Synthesis and biological evaluation of tylophorine-derived dibenzoquinolines as orally active agents: exploration of the role of tylophorine e ring on biological activity.

Abstract

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.

• Authors: Yue-Zhi Lee, Cheng-Wei Yang, Hsing-Yu Hsu, Ya-Qi Qiu, Teng-Kuang Yeh, Hsin-Yu Chang, Yu-Sheng Chao, Shiow-Ju Lee
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 23 Pg. 10363-77 (Dec 13 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 23167614 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Alkaloids
• Indolizines
• Phenanthrenes
• tylophorine

Topics

• Administration, Oral
• Alkaloids (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• Animals
• Biological Availability
• Cell Line
• Cell Line, Tumor
• Coronavirus (drug effects, physiology)
• Drug Screening Assays, Antitumor
• Humans
• Indolizines (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• Magnetic Resonance Spectroscopy
• Mass Spectrometry
• Mice
• Phenanthrenes (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• Virus Replication (drug effects)