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. 1989 Jan;86(2):651–655. doi: 10.1073/pnas.86.2.651

Bis(benzyl)polyamine analogs inhibit the growth of chloroquine-resistant human malaria parasites (Plasmodium falciparum) in vitro and in combination with alpha-difluoromethylornithine cure murine malaria.

A J Bitonti 1, J A Dumont 1, T L Bush 1, M L Edwards 1, D M Stemerick 1, P P McCann 1, A Sjoerdsma 1
PMCID: PMC286531  PMID: 2463635

Abstract

A number of bis(benzyl)polyamine analogs were found to be potent inhibitors of both chloroquine-resistant and chloroquine-sensitive strains of the human malaria parasite Plasmodium falciparum in vitro (IC50 values = 0.2-14 microM). Administration of one of the compounds, MDL 27695, which is N,N'-bis(3-[(phenylmethyl)amino]propyl)-1,7-diaminoheptane (C6H5CH2NH(CH2)3NH(CH2)7NH(CH2)3NHCH2C6H5), at 10-15 mg/kg i.p. three times per day for 3 days in combination with 2% alpha-difluoromethylornithine (DFMO; eflornithine) in drinking water effected cures of 47/54 mice infected with Plasmodium berghei. Cured mice were found to be immune upon rechallenge with the same P. berghei strain 4 months after the initial infection and drug-induced cure. MDL 27695 rapidly inhibited the incorporation of [3H]hypoxanthine into P. falciparum RNA and DNA, whereas the incorporation of [3H]isoleucine was not affected until much later. We conclude, therefore, that the major cytotoxic event may be direct binding of MDL 27695 to DNA with subsequent disruption of macromolecular biosynthesis and cell death. These compounds offer a lead in the search for new agents for chemotherapy of malaria.

