American Chemical Society
jm300705j_si_001.pdf (1.49 MB)

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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journal contribution
posted on 2012-12-13, 00:00 authored by Yue-Zhi Lee, Cheng-Wei Yang, Hsing-Yu Hsu, Ya-Qi Qiu, Teng-Kuang Yeh, Hsin-Yu Chang, Yu-Sheng Chao, Shiow-Ju Lee
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.