Naslov
Distribution of Furamidine Analogues in Tumor Cells: Influence of the Number of Positive Charges

Autori
Lansiaux, Amelie ; Dassonneville, Laurent ; Facompre, Michael ; Kumar, Arvind ; Stephens, Chad ; Bajić, Miroslav ; Tanious, Farial ; Wilson, W, David ; Boykin, David, W ; Bailly, Christian

Izvornik
Journal of medicinal chemistry (0022-2623) 45 (2002), 10; 1994-2002

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
DNA minor-groove; Nucleic-acid interactions; Diphenylfuran derivatives; Pneumocystis-carinii; Aromatic dication; Resistant cells; Binding mode; Localization; Accumulation; Dimer
(DNA minor-groove; nucleic-acid interactions; diphenylfuran derivatives; pneumocystis-carinii; aromatic dication; resistant cells; binding mode; localization; accumulation; dimer)

Sažetak
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 monocationiccompounds, 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 infacilitating nuclear accumulation into cells, probably as aresult 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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

POVEZANOST RADA