in the Atlantic killifish[J].Chem Biol Interact,2006,164(1/2):85-92.
[5] TOREL J,CILLARD J,CILLARD P.Antioxidant activity of flavonoids and reactivity with peroxy[J].Phytochemistry,1986,25(2):383-385.
[6] 王秋亚,王烨娟,高锦红.白杨素衍生物的合成及生理活性研究进展[J].化学研究,2011,22(1):96-103.
[7] ZHENG X,MENG W D,XU Y Y,et al.Synthesis and anticancer effect of chrysin derivatives[J].Bioorg Med Chem Lett,2003,13(5):881-884.
[8] 胡昆,王炜,任杰.白杨素Mannich碱衍生物的合成及其抗癌活性[J].沈阳药科大学学报,2010,27(6):449-452.
[9] 陈光亮,徐叔云.高尿酸血症研究进展[J].中国药理学通报,2003,19(10):1088-1092.
[10] 仲崇琳,杨美林,全哲山,等.白杨素衍生物及其制备在治疗高尿酸血症中的研究:中国,201610256522.7[P].2017-03-15.
[11] SOWNDHARARAJAN K,JOSEPH J M,RAJENDRAKUMARAN D.In vitro xanthine oxidase inhibitory activity of methanol extracts of Erythrina indica Lam.leaves and stem bark[J].Asian Pac J Trop Biomed,2012,2(3):1415-1417.
[12] HU Q H,ZHU J X,JI J,et al.Fructus gardenia extract ameliorates oxonate-induced hyperuricemia with renal dysfunction in mice by regulating organic ion transporters and mOIT3[J].Molecules,2013,18(8):8976-8993.
[13] WU X H,RUAN J L,ZHANG J,et al.Pallidifloside D,a saponin glycoside constituent from Smilax riparia,resist to hyperuricemia based on URAT1 and GLUT9 in hyperuricemic mice[J].J Ethnopharmacol,2014,157(17):201-205.
[14] ZHENG X,ZHAO F F,LIU Y M,et al.Synthesis and preliminary biological evalution of chrysin deri-vatives as potential anticancer drugs[J].Med Chem,2010,6(1):6-8.