Probing the Structural Properties of DNA/RNA Grooves with Sterically Restricted Phosphonium Dyes: Screening of Dye Cytotoxicity and Uptake

Authors

  • Dr. Ivo Crnolatac,

    1. Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, PO Box 180, 10002 Zagreb (Croatia)
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  • Dr. Lidija-Marija Tumir,

    1. Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, PO Box 180, 10002 Zagreb (Croatia)
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  • Nedyalko Y. Lesev,

    1. Faculty of Chemistry, University of Sofia, J. Bourchier Avenue, 1164 Sofia (Bulgaria)
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  • Dr. Aleksey A. Vasilev,

    1. Faculty of Chemistry, University of Sofia, J. Bourchier Avenue, 1164 Sofia (Bulgaria)
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  • Prof. Todor G. Deligeorgiev,

    1. Faculty of Chemistry, University of Sofia, J. Bourchier Avenue, 1164 Sofia (Bulgaria)
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  • Dr. Katarina Mišković,

    1. Department of Medicinal Chemistry and Biochemistry, Clinical Institute of Nuclear Medicine and Radiation Protection, School of Medicine, University Hospital Centre Osijek, 31000 Osijek (Croatia)
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  • Prof. Ljubica Glavaš-Obrovac,

    1. Department of Medicinal Chemistry and Biochemistry, Clinical Institute of Nuclear Medicine and Radiation Protection, School of Medicine, University Hospital Centre Osijek, 31000 Osijek (Croatia)
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  • Dr. Oliver Vugrek,

    1. Division of Molecular Medicine, Ruđer Bošković Institute, PO Box 180, 10002 Zagreb (Croatia)
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  • Dr. Ivo Piantanida

    Corresponding author
    1. Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, PO Box 180, 10002 Zagreb (Croatia)
    • Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, PO Box 180, 10002 Zagreb (Croatia)
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Abstract

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.

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