Skip to main content
SpringerLink
Log in

Polyamine Structure and Synthetic Analogs

  • Chapter
Polyamine Cell Signaling

Abstract

The polyamines putrescine (1,4-diaminobutane), spermidine (1,8-diamino-4-azaoctane, 2), and spermine (1,12-diamino-4,9-diazadodecane, 3) (Fig. 1) are ubiquitous polycationic compounds that are found in significant amounts in nearly every prokaryotic and eukaryotic cell type. Spermidine and spermine primarily exist in aqueous solution at pH 7.4 as fully protonated polycations and possess the pKa values indicated in Fig. 1 (1). This high degree of positive charge is an important factor in the biological functions of these molecules, and, as will be discussed later in this chapter, alterations in the pKa of polyamine nitrogens can affect and disrupt their cellular function. Polyamines are widely distributed in nature and are known to be required in micromolar to millimolar concentrations to support a wide variety of cellular functions. However, data that establish the precise role of the polyamines and their analogs in cellular processes are incomplete. The ongoing identification of new functions for the polyamines ensures that new avenues for research are arising continuously in an extremely diverse set of disciplines. The human and mammalian pathways for polyamine metabolism have been extensively studied, and analogous pathways have been elucidated for a relatively small number of organisms. There are important interspecies differences in polyamine metabolism, especially among eukaryotic cells, plants, and some bacteria and protozoa. In some prokaryotes, only putrescine and spermidine are synthesized, whereas in other cases, such as certain thermophilic bacteria, polyamines with chains longer than spermine are found. In some parasitic organisms, there are additional enzymes that are not present in the host cell, and, as such, provide a target for the design of specific antiparasitic agents. The enzymes involved in human and mammalian polyamine metabolism are reasonably similar, and inhibitors targeted to these enzymes rely on the observation that polyamine metabolism is accelerated, and polyamines are required in higher quantities, in target cell types. The diversity of biological research in the polyamine field is the subject of an excellent book (2). Keeping in mind the diverse nature of polyamine distribution and function, it is reasonable to assume that carefully designed polyamine analogs could have the potential to disrupt polyamine metabolism, and thus such agents have been investigated as potential therapeutic agents in vitro and in vivo. The polyamine pathway represents an important target for chemotherapeutic intervention because depletion of polyamines results in the disruption of a variety of cellular functions and may, in specific cases, result in cytotoxicity (3,4). This chapter will summarize the development of synthetic derivatives of the polyamines, and describe their use as potential chemotherapeutic agents. A comprehensive review of polyamine biosynthesis inhibitors (4) and a review of the role of polyamines in normal and tumor cell metabolism (5) have recently been published.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Bergeron, R. J., McManis, J. S., Weimar, W. R., et al. (1995) The role of charge in polyamine analog recognition. J. Med. Chem. 38, 2278–2285.

    Article  PubMed  Google Scholar 

  2. Cohen, S. A. (ed.) (1998) Guide to the Polyamines. Oxford University Press, New York.

    Google Scholar 

  3. Sunkara, P. S., Baylin, S. B., and Luk, G. D. (1987) Inhibitors of polyamine biosynthesis: Cellular in vivo effects on tumor proliferation. In: Inhibition of Polyamine Metabolism: Biological Significance and Basis for New Therapies (McCann, P. P., Pegg, A. E., and Sjoerdsma, A., eds.), Academic Press, New York, pp. 121–

    Google Scholar 

  4. Casero, Jr., R. A. and Woster, P. M. (2001) Terminally alkylated polyamine analogues as chemotherapeutic agents. J. Med. Chem. 44, 1–29.

    Article  PubMed  CAS  Google Scholar 

  5. Gerner, E. W. and Meyskens, F. L. (2004) Polyamines and cancer: Old molecules, new understanding. Nat. Rev. Cancer 4, 781–792.

    Article  PubMed  CAS  Google Scholar 

  6. Pegg, A. E. and McCann, P. P. (1992) S-adenosylmethionine decarboxylase as an enzyme target for therapy. Pharmacol. Ther. 56, 359–377.

