Permanent positive charge strongly influences DNA/RNA binding and antiproliferative activity of urea–phenanthridinium conjugates

An introduction of the permanent positive charge by methylation of heterocyclic nitrogen on a series of previously studied bis-urea phenanthridine derivatives substantially changed their interactions with DNA and RNA as well as biological activity. At variance to non-methylated analogues, novel methylated derivatives interacted with DNA/RNA not only at pH 5 but also at pH 7, and some compounds switched the DNA binding mode from the minor groove binding (non-methylated derivatives) to the intercalation (novel, methylated derivatives). Moreover, selective ds-RNA over ds-DNA thermal stabilization of previously observed non-methylated derivatives was reversed for novel, methylated derivatives. The variation of a linker length connecting two urea–phenanthridinium conjugates regulated their binding modes toward double stranded polynucleotides. All novel compounds were able to distinguish between polynucleotides of A–T(U) and G–C basepair composition by a specific fluorescence change. Moreover, the introduction of the permanent positive charge on the phenanthridinium moiety resulted in significantly higher biological potency in respect to non-methylated analogues.

Graphical abstractA methylation of heterocyclic nitrogen on a previously studied bis-urea phenanthridines substantially changed their interactions with DNA, RNA and biological activity. Novel compounds act as basepair selective fluorescence probes.Figure optionsDownload full-size imageDownload as PowerPoint slide