Synthesis and Biological Evaluation of Tylophorine-Derived Dibenzoquinolines as Orally Active Agents: Exploration of the Role of Tylophorine E Ring on Biological Activity
Synthesis and Biological Evaluation of Tylophorine-Derived Dibenzoquinolines as Orally Active Agents: Exploration of the Role of Tylophorine E Ring on Biological Activity
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DOI：
10.1021/jm300705j
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发表时间：
2012-12-13
影响因子：
7.3
通讯作者：
Lee, Shiow-Ju
中科院分区：
文献类型：
--
作者：
Lee, Yue-Zhi;Yang, Cheng-Wei;Lee, Shiow-Ju
本文合成了一系列新的由雷公藤甲素衍生的二苯并喹啉类化合物，并对其生物活性进行了评价。进行了三项试验：抑制癌细胞增殖、抑制TGEV复制以抑制病毒活性和抑制RAW 264.7细胞中的一氧化氮产生（抗炎的量度）。来自这些测定的最有效的化合物二苯并喹啉33 b显示出与雷公藤红素9a相比改善的溶解度、在肺A549异种移植肿瘤小鼠模型和鼠爪水肿模型中的体内功效、良好的生物利用度和无显著的神经毒性（如通过运动协调的旋转杆测试所测试的）。这是第一项详细探讨了雷公藤甲素E环对生物活性的作用的研究，并且非常强烈地表明雷公藤甲素衍生的二苯并喹啉值得进一步开发为口服活性剂。
A series of novel tylophorine-derived dibenzoquinolines has been synthesized and their biological activity evaluated. Three assays were conducted: inhibition of cancer cell proliferation, inhibition of TGEV replication for anticoronavirus activity, and suppression of nitric oxide production in RAW264.7 cells (a measure of anti-inflammation). The most potent compound from these assays, dibenzoquinoline 33b, showed improved solubility compared to tylophorine 9a, in vivo efficacies in a lung A549 xenografted tumor mouse model and a murine paw edema model, good bioavailability, and no significant neurotoxicity (as tested by a rota-rod test for motor coordination). This is the first study to explore in detail the role of the tylophorine E ring on biological activity and very strongly suggests that tylophorine-derived dibenzoquinolines merit further development into orally active agents.