    Article  PubMed  CAS  Google Scholar 

  7. Pegg, A. E. (1988) Polyamine metabolism and its importance in neoplastic growth and as a target for chemotherapy. Cancer Res. 48, 759–774.

    PubMed  CAS  Google Scholar 

  8. Murikami, Y., Matsufuji, S., Kameji, T., et al. (1992) Ornithine decarboxylase is degraded by the 26S proteasome without ubiquitination. Nature 360, 597–599.

    Article  Google Scholar 

  9. Metcalf, B. W., Bey, P., Danzin, C., Jung, M. J., Casara, P., and Vevert, J. P. (1978) Catalytic, irreversible inhibition of mammalian ornithine decarboxylase (E.C. 4.1.1.17) by substrate and product analogues. J. Am. Chem. Soc. 100, 2551–2553.

    Article  CAS  Google Scholar 

  10. Tang, K.-C., Mariuzza, R., and Coward, J.K. (1981) Synthesis and evaluation of some stable multisubstrate adducts as specific inhibitors of spermidine synthase. J. Med. Chem. 24, 1277–1284.

    Article  PubMed  CAS  Google Scholar 

  11. Woster, P. M., Black, A. Y., Duff, K. J., Coward, J. K., and Pegg, A. E. (1989) Synthesis and biological evaluation of S-adenosyl-1,12-diamino-3-thio-9-azadodecane, a multisubstrate adduct inhibitor of spermine synthase. J. Med. Chem. 32, 1300–1307.

    Article  PubMed  CAS  Google Scholar 

  12. Recsei, P. A. and Snell, E. E. (1984) Pyruvoyl enzymes. Ann. Rev. Biochem. 53, 357–387.

    Article  PubMed  CAS  Google Scholar 

  13. Danzin, C., Marchal, P., and Casara, P. (1990) Irreversible inhibition of rat S-adenosylmethioninedecarboxylase by 5′[(Z)-4-amino-2-butenyl]methylamino-5′-deoxyadenosine. Biochem. Pharmacol. 40, 1499–1503.

    Article  PubMed  CAS  Google Scholar 

  14. Marchant, P., Dredar, S., Manneh, V., et al. (1989) A selective inhibitor of N8-acetylspermidine deacetylation in mice and HeLa cells without effects on histone deacetylation. Arch. Biochem. Biophys. 15, 128–136.

    Article  Google Scholar 

  15. Casero, R. A. and Pegg, A. E. (1993) Spermidine/spermine-N1-acetyltransferase-the turning point in polyamine metabolism. FASEB J. 7, 653–661.

    PubMed  CAS  Google Scholar 

  16. Cullis, P. M., Green, R. E., Merson-Davies, L., and Travis, N. G. (1998) Chemical highlights of polyamine transport. Biochem. Soc. Trans. 26, 595–601.

    PubMed  CAS  Google Scholar 

  17. Seiler, N., Delcros, J. G., and Moulinoux, J. P. (1996) Polyamine transport in mammalian cells. An update. Int. J. Biochem. Cell Biol. 8, 843–861.

    Article  Google Scholar 

  18. Kashiwagi, K., Endo, H., Kobayashi, H., Takio, K., and Igarashi, K. (1995) Spermidinepreferential uptake system in Escherichia coli. ATP hydrolysis by PotA protein and its association with membrane. J. Biol. Chem. 270, 25377–25382.

    Article  PubMed  CAS  Google Scholar 

  19. Seiler, N. (2003) Thirty years of polyamine-related approaches to cancer therapy. Retrospect and prospect. Part 2. Structural analogues and derivatives. Curr. Drug Targets 7, 565–585.

    Article  Google Scholar 

  20. Edwards, M. L., Prakash, N. J., Stemerick, D. M., et al. (1990) Polyamine analogues with antitumor activity. J. Med. Chem. 33, 1369–1375.

    Article  PubMed  CAS  Google Scholar 

  21. Edwards, M. L., Snyder, R. D., and Stemerick, D. M. (1991) Synthesis and DNA-binding properties of polyamine analogues. J. Med. Chem. 34, 2414–2420.

    Article  PubMed  CAS  Google Scholar 

  22. Porter, C. W. and Sufrin, J. (1986) Interference with polyamine biosynthesis and/or function by analogues of polyamines or methionine as a potential anticancer chemotherapeutic strategy. Anticancer Res. 6, 525–542.

