Antiparasitic Activity of Marine Pyridoacridone Alkaloids Related to the Ascididemins

Abstract

A series of pyridoacridone alkaloids, including the marine alkaloid ascididemin were tested in vitro for antiparasitic activity against P. falciparum (K1, NF54), L. donovani, T. cruzi, T. b. rhodesiense and two mammalian cell lines (L6, RAW 264.7). Most compounds showed high antiplasmodial activity, moderate antileishmanial activity against both extra- and intracellular forms, and significant trypanocidal effects against T. cruzi and T. b. brucei. However, when tested against mammalian cell lines, most of the compounds were also toxic for macrophage-like RAW 264.7 cells and skeletal muscle myoblast L6 cells. Correlations between molecular structures and antiparasitic activity are discussed in detail. Specific compounds are illustrated with emphasis on their potential as new antiparasitic drug leads.

Key words

Marine metabolites - Leishmania - Plasmodium - Trypanosoma - alkaloids - pyridoacridone

References

• 1 World Health Organization  Health. A precious asset (accelerating follow-up to the World Summit for Social Development. Proposals by the World Health Organization). World Health Organization 2000: WHO/HSD/HID/00.1
• 2 El Sayed K A, Dunbar D C, Goins D K, Cordova C R, Perry T L, Wesson K J, Sanders S C, Janus S A, Hamann M T. The marine environment: a resouce for prototype antimalarial agents.  Journal of Natural Toxins. 1996;  5 261-85
• 3 Molinski T F. Developments in marine natural products. Receptor-specific bioactive compounds.  Journal of Natural Products. 1993;  56 1-8
• 4 König G M, Wright A D. Marine natural products research: current directions and future potential.  Planta Medica. 1996;  62 193-211
• 5 Ireland C M, Copp B R, Foster M P, McDonald L A, Radisky D C, Swersey J C. Biomedical potential of marine natural products. In: Pharmaceutical and Bioactive Natural Products, Marine Biotechnology Volume 1. Attaway, D, Zaborsky, OR, editors Plenum Publishing Corp New York, NY; 1993: pp. 1-43
• 6 Molinski T F. Marine pyridoacridines alkaloids: structure, synthesis, and biological chemistry.  Chemical Reviews. 1993;  93 1825-38
• 7 Lindsay B S, Barrows L R, Copp B R. Structural requirements for biological activity of the marine alkaloid ascididemin.  Bioorganic and Medicinal Chemistry Letters. 1995;  5 739-42
• 8 Lindsay B S, Christiansen H C, Copp B R. Structural studies of cytotoxic marine alkaloids: Synthesis of novel ring-E analogues of ascididemin and their in vitro and in vivo biological evaluation.  Tetrahedron. 2000;  56 497-505
• 9 Copp B R, Hansen R P, Appleton D R, Lindsay B S, Squire C J, Clark G R, Rickard C EF. A convenient new route to 4-substituted benzo[de] [3],[6]phenanthrolin-6(6H)-ones: Important intermediates in the synthesis of ring-A analogues of the cytotoxic marine alkaloid ascididemin.  Synthetic Communications. 1999;  29 2665-76
• 10 Matsumoto S S, Sidford M H, Holden J A, Barrows L R, Copp B R. Mechanism of action studies of cytotoxic marine alkaloids: Ascididemin exhibits thiol-dependent oxidative DNA cleavage.  Tetrahedron Letters. 2000;  41 1667-70
• 11 Thaithong S, Beale G H. Resistance of ten Thai isolates of Plasmodium falciparum to chloroquine and pyrimethamine by in vitro tests.  Transactions of the Royal Society of Tropical Medicine and Hygiene. 1981;  75 271-3
• 12 Ponnudurai T, Leeuwenberg A D, Meuwissen J H. Chloroquine sensitivity of isolates of Plasmodium falciparum adapted to in vitro culture.  Tropical and Geographical Medicine. 1981;  33 50-4
• 13 Desjardins R E, Canfield C J, Haynes J D, Chulay J D. Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique.  Antimicrobial Agents and Chemotherapy. 1979;  16 710-8
• 14 Kayser O, Kiderlen A F, Brun R. In vitro activity of aurones against Plasmodium falciparum strains K1 and NF54.  Planta Medica. 2001;  67 718-21
• 15 Huber W, Koella J C. A Comparison of three methods of estimating EC₅₀ in studies of drug resistance of malaria parasites.  Acta Tropica. 1993;  55 257-61
• 16 Baltz T, Baltz D, Giroud C, Crockett J. Cultivation in a semi-defined medium of animal infective forms of Trypanosoma brucei, T. equiperdum, T. evansi, T. rhodesiense and T. gambiense .  EMBO Journal. 1985;  4 273-7
• 17 Räz B, Iten M, Grether-Bühler Y, Kaminsky R, Brun R. The Alamar Blue assay to determine drug sensitivity of African trypanosomes (T.b. rhodesiense and T.b. gambiense) in vitro .  Acta Tropica. 1997;  68 39-47
• 18 Hills M, Hudson C, Smith P G. Global monitoring of the resistance of the malarial parasites to drugs: statistical treatment of the micro-test data. WHO 1986: WHO Working paper No. 2.8.5
• 19 Kayser O, Kiderlen A F, Folkens U, Kolodziej H. In vitro leishmanicidal activity of aurones.  Planta Medica. 1998;  65 316-9
• 20 Kayser O, Kiderlen A F. Leishmanicidal activity of aurones.  The Tokai Journal of Experimental and Clinical Medicine. 1998;  23 423-6
• 21 Kolodziej H, Kayser O, Kiderlen A F, Ito H, Hatano T, Yoshida T, Foo L Y. Antileishmanial activity of hydrolyzable tannins and their modulatory effects on nitric oxide and tumour necrosis factor-alpha release in macrophages in vitro .  Planta Medica. 2001;  67 825-32
• 22 Bonnard I, Bontemps N, Lahmy S, Banaigs B, Combaut G, Francisco C, Colson P, Houssier C, Waring M J, Bailly C. Binding to DNA and cytotoxic evaluation of ascididemin, the major alkaloid from the Mediterranean ascidian Cystodytes dellechiajei .  Anti-Cancer Drug Design. 1995;  10 333-46