title: Anti-dengue-virus activity and structure-activity relationship studies of lycorine derivatives.
abstract: Dengue is a systemic viral infection that is transmitted to humans by Aedes mosquitoes. No vaccines or specific therapeutics are currently available for dengue. Lycorine, which is a natural plant alkaloid, has been shown to possess antiviral activities against flaviviruses. In this study, a series of novel lycorine derivatives were synthesized and assayed for their inhibition of dengue virus (DENV) in cell cultures. Among the lycorine analogues, 1-acetyllycorine exhibited the most potent anti-DENV activity (EC50 =0.4 μM) with a reduced cytotoxicity (CC50 >300 μM), which resulted in a selectivity index (CC50 /EC50 ) of more than 750. The ketones 1-acetyl-2-oxolycorine (EC50 =1.8 μM) and 2-oxolycorine (EC50 =0.5 μM) also exhibited excellent antiviral activities with low cytotoxicity. Structure-activity relationships for the lycorine derivatives against DENV are discussed. A three-dimensional quantitative structure-activity relationship model was established by using a comparative molecular-field analysis protocol in order to rationalize the experimental results. Further modifications of the hydroxy group at the C1 position with retention of a ketone at the C2 position could potentially lead to inhibitors with improved overall properties.
authors.affiliation: Department of Chemistry, Nankai University, Tianjin 300071 (P.R. China); State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071 (P.R. China).
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.forename: Lin-Feng
authors.initials: LF
authors.lastname: Li
authors.forename: Qing-Yin
authors.initials: QY
authors.lastname: Wang
authors.forename: Lu-Qing
authors.initials: LQ
authors.lastname: Shang
authors.forename: Pei-Yong
authors.initials: PY
authors.lastname: Shi
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yin
mesh_terms: D047151:Amaryllidaceae Alkaloids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003716:Dengue Virus / Q000187:drug effects; D008968:Molecular Conformation; D010617:Phenanthridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
chemical_list: D047151:Amaryllidaceae Alkaloids; D000998:Antiviral Agents; D010617:Phenanthridines; C015330:lycorine
keywords: alkaloids; antiviral agents; dengue virus; lycorine; structure-activity relationships