    PubMed  CAS  Google Scholar 

  23. Bergeron, R. J., Neims, A. H., McManis, J. S., et al. (1988) Synthetic polyamine analogues as antineoplastics. J. Med. Chem. 31, 1183–1190.

    Article  PubMed  CAS  Google Scholar 

  24. Yajima, H., Takeyama, M., Kanaki, J., Nishimura, O., and Fujino, M. (1978) Studies on peptides. LXXX. NG-Mesitylene-2-sulfonylarginine. Chem. Pharm. Bull. 26, 3752–3757.

    CAS  Google Scholar 

  25. Roemmele, R. C., and Rappoport, H. (1998) Removal of N-arylsulfonyl groups from hydroxy α-amino acids. J. Org. Chem. 53, 2367–2371.

    Article  Google Scholar 

  26. Porter, C. W., Berger, F. G., Pegg, A. E., Ganis, B., and Bergeron, R. J. (1987) Regulation of ornithine decarboxylase activity by spermidine or the spermidine analog N1, N8-bis(ethyl)spermidine (BES). Biochem. J. 242, 433–440.

    PubMed  CAS  Google Scholar 

  27. Casero, R. A., Ervin, S. J., Celano, P., Baylin, S. B., and Bergeron, R. J. (1989) Differential response to treatment with bis(ethyl)polyamine analogues between human small cell lung carcinoma and undifferentiated large cell lung carcinoma in culture. Cancer Res. 49, 639–643.

    PubMed  CAS  Google Scholar 

  28. Porter, C. W., Ganis, B., Libby, P. R., and Bergeron, R. J. (1991) Correlations between polyamine analogue-induced increases in spermidine/spermine-N1-acetyltransferase activity, polyamine pool depletion, and growth inhibition in human melanoma cell lines. Cancer Res. 51, 3715–3720.

    PubMed  CAS  Google Scholar 

  29. Casero, R. A., Mank, A. R., Xiao, L., Smith, J., Bergeron, R. J., and Celano, P. (1992) Steady-state messenger RNA and activity correlates with sensitivity to N1, N12-bis(ethyl)spermine in human cell lines representing the major forms of lung cancer. Cancer Res. 52, 5359–5363.

    PubMed  CAS  Google Scholar 

  30. Bergeron, R. J., Hawthorne, T. R., Vinson, J. R. T., Beck, D. E., Jr., and Ingeno, M. J. (1989) Role of the methylene backbone in the antiproliferative activity of polyamine analogues in L1210 cells. Cancer Res. 49, 2959–2964.

    PubMed  CAS  Google Scholar 

  31. Bergeron, R. J., McManis, J. S., Liu, C. Z, et al. (1994) Antiproliferative properties of polyamine analogues: a structure-activity study. J. Med. Chem. 37, 3464–3476.

    Article  PubMed  CAS  Google Scholar 

  32. Bergeron, R. J., Wiegand, J., McManis, J. S., et al. (2001) Polyamine analogue antidiarrheals: a structure-activity study. J. Med. Chem. 44, 232–244.

    Article  PubMed  CAS  Google Scholar 

  33. Berchtold, C. M., Tamez, P., Kensler, T. W., and Casero, R. A. (1998) Inhibition of cell growth in CaCO2 cells by the polyamine analogue N1, N12-bis(ethyl)spermine is preceded by a reduction in MYC oncoprotein levels. J. Cell Physiol. 174, 380–386.

    Article  PubMed  CAS  Google Scholar 

  34. Gabrielson, E. W., Pegg, A. E., and Casero, R. A. (1999) The induction of spermidine/spermine-N1-acetyltransferase (SSAT) is a common event in the response of human primary non-small cell lung carcinomas to exposure to a new antitumor polyamine analogue, N1, N11-bis(ethyl)norspermine. Clin. Cancer Res. 5, 1638–1641.

    PubMed  CAS  Google Scholar 

  35. Wilding, G., King, D., Tutsch, K., et al. (2004) Phase I trial of the polyamine analog N1, N14-diethylhomospermine (DEHSPM) in patients with advanced solid tumors. Invest. New Drugs. 22, 131–8.

