Novel pentamidine derivatives: Synthesis, anti-tumor properties and polynucleotide-binding activities

Novel amidino-substituted conformationally restricted derivatives of pentamidine were synthesized and their antiproliferative activity against several human cancer cell lines determined. It was found that introduction of furandicarboxamide core moiety (9, 10) increases antiproliferative activity as well as selectivity against certain tumor cell lines in comparison with amidino-substituted furan-mono-carboxamide (5, 6). Unlike the furan series where iso-propyl substituted amidine (10) exhibits more potent overall antiproliferative activity and selectivity toward certain cell lines, the same was found for unsubstituted amidines in pyridine series. Amongst all tested compounds the compound 10 is the only one that possesses antiproliferative activity against SW 620 cell line (4 μM). Spectroscopic studies of the interactions of prepared diamidines with double-stranded DNA and RNA polynucleotides show that all compounds preferentially bind into the minor groove of DNA, while most of them intercalate into RNA. The structure-dependant biological activity and the lack of DNA/RNA selective binding suggest that the mechanism of action of the here-presented compounds is controlled not only by the interactions with cellular nucleic acids, but also with other more specific protein targets.

Newly synthesized conformationally restricted derivatives of pentamidine showed significant interactions with polynucleotides, as well as interesting antiproliferative activities. Compound 10 was the only one that possesses antiproliferative activity against SW 620 cell line (4 μM).Figure optionsDownload as PowerPoint slideHighlights
► Novel amidino-substituted derivatives of pentamidine was synthesized.
► Antiproliferative activity against several human cancer cell lines were determined.
► Furan and pyridine derivatives exhibit potent antiproliferative activity and selectivity.
► All compounds bind into the minor groove of DNA, but most of them intercalate into RNA.
► Mechanism of biological action controlled by the interactions with cellular DNA and more specific protein targets.