Advertisement

Ellipticine

  • K. W. Kohn
  • W. E. Ross
  • D. Glaubiger
Part of the Antibiotics book series (ANTIBIOTICS, volume 5 / 2)

Abstract

In an examination of Australian plants for substances with antitumor activity, extracts of two botanically related species, Ochrosia moorei and Excavatia coccinea, were tested by the National Cancer Institute, U.S.A. They were found active against several transplantable tumors in mice; the activity was mostly accounted for by two alkaloids, ellipticine and 9-methoxy-ellipticine (Dalton et al, 1967). These alkaloids are widely distributed in the related genera Aspidosperma and Ochrosia. Ellipticine was first identified in extracts of leaves of O. elliptica Labill. (family Apocynaceae), a small tropical evergreen tree (Goodwin et al., 1959); the genus Ochrosia is a member of the tribe Plumiereae along with the alkaloid-producing genus Rauwolfia. Ellipticine and reserpine alkaloids, which are both based on indole, often occur together in the same plant material. Kilminster et al. (1972), in a search for a good botanical source of the alkaloids, extracted ellipticines from various parts of the plant Bleekeria vitiensis, a small tree indigenous to the island of Fiji. Ellipticine itself was not present in the leafy material but occurred in other organs of the plant ; 9-methoxyellipticine was the major alkaloid and occurred in all parts of the plant examined, the bark and wood being an especially rich source. Several chemical syntheses of ellipticines have been devised (see Guthrie et al., 1974 for references).

