新型6-烷氧基大黄酸-氨基酸加合物的合成及抗肿瘤活性
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摘要
以大黄素为起始原料,经乙酰化、氧化、去乙酰化、酯化、醚化、水解和缩合反应,合成了11个结构新颖的6-烷氧基取代的大黄酸-氨基酸加合物(8aa～8ee),其结构经~1H NMR,~(13)C NMR和HR-MS(ESI-TOF)表征。采用四甲基偶氮唑盐法(MTT法)考察了目标化合物对子宫颈癌细胞(Hela)、人乳腺癌细胞(MCF-7)、人胚肾细胞(HEK-293T)和人胃癌细胞(SGC-7901)的体外抑制活性。结果表明:8ea对4株肿瘤细胞均有一定的抑制活性,并体现出较好的选择性。其中对SGC-7901的抑制活性(IC_(50)=9.78μmol·L~(-1))与阳性对照物顺铂和阿霉素相当。
Eleven novel 6-alkoxy rhein-amino acids adducts(8 aa～8 ee) were synthesized using emodin as starting material via acetylation, oxidation, deacetylation, esterification, etherification, hydrolysis and condensation. The structures were characerized by ~1H NMR, ~(13)C NMR and HR-MS(ESI-TOF). The in vitro anti-proliferation activities of 8 aa～8 ee against four tumor cell lines including Hela, MCF-7, HEK-293 T and SGC-7901 were evaluated by methyl thiazolyl tetrazolium(MTT) method, and the results indicated that compound 8 ea demonstrated moderate cytotoxic activities against four tumor cell lines. Moreover, this compound showed excellent selectivity with IC_(50) of 9.78 μmol·L~(-1) aganist SGC-7901, which is similar with positive control substrates of cisplatin and adriamycin.
Eleven novel 6-alkoxy rhein-amino acids adducts(8 aa～8 ee) were synthesized using emodin as starting material via acetylation, oxidation, deacetylation, esterification, etherification, hydrolysis and condensation. The structures were characerized by ~1H NMR, ~(13)C NMR and HR-MS(ESI-TOF). The in vitro anti-proliferation activities of 8 aa～8 ee against four tumor cell lines including Hela, MCF-7, HEK-293 T and SGC-7901 were evaluated by methyl thiazolyl tetrazolium(MTT) method, and the results indicated that compound 8 ea demonstrated moderate cytotoxic activities against four tumor cell lines. Moreover, this compound showed excellent selectivity with IC_(50) of 9.78 μmol·L~(-1) aganist SGC-7901, which is similar with positive control substrates of cisplatin and adriamycin.
引文
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[2] 傅兴圣,陈菲,刘训红,等. 大黄化学成分与药理作用研究新进展[J].中国新药杂志,2011,20(16):1534-1538.
[3] 郭美姿,徐海荣,李孝生. 大黄酸对小鼠急性肝损伤的影响[J].中医药研究,2002,18(1):37-38.
[4] 邹洪,袁绰斌. 大黄酸的极谱研究[J].中国科学技术大学学报,2000,30(2):208-210.
[5] SPENCER C M, WILDE M I. Diacerhein[J].Drugs,1997,53(1):98-106.
[6] FANCIULLI M, GENTILE F P, BRUNO T, et al. Inhibition of membrane redox activity by rhein and adriamycin in human glioma cells[J].Anti-cancer Drugs,1992,3(6):615-621.
[7] 黄云虹,甄永苏. 大黄酸诱导肿瘤细胞凋亡及与丝裂霉素的协同作用[J].药学学报,2001,36(5):334-338.
[8] CICHEWICZ R H, ZHANG Y, SEERAM N P, et al. Inhibition of human tumor cell proliferation by novel anthraquinones from daylilies[J].Life Sci,2004,74(14):1791-1799.
[9] JOUNG D K, JOUNG H, YANG D W, et al. Synergistic effect of rhein in combination with ampicillin or oxacillin against methicillin-resistant Staphylococcus aureus[J].Exp Ther Med,2012,3(4):608-612.
[10] 朱小康,叶小利,袁吕江,等. 微波辐射下6-烷氧基大黄酸的合成及抑菌活性研究[J].有机化学,2010,30(9):1335-1341.
[11] ZHU X, YE X, YUAN L, et al. Synthesis and hypoglycemic activity evaluation of 7-alkoxyl-rhein[J].Med Chem Res,2012,21(4):421-427.
[12] ZHU X, YE X, SONG L, et al. Synthesis and hypoglycemic activity evaluation of rhein amide derivatives[J].Med Chem Res,2013,22(5):2228-2234.
[13] YANG X, SUN G, YANG C, et al. Novel rhein analogues as potential anticancer agents[J].Chem Med Chem,2011,6(12):2294-2301.
[14] LIANG Y K, YUE Z Z, LI J X, et al. Natural product-based design, synthesis and biological evaluation of anthra[2,1-d]thiazole-6,11-dione derivatives from rhein as novel antitumour agents[J].Eur J Med Chem,2014,84:505-515.
[15] 黄新炜. 大黄酸酯类衍生物的合成及体外抗肿瘤活性研究[J].化学工程师,2017,(9):18-20,23.
[16] 张汪伟,黄骏凯,何黎琴,等. 大黄酸衍生物的设计、合成及其抗肿瘤活性[J].化学世界,2017,(6):346-352.
[17] VIAYNA E, SOLA I, BARTOLINI M, et al. Synthesis and multitarget biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents[J].J Med Chem,2014,57(6):2549-2567.
[18] LI S Y, JIANG N, XIE S S, et al. Design,synthesis and evaluation of novel tacrine-rhein hybrids as multifunctional agents for the treatment of Alzheimer’s disease[J].Org Biomol Chem,2014,12(5):801-814.
[19] YAO G Y, YE M Y, HUANG R Z, et al. Synthesis and antitumor activities of novel rhein-aminophosphonates conjugates[J].Bioorg Med Chem Lett,2014,24(2):501-507.
[20] 张洁,周昌健,谢建伟,等. 大黄酸-缬氨酸加合物的合成及初步抗肿瘤活性[J].高等学校化学学报,2016,(12):2159-2167.
[21] 周昌健,谢建伟,张洁,等. 大黄酸-氨基酸缀合物的合成及初步抗肿瘤活性研究[J].有机化学,2017,37(1):122-132.
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