甲基橙皮素-7-烷基醚同系物的合成及其抗炎作用  

Synthesis and anti-inflammatory activities of methylhesperetin-7-alkyl ether analogues

作　　者：张保顺[1] 叶小利[2] 陈竹[3] 姚波[1] 谭平[1] 李学刚[1] 

机构地区：[1]西南大学药学院 [2]西南大学生命科学学院 [3]重庆医药高等专科学校药学系

出　　处：《药学学报》2011年第7期811-817,共7页Acta Pharmaceutica Sinica

基　　金：中央高校基本科研业务经费专项项目(XDJK2009C087;XDJK2009C095);重庆市卫生局医药科技研究资助项目(2009-2-140)

摘　　要：为了研究甲基橙皮素-7-烷基醚同系物的结构与抗炎活性之间的相关性,本研究以甲基橙皮苷(1)为先导化合物,合成出甲基橙皮素(2)、甲基橙皮素-7-乙基醚(3)、7-正丁基醚(4)、7-正己基醚(5)、7-正辛基醚(6)、7-正癸基醚(7)、7-正十二烷基醚(8)、7-正十四烷基醚(9)和7-正十六烷基醚(10)9个新化合物,用UV、1H NMR、MS和HR-MS对化合物的结构进行了确证;同时采用氟氏完全佐剂(FCA)致小鼠关节炎实验、醋酸致小鼠毛细血管通透性实验,观察新合成化合物口服给药300 mg.kg·1.d·1时在体内的抗炎作用。结果表明随着烷基链的增长,醚化衍生物的抗炎作用先增强后降低。化合物6、7、8在给药25天时,对佐剂性关节炎(AA)小鼠的足肿胀抑制率分别为31.9%、38.5%和39.1%;对血清中的COX-2的浓度分别为79.3、75.4和73.9 ng.L·1;对血清中的PGE2的浓度分别为275.4、258.9和242.6 ng.L·1。化合物6、7在给药5天时,对醋酸致小鼠毛细血管通透性的抑制率分别为42.4%和41.5%。化合物6、7、8相比甲基橙皮苷先导化合物,抗炎活性得到了提高,对小鼠关节炎炎症和毛细血管通透性有明显的抑制作用。To investigate the relationship between the structures of methylhesperetin-7-alkyl ether analogues and their anti-inflammatory activities,nine new compounds,methyl-hesperetin（2）,methylhesperetin-7-ethyl ether（3）,7-n-butyl ether（4）,7-n-hexyl ether（5）,7-n-octyl ether（6）,7-n-decyl ether（7）,7-n-dodecyl ether（8）,7-n-tetradecyl ether（9） and 7-n-hexadecyl ether（10）,were synthesized with the lead compound of methylhesperidin（1）.Their structures were confirmed by UV,1H NMR,MS and HR-MS spectral data.The in vivo anti-inflammatory activities of these compounds were tested on mouse paw edema induced by Freund＇s complete adjuvant（FCA） and mouse capillary permeability induced by acetic acid with po dose of 300 mg·kg-1·d-1.The result indicated that the anti-inflammatory activities of the synthetic compounds increased firstly and then decreased with the elongating of the length of alkyl chain.After 25-day oral administration of compounds 6,7 and 8,the inhibitory rates on mouse paw edema of adjuvant arthritis（AA） were 31.9%,38.5%,39.1%,respectively.They showed the concentrations of COX-2 in serum of AA mice respectively were 79.3,75.4,73.9 ng·L-1 and the concentrations of PGE2 were in correspondence with 275.4,258.9,242.6 ng·L-1.The inhibitory rates of compounds 6 and 7 on mouse capillary permeability induced by acetic acid were,respectively,42.4% and 41.5% after 5-day oral administration.Compared with the lead compound of methylhesperidin,the anti-inflammatory activities of compounds 6,7 and 8 were increased and showed an effective inhibition on the symptom of adjuvant arthritis and capillary permeability in mice.

关 键 词：甲基橙皮苷 甲基橙皮素同系物 合成 抗炎作用 毛细血管通透性 

分 类 号：R916[医药卫生—药学]