    Article  PubMed  CAS  Google Scholar 

  36. Sninsky, C. A. and Bergeron, R. (1993) Potent anti-diarrheal activity of a new class of compounds: synthetic analogs of the polyamine pathway. Gastroenterology 104, A584.

    Google Scholar 

  37. Bergeron, R. J., Weimar, W. R., Luchetta, G., et al. (1995) Metabolism and pharmacokinetics of N1, N11-diethylnorspermine. Drug Metab. Disp. 23, 1117–1125.

    CAS  Google Scholar 

  38. Bergeron, R. J., Weimer, W. R., Luchetta, G., Sninsky, C. A., and Wiegand, J. (1996) Metabolism and pharmacokinetics of N1, N14-diethylhomospermine. Drug Metab. Disp. 24, 334–343.

    CAS  Google Scholar 

  39. Bergeron, R. J., Yao, G. W., Yao, H., et al. (1996) Metabolically programmed polyamine analogue antidiarrheals. J. Med. Chem. 39, 2461–2471.

    Article  PubMed  CAS  Google Scholar 

  40. Basu, H. S., Pellarin, M., Feuerstein, B. G., Deen, D. F., and Marton, L. J. (1991) Effect of N1, N14-bis(ethyl)homospermine (BE-4X4) on the growth of U251, MG and SF-188 brain tumor cells. Int. J. Cancer 30, 873–878.

    Article  Google Scholar 

  41. Basu, H. S., Pellarin, M., Feuerstein, B. G., Deen, D. F., and Marton, L. J. (1993) Effects of the polyamine analogs BE-3-7-3, 3-8-3, and BE-3-8-3 on human brain tumor cell growth and survival. Anticancer Res. 13, 1525–1532.

    PubMed  CAS  Google Scholar 

  42. Jeffers, L., Church, D., Basu, H., Marton, L., and Wilding, G. (1997) Effects of the polyamine analogues BE-4-4-4-4, BE-3-7-3 and BE-3-3-3 on the proliferation of three prostate cancer cell lines. Cancer Chemother. Pharmacol. 40, 172–179.

    Article  PubMed  CAS  Google Scholar 

  43. Reddy, V. K., Valasinas, A., Sarkar, A., Basu, H. S., Marton, L. J., and Frydman, B. (1998) Conformationally restricted analogues of 1N,12N-bisethylspermine: synthesis and growth inhibitory effects on human tumor cell lines. J. Med. Chem. 41, 4723–4732.

    Article  PubMed  CAS  Google Scholar 

  44. Seiler, N., Delcros, J. G., Vaultier, M., et al. (1996) Bis(7-amino-4-azaheptyl)dimethylsilane and bis(7-ethylamino-4-azaheptyl)dimethylsilane: inhibition of tumor cell growth in vitro and in vivo. Cancer Res. 56, 5624–5630.

    PubMed  CAS  Google Scholar 

  45. Waters, W. R., Frydman, B., Marton, L. J., et al. (2000) [1N,12N]Bis(ethyl)-cis-6,7-dehydrospermine: a new drug for treatment and prevention of Cryptosporidium parvum infection of mice deficient in T-cell receptor alpha. Antimicrobial Agents Chemother. 44, 2891–2894.

    Article  CAS  Google Scholar 

  46. Frydman, B., Porter, C. W., Maxuitenko, Y., et al. (2003) A novel polyamine analog (SL-11093) inhibits growth of human prostate tumor xenografts in nude mice. Cancer Chemother. Pharmacol. 51, 488–492.

    PubMed  CAS  Google Scholar 

  47. Valasinas, A., Sarkar, A., Reddy, V., Marton, L. J., Basu, H. S., and Frydman, B. (2001) Conformationally restricted analogues of 1N,14N-bisethylhomospermine (BE-4-4-4): Synthesis and growth inhibitory effects on human prostate cancer cells. J. Med. Chem. 44, 390–403.

