张保顺 叶小利 陈 竹 姚 波 谭 平 李学刚. 甲基橙皮素-7-烷基醚同系物的合成及其抗炎作用J. 药学学报, 2011,46(7): 811-817.
引用本文: 张保顺 叶小利 陈 竹 姚 波 谭 平 李学刚. 甲基橙皮素-7-烷基醚同系物的合成及其抗炎作用J. 药学学报, 2011,46(7): 811-817.
ZHANG Bao-Shun, XIE Xiao-Li, CHEN Zhu, TAO Bei, TAN Beng, LI Hua-Gang. Synthesis and anti-inflammatory activities of methylhesperetin-7-alkyl ether analoguesJ. 药学学报, 2011,46(7): 811-817.
Citation: ZHANG Bao-Shun, XIE Xiao-Li, CHEN Zhu, TAO Bei, TAN Beng, LI Hua-Gang. Synthesis and anti-inflammatory activities of methylhesperetin-7-alkyl ether analoguesJ. 药学学报, 2011,46(7): 811-817.

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

  • 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) 7-正十六烷基醚 (10) 9个新化合物, UV1H NMRMSHR-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678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%39.1%; 对血清中的COX-2的浓度分别为79.375.473.9 ng·L−1; 对血清中的PGE2的浓度分别为275.4258.9242.6 ng·L−1。化合物67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%41.5%。化合物678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。

     

    Abstract:

    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.

     

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