Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 55, Issue 23, Pages 10363-10377Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm300705j
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Funding
- National Health Research Institutes, Taiwan, R.O.C.
- National Science Council of Taiwan, R.O.C. [99-320-B-400-010-MY3]
- National Tsing Hua University
- National Health Research Institutes
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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.
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