Distribution of furamidine analogues in tumor cells

Influence of the number of positive charges

Amélie Lansiaux, Laurent Dassonneville, Michaël Facompré, Arvind Kumar, Chad E. Stephens, Miroslav Bajic, Farial Tanious, David W. Wilson, David W. Boykin, Christian Bailly

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Fluorescence microscopy has been used to study the cellular distribution properties of a series of DNA binding cationic compounds related to the potent antiparasitic drug furamidine (DB75). The compounds tested bear a diphenylfuran or a phenylfuranbenzimidazole unfused aromatic core substituted with one or two amidine or imidazoline groups. The synthesis of five new compounds is reported. The B16 melanoma cell line was used to compare the capacities of mono-, bis-, and tetracations to enter the cell and nuclei. The high-resolution fluorescence pictures show that in the furamidine series, the compounds with two or four positive charges selectively accumulate in the cell nuclei whereas, in most cases, those bearing only one positive charge show reduced cell uptake capacities. One of the monocationic compounds, DB607, distributes in the cytoplasm, possibly in mitochondria, with no distinct nuclear accumulation. In sharp contrast, furamidine and benzimidazole analogues, including the drug DB293 that forms DNA minor groove dimers, efficiently accumulate in the cell nuclei and the intranuclear distribution of these DNA minor groove binders is significantly different from that seen with the DNA intercalating drug propidium iodide. The results suggest that the presence of two amidine terminal groups plays a role in facilitating nuclear accumulation into cells, probably as a result of nucleic acid binding. The determination of DNA melting temperature increases on addition of these compounds supports the importance of DNA binding in nuclear uptake.

Original languageEnglish (US)
Pages (from-to)1994-2002
Number of pages9
JournalJournal of Medicinal Chemistry
Volume45
Issue number10
DOIs
StatePublished - May 9 2002
Externally publishedYes

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Cell Count
Cell Nucleus
Amidines
DNA
Neoplasms
Nucleic Acid Denaturation
Imidazolines
Antiparasitic Agents
Experimental Melanomas
Propidium
Fluorescence Microscopy
Pharmaceutical Preparations
Nucleic Acids
Mitochondria
Cytoplasm
Fluorescence
furamidine
Cell Line
Temperature

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Distribution of furamidine analogues in tumor cells : Influence of the number of positive charges. / Lansiaux, Amélie; Dassonneville, Laurent; Facompré, Michaël; Kumar, Arvind; Stephens, Chad E.; Bajic, Miroslav; Tanious, Farial; Wilson, David W.; Boykin, David W.; Bailly, Christian.

In: Journal of Medicinal Chemistry, Vol. 45, No. 10, 09.05.2002, p. 1994-2002.

Research output: Contribution to journalArticle

Lansiaux, A, Dassonneville, L, Facompré, M, Kumar, A, Stephens, CE, Bajic, M, Tanious, F, Wilson, DW, Boykin, DW & Bailly, C 2002, 'Distribution of furamidine analogues in tumor cells: Influence of the number of positive charges', Journal of Medicinal Chemistry, vol. 45, no. 10, pp. 1994-2002. https://doi.org/10.1021/jm010539n
Lansiaux, Amélie ; Dassonneville, Laurent ; Facompré, Michaël ; Kumar, Arvind ; Stephens, Chad E. ; Bajic, Miroslav ; Tanious, Farial ; Wilson, David W. ; Boykin, David W. ; Bailly, Christian. / Distribution of furamidine analogues in tumor cells : Influence of the number of positive charges. In: Journal of Medicinal Chemistry. 2002 ; Vol. 45, No. 10. pp. 1994-2002.
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