Southern Medical University, Guangzhou, People's Republic of China.
Int Immunopharmacol. 2013 Oct;17(2):168-77. doi: 10.1016/j.intimp.2013.05.032. Epub 2013 Jun 19.
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 E2 (PGE2), tumor necrosis factor α (TNF-α) 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 100mg/kg, and inhibited mouse hemolysin production, DTH response, and adjuvant-induced rat arthritis at the doses from 50 to 200mg/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, PGE2 and TNF-α, slightly promoted IL-10 production and suppressed the splenocyte proliferation stimulated by Con A or LPS at the concentrations from 10 to 40μM. 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.
本研究旨在探讨 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型药物的先导化合物的潜力。采用体内炎症模型（特别是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足肿胀）和体外模型（特别是脂多糖（LPS）诱导的小鼠腹腔巨噬细胞和 RAW264.7 细胞产生一氧化氮（NO）、前列腺素 E2（PGE2）、肿瘤坏死因子 α（TNF-α）和白细胞介素 10（IL-10））来评估抗炎活性。免疫体内模型（特别是兔红细胞（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（特别是刀豆球蛋白 A（Con A）和 LPS 刺激的小鼠脾细胞增殖）用于估计免疫抑制作用。结果发现，ZL-5015 在 25 至 100mg/kg 剂量下显著降低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足肿胀，在 50 至 200mg/kg 剂量下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，该化合物在抑制炎症方面比抑制免疫功能更为有效。体外研究表明，ZL-5015 可显著抑制 NO、PGE2 和 TNF-α的产生，轻微促进 IL-10 的产生，并在 10 至 40μM 浓度下抑制 Con A 或 LPS 刺激的脾细胞增殖。综上所述，本研究表明，四氢嘧啶衍生物 ZL-5015 具有抗炎和免疫抑制活性，但其效力尚不理想。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。
