Insufficiently charged isosteric analogue of spermine: interaction with polyamine metabolism and uptake, effect on Caco-2 cell growth

L. Turchanova, A. S. Shvetsov, A. V. Demin, A. R. Khomutov, Heather Mann Wallace, J. Stein, V. Milovic

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

We characterised a novel, charge-insufficient isosteric analogue of spermine, 11-[(amino)oxy]-4,9-diaza-l-aminoundecane (AOSPM). This analogue was synthesised by displacing aminopropyl group by aminooxyethyl group, the latter having pK(a) of about 5. Charge deficiency of the AOSPM molecule was fixed at a definite atom, while pK(a) of the rest nitrogen was similar to the parent polyamine. AOSPM competed with putrescine, spermidine and spermine for the uptake into the cell, and was accumulated in the cells in high amounts when exogenous polyamine synthesis was impaired. It was not recognised by the cells as growth-promoting polyamine, since it was unable to restore growth arrest due to polyamine deprivation. Like natural spermine, this polyamine analogue prevented oxidative DNA damage. AOSPM could be used not only as a tool to study polyamine homeostasis in the cell, but may have distinct applications either as radiation protector, a stable and non-toxic inhibitor of polyamine uptake or, as an appropriate vector, to enhance the uptake of impermeable compounds into the cell. (C) 2002 Elsevier Science Inc. All rights reserved.

Original languageEnglish
Pages (from-to)649-655
Number of pages6
JournalBiochemical Pharmacology
Volume64
DOIs
Publication statusPublished - 2002

Keywords

  • aminooxyspermine
  • polyamine transport
  • putrescine
  • spermidine
  • spermine
  • HUMAN CANCER-CELLS
  • AMINOOXY ANALOGS
  • COLON-CANCER
  • SPERMIDINE/SPERMINE N-1-ACETYLTRANSFERASE
  • NUCLEIC-ACIDS
  • DNA HYBRIDS
  • PUTRESCINE
  • INHIBITORS
  • BIOSYNTHESIS
  • METABOLISM

Cite this

Insufficiently charged isosteric analogue of spermine: interaction with polyamine metabolism and uptake, effect on Caco-2 cell growth. / Turchanova, L.; Shvetsov, A. S.; Demin, A. V.; Khomutov, A. R.; Wallace, Heather Mann; Stein, J.; Milovic, V.

In: Biochemical Pharmacology, Vol. 64, 2002, p. 649-655.

Research output: Contribution to journalArticle

Turchanova, L. ; Shvetsov, A. S. ; Demin, A. V. ; Khomutov, A. R. ; Wallace, Heather Mann ; Stein, J. ; Milovic, V. / Insufficiently charged isosteric analogue of spermine: interaction with polyamine metabolism and uptake, effect on Caco-2 cell growth. In: Biochemical Pharmacology. 2002 ; Vol. 64. pp. 649-655.
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abstract = "We characterised a novel, charge-insufficient isosteric analogue of spermine, 11-[(amino)oxy]-4,9-diaza-l-aminoundecane (AOSPM). This analogue was synthesised by displacing aminopropyl group by aminooxyethyl group, the latter having pK(a) of about 5. Charge deficiency of the AOSPM molecule was fixed at a definite atom, while pK(a) of the rest nitrogen was similar to the parent polyamine. AOSPM competed with putrescine, spermidine and spermine for the uptake into the cell, and was accumulated in the cells in high amounts when exogenous polyamine synthesis was impaired. It was not recognised by the cells as growth-promoting polyamine, since it was unable to restore growth arrest due to polyamine deprivation. Like natural spermine, this polyamine analogue prevented oxidative DNA damage. AOSPM could be used not only as a tool to study polyamine homeostasis in the cell, but may have distinct applications either as radiation protector, a stable and non-toxic inhibitor of polyamine uptake or, as an appropriate vector, to enhance the uptake of impermeable compounds into the cell. (C) 2002 Elsevier Science Inc. All rights reserved.",
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AU - Turchanova, L.

AU - Shvetsov, A. S.

AU - Demin, A. V.

AU - Khomutov, A. R.

AU - Wallace, Heather Mann

AU - Stein, J.

AU - Milovic, V.

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N2 - We characterised a novel, charge-insufficient isosteric analogue of spermine, 11-[(amino)oxy]-4,9-diaza-l-aminoundecane (AOSPM). This analogue was synthesised by displacing aminopropyl group by aminooxyethyl group, the latter having pK(a) of about 5. Charge deficiency of the AOSPM molecule was fixed at a definite atom, while pK(a) of the rest nitrogen was similar to the parent polyamine. AOSPM competed with putrescine, spermidine and spermine for the uptake into the cell, and was accumulated in the cells in high amounts when exogenous polyamine synthesis was impaired. It was not recognised by the cells as growth-promoting polyamine, since it was unable to restore growth arrest due to polyamine deprivation. Like natural spermine, this polyamine analogue prevented oxidative DNA damage. AOSPM could be used not only as a tool to study polyamine homeostasis in the cell, but may have distinct applications either as radiation protector, a stable and non-toxic inhibitor of polyamine uptake or, as an appropriate vector, to enhance the uptake of impermeable compounds into the cell. (C) 2002 Elsevier Science Inc. All rights reserved.

AB - We characterised a novel, charge-insufficient isosteric analogue of spermine, 11-[(amino)oxy]-4,9-diaza-l-aminoundecane (AOSPM). This analogue was synthesised by displacing aminopropyl group by aminooxyethyl group, the latter having pK(a) of about 5. Charge deficiency of the AOSPM molecule was fixed at a definite atom, while pK(a) of the rest nitrogen was similar to the parent polyamine. AOSPM competed with putrescine, spermidine and spermine for the uptake into the cell, and was accumulated in the cells in high amounts when exogenous polyamine synthesis was impaired. It was not recognised by the cells as growth-promoting polyamine, since it was unable to restore growth arrest due to polyamine deprivation. Like natural spermine, this polyamine analogue prevented oxidative DNA damage. AOSPM could be used not only as a tool to study polyamine homeostasis in the cell, but may have distinct applications either as radiation protector, a stable and non-toxic inhibitor of polyamine uptake or, as an appropriate vector, to enhance the uptake of impermeable compounds into the cell. (C) 2002 Elsevier Science Inc. All rights reserved.

KW - aminooxyspermine

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KW - spermidine

KW - spermine

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KW - COLON-CANCER

KW - SPERMIDINE/SPERMINE N-1-ACETYLTRANSFERASE

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KW - DNA HYBRIDS

KW - PUTRESCINE

KW - INHIBITORS

KW - BIOSYNTHESIS

KW - METABOLISM

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JO - Biochemical Pharmacology

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SN - 0006-2952

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