Anti-inflammatory and immunosuppressive activities of 1,3-dicyclopentyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylic acid diethyl ester (ZL-5015)
Anti-inflammatory and immunosuppressive activities of 1,3-dicyclopentyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylic acid diethyl ester (ZL-5015)
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DOI：
10.1016/j.intimp.2013.05.032
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发表时间：
2013-10-01
影响因子：
5.6
通讯作者：
Lei, Linsheng
中科院分区：
文献类型：
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作者：
Lun, Yuning;Xia, Hong;Lei, Linsheng
本研究的目的是研究ZL-5015（1，3-二环戊基-1，2，3，6-四氢嘧啶-4，5-二羧酸二乙酯）的抗炎和免疫抑制作用，以确定其作为开发具有抗炎和免疫抑制活性的新药的先导化合物的潜力。体内炎症模型（具体地，乙酸诱导的小鼠扭体、二甲苯诱导的小鼠耳肿胀和角叉菜胶诱导的大鼠爪水肿）和体外模型（具体地，脂多糖（LPS）诱导的一氧化氮（NO）、前列腺素E-2（PGE（2））、肿瘤坏死因子α（TNF-α）和白细胞介素10（IL-10））用于评价抗炎活性。应用免疫学体内模型（具体地，兔红细胞（RRBC）诱导的小鼠溶血素产生、2，4-二硝基氟苯（DNFB）诱导的迟发型超敏反应（DTH）和佐剂诱导的大鼠关节炎）和体外模型（具体地，刀豆球蛋白A（Con A）和LPS刺激的小鼠脾细胞增殖）来评估免疫抑制作用。结果发现，ZL-5015在25 - 100 mg/kg剂量下显著降低醋酸诱导的小鼠扭体反应、二甲苯诱导的小鼠耳肿胀和角叉菜胶诱导的大鼠足肿胀，在50 - 200 mg/kg剂量下显著抑制小鼠溶血素产生、DTH反应和佐剂诱导的大鼠关节炎。根据最小统计学有效剂量判断，该化合物对炎症的抑制作用似乎比对免疫功能的抑制作用更强。体外实验表明，ZL-5015在10 - 40 μ M浓度范围内显著抑制NO、PGE（2）和TNF-α的产生，轻微促进IL-10的产生，并抑制ConA或LPS刺激的脾细胞增殖。总之，我们的研究表明，四氢嘧啶衍生物，ZL-5015，具有抗炎和免疫抑制活性，虽然它的效力是不令人满意的。因此，ZL-5015应被视为进一步结构修饰的先导化合物，以继续寻找该领域的新型有效药物。(C)2013爱思唯尔有限公司版权所有。
The aim of this study is to investigate the anti-inflammatory and immunosuppressive effects of ZL-5015 (1,3-dicyclopentyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylic acid diethyl ester) in order to determine its potential as a lead compound to develop novel drugs with both anti-inflammatory and immunosuppressive activities. Inflammatory in vivo models (specifically, acetic acid-induced mouse writhing, xylene-induced mouse ear swelling and carrageenan-induced rat paw edema) and in vitro models (specifically, lipopolysaccharide (LPS)-induced production of nitric oxide (NO), prostaglandin E-2 (PGE(2)), tumor necrosis factor alpha (TNF-alpha) and interleukin 10 (IL-10) by mouse peritoneal macrophages and RAW264.7 cells) were used to evaluate the anti-inflammatory activities. Immunological in vivo models (specifically, rabbit red blood cells (RRBC)-induced mouse hemolysin production, 2,4-dinitrofluorobenzene (DNFB)-induced delayed type hypersensitivity (DTH) and adjuvant-induced rat arthritis) and in vitro models (specifically, concanavalin A (Con A) and LPS-stimulated mouse splenocyte proliferation) were applied to estimate the immunosuppressive effects. It was found that ZL-5015 significantly decreased acetic acid-induced mouse writhing, xylene-induced mouse ear swelling, and carrageenan-induced rat paw edema at the doses from 25 to 100 mg/kg, and inhibited mouse hemolysin production, DTH response, and adjuvant-induced rat arthritis at the doses from 50 to 200 mg/kg. The compound appeared to be more potent in inhibition of inflammation than in suppression of immune function, as judged by the minimal statistically effective dose. The in vitro studies revealed that ZL-5015 greatly inhibited the production of NO, PGE(2) and TNF-alpha, slightly promoted IL-10 production and suppressed the splenocyte proliferation stimulated by Con A or LPS at the concentrations from 10 to 40 mu M. In conclusion, our study demonstrates that the tetrahydropyrimidine derivative, ZL-5015, has both anti-inflammatory and immunosuppressive activities, although its potency is not satisfactory. Therefore ZL-5015 should be considered as a lead compound for further structural modification in the continuing search for novel and effective drugs in this area. (C) 2013 Elsevier B.V. All rights reserved.