Synthesis and biological evaluation of methylated scutellarein analogs based on metabolic mechanism of scutellarin in vivo
Synthesis and biological evaluation of methylated scutellarein analogs based on metabolic mechanism of scutellarin in vivo
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DOI：
10.1016/j.ejmech.2015.10.039
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发表时间：
2015-12-01
影响因子：
6.7
通讯作者：
Duan, Jin-Ao
中科院分区：
文献类型：
--
作者：
Shi, Zhi-Hao;Li, Nian-Guang;Duan, Jin-Ao
灯盏乙素(1)在体内可被水解成灯盏花素(2)，然后转化为甲基化、硫酸化和葡萄糖醛酸化形式。为了研究这些甲基化代谢产物的生物活性，采用半合成方法合成了8个灯盏花素(2)的甲基化类似物。通过凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、凝血酶时间(TT)和纤维蛋白原(FIB)的测定评价化合物的抗血栓活性。通过测定它们对1，1-二苯基-2-苦基肼自由基(DPPH)的清除能力和保护PC12细胞免受H_2O_2诱导的细胞毒性的能力来评价它们的抗氧化活性。此外，还考察了这些化合物的水溶解性和亲脂性等物理化学性质。结果表明，与灯盏乙素(1)相比，6-O-甲基灯盏花素(5)具有较强的抗血栓活性、较强的抗氧化活性和平衡的溶解性和通透性，值得进一步开发为治疗缺血性脑血管疾病的先导化合物。(C)2015年爱思唯尔·马森公司。版权所有。
Scutellarin (1) could be hydrolyzed into scutellarein (2) in vivo and then converted into methylated, sulfated and glucuronidated forms. In order to investigate the biological activities of these methylated metabolites, eight methylated analogs of scutellarein (2) were synthesized via semi-synthetic methods. The antithrombotic activities of these compounds were evaluated through the analyzation of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and fibrinogen (FIB). Their antioxidant activities were assessed by measuring their scavenging capacities toward 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and the ability to protect PC12 cells against H2O2-induced cytotoxicity. Furthermore, the physicochemical properties of these compounds including aqueous solubility and lipophilicity were also investigated. The results showed that 6-O-methylscutellarein (5) demonstrated potent antithrombotic activity, stronger antioxidant activity and balanced solubility and permeability compared with scutellarin (1), which warrants further development of 5 as a promising lead for the treatment of ischemic cerebrovascular disease. (C) 2015 Elsevier Masson SAS. All rights reserved.