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    DNA-binding studies of AV-153, an antimutagenic and DNA repair-stimulating derivative of 1,4-dihydropiridine.
    Chem Biol Interact 2014 Sep 10;220:200-7. Epub 2014 Jul 10.
    Department of Medical Biochemistry, Faculty of Medicine, University of Latvia, No. 4 Kronvalda Boulevard, Riga LV-1010, Latvia; Latvian Institute of Organic Synthesis, No. 21 Aizkraukles Street, Riga LV-1006, Latvia. Electronic address:
    Unlabelled: The ability to intercalate between DNA strands determines the cytotoxic activity of numerous anticancer drugs. Strikingly, intercalating activity was also reported for some compounds considered to be antimutagenic. The aim of this study was to determine the mode of interaction of DNA with the antimutagenic and DNA repair-stimulating dihydropyridine (DHP) AV-153. DNA and AV-153 interactions were studied by means of UV/VIS spectroscopy, fluorimetry and infrared spectroscopy. Compound AV-153 is a 1,4 dihydropyridine with ethoxycarbonyl groups in positions 3 and 5. Computer modeling of AV-153 and DNA interactions suggested an ability of the compound to dock between DNA strands at a single strand break site in the vicinity of two pyrimidines, which was confirmed in the present study. AV-153 evidently interacted with DNA, as addition of DNA to AV-153 solutions resulted in pronounced hyperchromic and bathochromic effects on the spectra. Base modification in a plasmid by peroxynitrite only minimally changed binding affinity of the compound; however, induction of single-strand breaks using Fenton's reaction greatly increased binding affinity. The affinity did not change when the ionic strength of the solution was changed from 5 to 150 mM NaCl, although it increased somewhat at 300 mM. Neither was it influenced by temperature changes from 25 to 40°C, however, it decreased when the pH of the solution was changed from 7.4 to 4.7. AV-153 competed with EBr for intercalation sites in DNA: 116 mM of the compound caused a two-fold decrease in fluorescence intensity. FT-IR spectral data analyses indicated formation of complexes between DNA and AV-153. The second derivative spectra analyses indicated interaction of AV-153 with guanine, cytosine and thymine bases, but no interaction with adenine was detected.

    Conclusions: The antimutagenic substance AV-153 appears to intercalate between the DNA strands at the site of a DNA nick in the vicinity of two pyrimidines.

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