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Selected References

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  1. Assaraf Y. G., Abu-Elheiga L., Spira D. T., Desser H., Bachrach U. Effect of polyamine depletion on macromolecular synthesis of the malarial parasite, Plasmodium falciparum, cultured in human erythrocytes. Biochem J. 1987 Feb 15;242(1):221–226. doi: 10.1042/bj2420221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Assaraf Y. G., Golenser J., Spira D. T., Bachrach U. Plasmodium falciparum: synchronization of cultures with DL-alpha-difluoromethylornithine, an inhibitor of polyamine biosynthesis. Exp Parasitol. 1986 Apr;61(2):229–235. doi: 10.1016/0014-4894(86)90156-6. [DOI] [PubMed] [Google Scholar]
  3. Bitonti A. J., McCann P. P., Sjoerdsma A. Plasmodium falciparum and Plasmodium berghei: effects of ornithine decarboxylase inhibitors on erythrocytic schizogony. Exp Parasitol. 1987 Oct;64(2):237–243. doi: 10.1016/0014-4894(87)90148-2. [DOI] [PubMed] [Google Scholar]
  4. Canellakis E. S., Bellantone R. A. Diacridines: bifunctional intercalators. II. The biological effects of putrescine, sperimidine and spermine diacridines on HeLa cells and on the L-1210 and P-388 leukemia cells. Biochim Biophys Acta. 1976 Feb 5;418(3):290–299. doi: 10.1016/0005-2787(76)90291-4. [DOI] [PubMed] [Google Scholar]
  5. Canellakis E. S., Bono V., Bellantone R. A., Krakow J. S., Fico R. M., Schulz R. A. Diacridines: bifunctional intercalators. III. Definition of the general site of action. Biochim Biophys Acta. 1976 Feb 5;418(3):300–314. doi: 10.1016/0005-2787(76)90292-6. [DOI] [PubMed] [Google Scholar]
  6. Canellakis E. S., Shaw Y. H., Hanners W. E., Schwartz R. A. Diacridines: bifunctional intercalators. I. Chemistry, physical chemistry and growth inhibitory properties. Biochim Biophys Acta. 1976 Feb 5;418(3):277–289. doi: 10.1016/0005-2787(76)90290-2. [DOI] [PubMed] [Google Scholar]
  7. Desjardins R. E., Canfield C. J., Haynes J. D., Chulay J. D. Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique. Antimicrob Agents Chemother. 1979 Dec;16(6):710–718. doi: 10.1128/aac.16.6.710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Feuerstein B. G., Pattabiraman N., Marton L. J. Spermine-DNA interactions: a theoretical study. Proc Natl Acad Sci U S A. 1986 Aug;83(16):5948–5952. doi: 10.1073/pnas.83.16.5948. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gillet J. M., Boné G., Herman F. Inhibitory action of alpha-difluoromethylornithine on rodent malaria (Plasmodium berghei). Trans R Soc Trop Med Hyg. 1982;76(6):776–777. doi: 10.1016/0035-9203(82)90105-5. [DOI] [PubMed] [Google Scholar]
  10. Gillet J. M., Charlier J., Boné G., Mulamba P. L. Plasmodium berghei: inhibition of the sporogonous cycle by alpha-difluoromethylornithine. Exp Parasitol. 1983 Oct;56(2):190–193. doi: 10.1016/0014-4894(83)90062-0. [DOI] [PubMed] [Google Scholar]
  11. Gu H. M., Warhurst D. C., Peters W. Rapid action of Qinghaosu and related drugs on incorporation of [3H]isoleucine by Plasmodium falciparum in vitro. Biochem Pharmacol. 1983 Sep 1;32(17):2463–2466. doi: 10.1016/0006-2952(83)90002-3. [DOI] [PubMed] [Google Scholar]
  12. Hollingdale M. R., McCann P. P., Sjoerdsma A. Plasmodium berghei: inhibitors of ornithine decarboxylase block exoerythrocytic schizogony. Exp Parasitol. 1985 Aug;60(1):111–117. doi: 10.1016/s0014-4894(85)80028-x. [DOI] [PubMed] [Google Scholar]
  13. Inselburg J., Banyal H. S. Synthesis of DNA during the asexual cycle of Plasmodium falciparum in culture. Mol Biochem Parasitol. 1984 Jan;10(1):79–87. doi: 10.1016/0166-6851(84)90020-3. [DOI] [PubMed] [Google Scholar]
  14. Jensen J. B., Trager W. Plasmodium falciparum in culture: establishment of additional strains. Am J Trop Med Hyg. 1978 Jul;27(4):743–746. doi: 10.4269/ajtmh.1978.27.743. [DOI] [PubMed] [Google Scholar]
  15. Kay J. E., Lindsay V. J. Control of ornithine decarboxylase activity in stimulated human lymphocytes by putrescine and spermidine. Biochem J. 1973 Apr;132(4):791–796. doi: 10.1042/bj1320791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. McCann P. P., Tardif C., Hornsperger J. M., Böhlen P. Two distinct mechanisms for ornithine decarboxylase regulation by polyamines in rat hepatoma cells. J Cell Physiol. 1979 May;99(2):183–190. doi: 10.1002/jcp.1040990204. [DOI] [PubMed] [Google Scholar]
  17. McCann P. P., Tardif C., Pegg A. E., Diekema K. The dual action of the non-physiological diamines 1,3 diaminopropane and cadaverine on ornithine decarboxylase of HTC cells. Life Sci. 1980 Jun 9;26(23):2003–2010. doi: 10.1016/0024-3205(80)90633-5. [DOI] [PubMed] [Google Scholar]
  18. Oduola A. M., Weatherly N. F., Bowdre J. H., Desjardins R. E. Plasmodium falciparum: cloning by single-erythrocyte micromanipulation and heterogeneity in vitro. Exp Parasitol. 1988 Jun;66(1):86–95. doi: 10.1016/0014-4894(88)90053-7. [DOI] [PubMed] [Google Scholar]
  19. Pegg A. E., McCann P. P. Polyamine metabolism and function. Am J Physiol. 1982 Nov;243(5):C212–C221. doi: 10.1152/ajpcell.1982.243.5.C212. [DOI] [PubMed] [Google Scholar]
  20. Peters W. The chemotherapy of rodent malaria, XXII. The value of drug-resistant strains of P. berghei in screening for blood schizontocidal activity. Ann Trop Med Parasitol. 1975 Jun;69(2):155–171. [PubMed] [Google Scholar]
  21. Peters W. The problem of drug resistance in malaria. Parasitology. 1985 Apr;90(Pt 4):705–715. doi: 10.1017/s003118200005232x. [DOI] [PubMed] [Google Scholar]
  22. Porter C. W., Berger F. G., Pegg A. E., Ganis B., Bergeron R. J. Regulation of ornithine decarboxylase activity by spermidine and the spermidine analogue N1N8-bis(ethyl)spermidine. Biochem J. 1987 Mar 1;242(2):433–440. doi: 10.1042/bj2420433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Porter C. W., Sufrin J. R. Interference with polyamine biosynthesis and/or function by analogs of polyamines or methionine as a potential anticancer chemotherapeutic strategy. Anticancer Res. 1986 Jul-Aug;6(4):525–542. [PubMed] [Google Scholar]
  24. Tofilon P. J., Oredsson S. M., Deen D. F., Marton L. J. Polyamine depletion influences drug-induced chromosomal damage. Science. 1982 Sep 10;217(4564):1044–1046. doi: 10.1126/science.6810463. [DOI] [PubMed] [Google Scholar]
  25. Trager W., Jensen J. B. Human malaria parasites in continuous culture. Science. 1976 Aug 20;193(4254):673–675. doi: 10.1126/science.781840. [DOI] [PubMed] [Google Scholar]
  26. Whaun J. M., Brown N. D. Ornithine decarboxylase inhibition and the malaria-infected red cell: a model for polyamine metabolism and growth. J Pharmacol Exp Ther. 1985 May;233(2):507–511. [PubMed] [Google Scholar]

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