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Probing the structural properties of DNA/RNA grooves by sterically restricted phosphonium dyes ; screening of dye cell toxicity and uptake

To explore in greater detail the recently reported rare kinetic differentiation between homo-polymeric and alternating AT-DNA sequences by using sterically restricted phosphonium dyes that form dimers within the DNA minor groove, new analogues were prepared in which the quinolone phosphonium moiety was kept constant, while the size and hydrogen bonding properties of the rest of the molecule were varied. Structure–activity relationship studies revealed that a slight increase in length by an additional methylene unit results in loss of kinetic AT selectivity, but yielded an AT-selective fluorescence response. These DNA/RNA-groove-bound dyes combine very low cytotoxicity with efficient cellular uptake and intriguingly specific fluorescent marking of mitochondria. In contrast to longer analogues, a decrease in length (by methylene unit removal) and rearrangement of positive charge resulted in dyes that had switched to the intercalative binding mode to GC DNA/dsRNA but that still form dimers in the minor groove of AT sequences, consequently yielding a significantly different chiro-optical response. The latter dyes also revealed strongly selective antiproliferative activity toward HeLa cancer cells.

cellular uptake; circular dichroism; DNA recognition; fluorescence; mitochondria; RNA recognition

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