Keywords

Intercalate Agent Intercalative Binding Developmental Therapeutics Program Apparent Association Constant Ellipticine Derivative 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Alazard, R., Boquet, P.L., Paoletti, C: Effects of 9-hydroxyellipticine on growth and macromolecular synthesis in Escherichia coli. FEBS Lett. 63, 278–282 (1976)PubMedCrossRefGoogle Scholar
  2. Andreé, J., Pfeiffer, A., Rochefort, H.: Inhibition of estrogen-receptor-DNA interaction by intercalating drugs. Biochem. 15, 2964–2969 (1976)CrossRefGoogle Scholar
  3. Ansari, B.M., Thompson, E.N.: Methoxy-9-ellipticine in refractory acute myeloid leukemia. Postgrad. Med. J. 51, 103–105 (1975)PubMedCrossRefGoogle Scholar
  4. Bénard, J., Riou, G.: Effects of 9-hydroxy ellipticine on in vitro transcription of Trypanosoma cruzi DNAs. Biochem. Biophys. Res. Commun. 77, 1189–1195 (1977)PubMedCrossRefGoogle Scholar
  5. Bhuyan, B.K., Fraser, T.J., Li, L.H.: Cell cycle phase specificity and biochemical effects of ellipticine on mammalian cells. Cancer Res. 32, 2538–2544 (1972)PubMedGoogle Scholar
  6. Branfman, A.R., Bruni, R.J., Reinhold, V.N., Silveira, D., Chadwick, M., Yesair, D.W.: Characterization of the metabolites of ellipticine in rat bile. Drug Metab. Dispos. 6, 542–548 (1978)PubMedGoogle Scholar
  7. Byvoet, P., Sayre, D.: Stimulation of histone methylation by intercalating anti-tumor drugs. Proc. Am. Assoc. Can. Res. 17, 156 (1977)Google Scholar
  8. Chadwick, M., Platz, B.B., Hayes, D., Silveria, D.: Comparative physiological disposition of ellipticine in several animal species after intravenous administration. Drug Metab. Dispos, (in press, 1978)Google Scholar
  9. Chanh, P.H., Sorbara, R., Dat-Xuong, N., Le Pecq, J.B., Paoletti, C: Action cardiovasculaire et toxicite de l’hydroxy-9-ellipticine chez le chien. C.R. Acad. Sci. D. 279, 1039–1043 (1974)Google Scholar
  10. Chanh, P.H., Dat-Xuong, N., Le Pecq, J.B., Paoletti, C.: Cardiovascular activity of 9-hydroxy-ellipticine. Pharmacology 14, 490–498 (1976)PubMedCrossRefGoogle Scholar
  11. Courseille, P.C., Busetta, B., Hospital, M.: Structure cristalline et moleculaire du dimethyl-5, 11 6H-pyrido[4,3-b] carbazole (ellipticine). Acta Cryst. 30, 2628–2631 (1974)CrossRefGoogle Scholar
  12. Cros, S., Sorbara, R., Moisand, Ch., Dat-Xuong, N., Lecointe, P., Paoletti, C: Toxicological and pharmacological studies on 9-hydroxy-ellipticine in mice. Toxicol. Appl. Pharmacol. 33, 484–497 (1975)PubMedCrossRefGoogle Scholar
  13. Dalton, L.K., Demerac, S., Elmes, B.L., Loder, J.W., Swan, J.M., Teitei, T.: Synthesis of the tumor-inhibitory alkaloids, ellipticine, 9-methoxyellipticine, and related pyrido[4,3-b]carbazoles. Aust. J. Chem. 20, 2715 (1967)CrossRefGoogle Scholar
  14. Delbarre, A., Roques, B.P., Le Pecq, J.B., Lallemand, J.Y., Dat-Xuong, N.: PMR studies of the self-association of DNA intercalating ellipticine derivatives in aqueous solution. Biophys. Chem. 4, 275–279 (1976)PubMedCrossRefGoogle Scholar
  15. Festy, B., Poisson, J., Paoletti, C: A new DNA intercalating drug: methoxy-9-ellipticine. FEBS Lett. 17, 321–323 (1971)PubMedCrossRefGoogle Scholar
  16. Goodwin, S., Smith, A.F., Horning, E.C.: Alkaloids of ochrosia elliptica labill. J. Am. Chem. Soc. 81, 1903 (1959)CrossRefGoogle Scholar
  17. Gosalvez, M., Blanco, M., Hunter, J., Miko, M., Chance, B.: Effects of anticancer agents on the respiration of isolated mitochondria and tumor cells. Eur. J. Cancer 10, 567–574 (1974)PubMedCrossRefGoogle Scholar
  18. Guthrie, R.W., Brossi, A., Mennona, F.A., Mullin, J.G., Kierstead, R.W.: Ellipticine derivatives. J. Chem. 18, 755–760 (1974)Google Scholar
  19. Hansch, C: Commentary: strategy in drug design. Cancer Chemother. Rep. 56, 433–441 (1972)PubMedGoogle Scholar
  20. Hardesty, C.T., Chaney, N.A., Mead, J.A.R.: The effect of route of administration on the distribution of ellipticine in mice. Cancer Res. 32, 1884–1889 (1972)PubMedGoogle Scholar
  21. Hayat, M., Mathe, G., Janot, M.M., Potier, P., Dat-Xuong, N., Cave, A., Sevenet, T., Kan-Fan, C., Poisson, J., Miet, J., Le Men, J., Le Goffic, F., Gouyette, A., Ahond, A., Dalton, L.K., Connors, T.A.: Experimental screening of 3 forms and 19 derivatives or analogs of ellipticine: oncostatic effect on L1210 leukemia and immunosuppressive effect of 4 of them. Biomedicine 21, 101–106 (1974)PubMedGoogle Scholar
  22. Herman, E., Vick, J., Burka, B.: The cardiovascular actions of ellipticine. Toxicol. Appl. Pharmacol. 18, 743–751 (1971)PubMedCrossRefGoogle Scholar
  23. Herman, E.H., Chadwick, D.P., Mhatre, R.M.: Comparison of the acute hemolytic and cardiovascular actions of ellipticine (NSC-71795) and some ellipticine analogs. Cancer Chemother. Rep. 58, 637–642 (1974)PubMedGoogle Scholar
  24. Juret, P., Tanguy, A., Girard, A., Le Talaer, J.Y., Dat-Xuong, N., Le Pecq, J.B., Paoletti, C.: Preliminary trial of 9-hydroxy-2-methylellipticinium (NSC 264-137) in advanced human cancers. Eur. J. Can. (in press, 1977)Google Scholar
  25. Kann, H.E., Jr., Kohn, K.W.: Effects of deoxyribonucleic acid-reactive drugs on ribonucleic acid synthesis in leukemia L1210 cells. Mol. Pharmacol. 8, 551–560 (1972)PubMedGoogle Scholar
