title: Antiviral (RNA) activity of selected Amaryllidaceae isoquinoline constituents and synthesis of related substances.
abstract: A series of 23 Amaryllidaceae isoquinoline alkaloids and related synthetic analogues were isolated or synthesized and subsequently evaluated in cell culture against the RNA-containing flaviviruses (Japanese encephalitis, yellow fever, and dengue viruses), bunyaviruses (Punta Toro, sandfly fever, and Rift Valley fever viruses), alphavirus (Venezuelan equine encephalomyelitis virus), lentivirus (human immunodeficiency virus-type 1) and the DNA-containing vaccinia virus. Narciclasine [1], lycoricidine [2], pancratistatin [4], 7-deoxypancratistatin [5], and acetates 6-8, isonarciclasine [13a], cis-dihydronarciclasine [14a], trans-dihydronarciclasine [15a], their 7-deoxy analogues 13b-15b, lycorines 16 and 17, and pretazettine [18] exhibited consistent in vitro activity against all three flaviviruses and against the bunyaviruses, Punta Toro and Rift Valley fever virus. Activity against sandfly fever virus was only observed with 7-deoxy analogues. In most cases, however, selectivity of the active compounds was low, with toxicity in uninfected cells (TC50) occurring at concentrations within 10-fold that of the viral inhibitory concentrations (IC50). No activity was observed against human immunodeficiency virus-type 1, Venezuelan equine encephalomyelitis virus, or vaccinia viruses. Pancratistatin [4] and its 7-deoxy analogue 5 were evaluated in two murine Japanese encephalitis mouse models (differing in viral dose challenge, among other factors). In two experiments (low LD50 viral challenge, variant I), prophylactic administration of 4 at 4 and 6 mg/kg/day (2% EtOH/saline, sc, once daily for 7 days, day -1 to +5) increased survival of Japanese-encephalitis-virus-infected mice to 100% and 90%, respectively. In the same model, prophylactic administration of 5 at 40 mg/kg/day in hydroxypropylcellulose (sc, once daily for 7 days, day -1 to +5) increased survival of Japanese-encephalitis-virus-infected mice to 80%. In a second variant (high LD50 viral challenge), administration of 4 at 6 mg/kg/day (ip, twice daily for 9 days, day -1 to +7) resulted in a 50% survival rate. In all cases, there was no survival in the diluent-treated control mice. Thus, 4 and 5 demonstrated activity in mice infected with Japanese encephalitis virus but only at near toxic concentrations. To our knowledge, however, this represents a rare demonstration of chemotherapeutic efficacy (by a substance other than an interferon inducer) in a Japanese-encephalitis-virus-infected mouse model.
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland 21702.
authors.forename: B
authors.initials: B
authors.lastname: Gabrielsen
authors.forename: T P
authors.initials: TP
authors.lastname: Monath
authors.forename: J W
authors.initials: JW
authors.lastname: Huggins
authors.forename: D F
authors.initials: DF
authors.lastname: Kefauver
authors.forename: G R
authors.initials: GR
authors.lastname: Pettit
authors.forename: G
authors.initials: G
authors.lastname: Groszek
authors.forename: M
authors.initials: M
authors.lastname: Hollingshead
authors.forename: J J
authors.initials: JJ
authors.lastname: Kirsi
authors.forename: W M
authors.initials: WM
authors.lastname: Shannon
authors.forename: E M
authors.initials: EM
authors.lastname: Schubert
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology*; D004672:Encephalitis, Japanese / Q000188:drug therapy / Q000382:microbiology; D007546:Isoquinolines / Q000138:chemical synthesis / Q000302:isolation & purification* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010946:Plants, Medicinal / Q000737:chemistry*; D012328:RNA Viruses / Q000187:drug effects; D010948:Viral Plaque Assay; D014780:Viruses / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D007546:Isoquinolines