Antiviral (RNA) activity of selected amaryllidaceae isoquinoline constituents and synthesis of related substances

Bjarne Gabrielsen, Thomas P. Monath, John W. Huggins, Deborah F. Kefauver, George Pettit, Grazyna Groszek, Melinda Hollingshead, Jorma J. Kirsi, William M. Shannon, Ernst M. Schubert, Jay DaRe, Bheema Ugarkar, Michael A. Ussery, Michael J. Phelan

Research output: Contribution to journalArticle

209 Scopus citations

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 (dififering 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.

Original languageEnglish (US)
Pages (from-to)1569-1581
Number of pages13
JournalJournal of Natural Products
Volume55
Issue number11
DOIs
StatePublished - Nov 1 1992

ASJC Scopus subject areas

  • Analytical Chemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

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    Gabrielsen, B., Monath, T. P., Huggins, J. W., Kefauver, D. F., Pettit, G., Groszek, G., Hollingshead, M., Kirsi, J. J., Shannon, W. M., Schubert, E. M., DaRe, J., Ugarkar, B., Ussery, M. A., & Phelan, M. J. (1992). Antiviral (RNA) activity of selected amaryllidaceae isoquinoline constituents and synthesis of related substances. Journal of Natural Products, 55(11), 1569-1581. https://doi.org/10.1021/np50089a003