    Article  PubMed  CAS  Google Scholar 

  48. Frydman, B., Blohkin, A. V., Brummel, S., et al. (2003) Cyclopropane-containing polyamine analogues are efficient growth inhibitors of a human prostate tumor xenograft in nude mice. J. Med. Chem. 46, 4586–46

    Article  PubMed  CAS  Google Scholar 

  49. Reddy, V. K., Sarkar, A., Valasinas, A., Marton, L. J., Basu, H. S., and Frydman, B. (2001) Cis-unsaturated analogues of 3,8,13,18,23-pentaazapentacosane (BE-4-4-4-4): synthesis and growth inhibitory effects on human prostate cancer cell lines. J. Med. Chem. 44, 404–417.

    Article  PubMed  CAS  Google Scholar 

  50. Valasinas, A., Reddy, V. K., Blohkin, A. V., et al. (2003) Long-chain polyamines (oligoamines) exhibit strong cytotoxicities against human prostate cancer cells. Bioorg. Med. Chem. 11, 4121–4131.

    Article  PubMed  CAS  Google Scholar 

  51. Frydman, B., Bhattacharya, S., Sarkar, A., et al. (2004) Macrocyclic polyamines deplete cellular ATP levels and inhibit cell growth in human prostate cancer cells. J. Med. Chem. 47, 1051–105

    Article  PubMed  CAS  Google Scholar 

  52. Saab, N. H., West, E. E., Bieszk, N. C., et al. (1993) Synthesis and evaluation of unsymmetrically substituted polyamine analogues as inhibitors of spermidine/spermine-N1-acetyltransferase (SSAT) and as potential antitumor agents. J. Med. Chem. 36, 2998–3004.

    Article  PubMed  CAS  Google Scholar 

  53. McCloskey, D. E., Yang, J., Woster, P. M., Davidson, N. E., Casero, R. A., Jr. (1996) Polyamine analogue induction of programmed cell death in human lung tumor cells. Clin. Cancer Res. 2, 441–446.

    PubMed  CAS  Google Scholar 

  54. Davidson, N. E., Hahm, H. A., McCloskey, D. E., Woster, P. M., and Casero, R. A. (1999) Clinical aspects of cell death in breast cancer: the polyamine pathway as a new target for treatment. Endocr. Related Cancer 6, 69–73.

    Article  CAS  Google Scholar 

  55. Ha, H. C., Woster, P. M., Yager, J. D., and Casero, R. A., Jr. (1997) The role of polyamine catabolism in polyamine analogue-induced programmed cell death. Proc. Natl. Acad. Sci. USA 94, 11,557–11,562.

    Article  PubMed  CAS  Google Scholar 

  56. Ha, H. C., Woster, P. M., and Casero, R. A., Jr. (1998) Unsymmetrically substituted polyamine analogue induces caspase-independent programmed cell death in Bcl-2 overexpressing cells. Cancer Res. 58, 2711–2714.

    PubMed  CAS  Google Scholar 

  57. Webb, H. K., Wu, Z. Q., Sirisoma, N., Ha, H. C., Casero, R., A., Jr., and Woster, P. M. (1999) 1-[N-(Alkyl)amino]-11-[N-(ethyl)amino]-4,8-diazaundecanes: simple synthetic polyamine analogues which differentially alter tubulin polymerization. J. Med. Chem. 42, 1415–1421.

    Article  PubMed  CAS  Google Scholar 

  58. Ekstrom, J. L., Mathews, I. I., Stanley, B. A., Pegg, A. E., and Ealick, S. E. (1999) The crystal structure of human S-adenosylmethionine decarboxylase at 2.25 angstroms resolution reveals a novel fold. Structure (London) 7, 583.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI

    Patrick M. Woster

Authors
  1. Patrick M. Woster
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Departments of Surgery and Pathology, University of Maryland School of Medicine and Baltimore Veterans Affairs Medical Center, Baltimore, MD

    Jian-Ying Wang

  2. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD

    Robert A. Casero Jr.

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Woster, P.M. (2006). Polyamine Structure and Synthetic Analogs. In: Wang, JY., Casero, R.A. (eds) Polyamine Cell Signaling. Humana Press. https://doi.org/10.1007/978-1-59745-145-1_1

Download citation

Publish with us

Policies and ethics

Search

Navigation