  26. Kilminster, K.N., Sainsbury, M., Webb, B.: Alkaloids and terpenoids of bleekevia vitiensis. Phytochemistry 11, 389 (1972)CrossRefGoogle Scholar
  27. Kohn, K.W., Snyder, A.L., Kann, H.E., Jr.: Size distributions of high molecular weight RNA synthesized by L1210 cells: effects of DNA-reactive drugs. Biochim. Biophys. Acta 324, 93–109 (1973)PubMedGoogle Scholar
  28. Kohn, K.W., Waring, M.J., Glaubiger, D., Friedman, C.A.: Intercalative binding of ellipticine to DNA. Cancer Res. 35, 71–76 (1975)PubMedGoogle Scholar
  29. Lee, I.P.: A possible mechanism of ellipticine-induced hemolysis. J. Pharmacol. Exp. Ther. 196, 525–535 (1976)Google Scholar
  30. Le Pecq, J.B., Dat-Xuong, N., Goose, C., Paoletti, C.: A new antitumoral agent: 9-hydroxyellipticine. Possibility of a rational design of anticancerous drugs in the series of DNA intercalating drugs. Proc. Natl. Acad. Sci. USA 71, 5078–5082 (1974a)PubMedCrossRefGoogle Scholar
  31. Le Pecq, J.B., LeBret, M., Goose, Ch., Paoletti, C.: Interest of quantum mechanical calculations for the design of anticancerous drugs in the series of ellipticines. In: Molecular and quantum pharmacology. Bergmann, E., Pullman, B. (eds.), pp. 515–535. Dordecht-Holland: D. Reidel 1974 bCrossRefGoogle Scholar
  32. Le Pecq, J.B., Goose, C., Dat-Xuong, N., Cros, S., Paoletti, C.: Antitumor activity of 9-hydroxyellipticine (NSC 210717) on L1210 mouse leukemia and the effect of route of injection. Cancer Res. 36, 3067–3076 (1976)PubMedGoogle Scholar
  33. Lerman, L.S.: Structural considerations in the interaction of DNA and acridines. J. Mol. Biol. 3, 18 (1961)PubMedCrossRefGoogle Scholar
  34. Lesca, P., Lecointe, P., Paoletti, C., Mansuy, D.: Induction des mono-oxygenases heatiques par l’ellipticine chez le rat: formation de cytochrome P488 activite hydroxylante. C.R. Acad. Sci. D 282, 1457–1460 (1976)Google Scholar
  35. Lesca, P., Lecointe, P., Paoletti, C.: The hydroxylation of the antitumor agent, ellipticine, by liver microsomes from differently pretreated rats. Biochem. Pharmacol. 27, 1203–1209 (1978)PubMedCrossRefGoogle Scholar
  36. Li, L.H., Cowie, C.H.: Biochemical effects of ellipticine leukemia L1210 cells. Biochim. Biophys. Acta 353, 375–384(1974)PubMedGoogle Scholar
  37. Liau, M.C., Lin, G.W., Knight, C.A., Huribert, R.B.: Inhibition of RNA methylation by intercalating agents. Cancer Res. 37, 4202–4210 (1977)PubMedGoogle Scholar
  38. Mathe, G., Hayat, M., De Vassal, F., Schwatzenberg, L., Schneider, J.R., Schlumberger, C., Jasmin, C., Rosenfeld, C.: Methoxy 9-ellipticine lactate III. Clinical screening: its action in acute myeloblastic leukemia. Rev. Eur. Etud. Clin. Biol. 15, 541 (1970)PubMedGoogle Scholar
  39. Müller, W., Crothers, D.M.: Studies of the binding of actinomycin and related compounds to DNA. Eur. J. Biochem. 35, 251–290 (1968)Google Scholar
  40. Müller, W., Crothers, D.M.: Interactions of heteroaromatic compounds with nucleic acids. 1. The influence of heteroatoms and polarizability on the base specificity of intercalating ligands. Eur. J. Biochem. 54, 267–277 (1975)PubMedCrossRefGoogle Scholar
  41. Mullin, J.G., Kierstead, R.W., Grunberg, E.: Ellipticine derivatives. J. Med. Chem. 18, 755–760 (1975)PubMedCrossRefGoogle Scholar
  42. Paoletti, C., Le Pecq, J.B., Dat-Xuong, N., Lesca, P., Lecointe, P.: New anticancer derivatives in the ellipticine series. Proc. 10th Int. Cancer Congr. (in press, 1977)Google Scholar
  43. Reinhold, V.N., Bruni, R.J.: Aromatic hydroxylation of ellipticine in rats: lack of an NIH shift. Biomed. Mass Spectromet. 3, 335–339 (1976)CrossRefGoogle Scholar
  44. Ross, W., Glaubiger, D., Kohn, K.W.: Protein-associated DNA breaks in cells treated with adriamycin or ellipticine. Biochim. Biophys. Acta 519, 23–30 (1978)PubMedGoogle Scholar
  45. Snyder, A.L., Kann, H.E., Jr., Kohn, K.W.: Inhibition of the processing of ribosomal precursor RNA by intercalating agents. J. Mol. Biol. 58, 555–565 (1971)PubMedCrossRefGoogle Scholar
  46. Sorace, R.A., Sheid, B.: Anti-tumor effects of DNA-ellipticine and DNA-ellipticine: daunomycin on the L1210(A) leukemia. Fed. Proc. 36, 335 (1977)Google Scholar
  47. Svoboda, G., Poore, G.A., Montfort, M.L.: Isolation of the alkaloids and study of the antitumor properties of 9-methoxyellipticine. J. Pharm. Sci. 57, 1720–1725 (1968)PubMedCrossRefGoogle Scholar
  48. Tobey, R.A.: A simple, rapid technique for determination of the effects of chemotherapeutic agents on mammalian cell-cycle traverse. Cancer Res. 32, 309–316 (1972)PubMedGoogle Scholar
  49. Wang, J.C.: The degree of unwinding of the DNA helix by ethidium. I. Titration of twisted PM2 DNA molecules in alkaline cesium chloride density gradients. J. Mol. Biol. 89, 783 (1974)PubMedCrossRefGoogle Scholar
  50. Waring, M.: Variation of the supercoils in closed circular DNA by binding of antibiotics and drugs: evidence from molecular models involving intercalation. J. Mol. Biol. 54, 247 (1970)PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin · Heidelberg 1979

Authors and Affiliations

  • K. W. Kohn
  • W. E. Ross
  • D. Glaubiger

There are no affiliations available

Personalised recommendations