Synthesis and Biological
Evaluation of Tylophorine-Derived
Dibenzoquinolines as Orally Active Agents: Exploration of the Role
of Tylophorine E Ring on Biological Activity
posted on 2012-12-13, 00:00authored byYue-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.