title: 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.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan.
authors.forename: Yue-Zhi
authors.initials: YZ
authors.lastname: Lee
authors.forename: Cheng-Wei
authors.initials: CW
authors.lastname: Yang
authors.forename: Hsing-Yu
authors.initials: HY
authors.lastname: Hsu
authors.forename: Ya-Qi
authors.initials: YQ
authors.lastname: Qiu
authors.forename: Teng-Kuang
authors.initials: TK
authors.lastname: Yeh
authors.forename: Hsin-Yu
authors.initials: HY
authors.lastname: Chang
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.forename: Shiow-Ju
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D000470:Alkaloids / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D045744:Cell Line, Tumor; D017934:Coronavirus / Q000187:drug effects / Q000502:physiology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007212:Indolizines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D010616:Phenanthrenes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000470:Alkaloids; D007212:Indolizines; D010616:Phenanthrenes; C004218:tylophorine