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Anticancer Activity and Topoisomerase II Inhibition of Naphthalimides with ω-Hydroxylalkylamine Side-Chains of Different Lengths

Author(s):

Mateusz D. Tomczyk, Anna Byczek Wyrostek, Klaudia Strama, Martyna Wawszków, Przemysław Kasprzycki and Krzysztof Z. Walczak*   Pages 1 - 10 ( 10 )

Abstract:


Background: The substituted 1,8-Naphthalimides (1H-benzo[de]isoquinoline-1,3(2H)- diones) are known as DNA intercalators stabilizing DNA-Topoisomerase II complexes. This interaction disrupts the cleavage-relegation equilibrium of Topo II, resulting in formation of broken strands of DNA.

Objective: To study the influence of type of substituent and substitution position in 1,8- naphthalimde skeleton on inhibition of Topoisomerase II activity.

Method: The starting 1,8-naphthalimide was prepared from acenaphthene by introduction of appropriate substituents followed by condensation with ω-hydroxylakylamines of different chain length. The substituent were introduced to 1,8-naphthalimide molecule by nucleophilic substitution of leaving groups like nitro or bromo present in 4 or 4,5- position using the ω- hydroxylalkylamines. The bioactivity of obtained compounds was examined in model cell lines.

Results: Antiproliferative activities of selected compounds against HCT 116 human colon cancer cells, human non-small cell lung cells A549 and non-tumorigenic BEAS-2B human bronchial epithelium cells was examined. Several of investigated compounds exhibit a significant activity (IC50 μM to 7 μM) against model tumour lines. It was demonstrated that upon treatment with concentration of 200 μM, all derivatives display Topo II inhibitory activity, which may be compared with activity of Amonafide.

Conclusion: The replacement of the nitro groups in the chromophore slightly reduces its anticancer activities, whereas the presence of both nitro group and ω-hydroxylalkylamine chain resulted in seriously increased anticancer activities. Obtained compounds showed Topo II inhibitory activity, moreover, influence of the substitution pattern on the ability to inhibit Topo II activity and cancer cells proliferation was observed.

Keywords:

Naphthalimide, Amonafide, Mitonafide, Anticancer, Topoisomerase II, DNA intercalator

Affiliation:

Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Faculty of Chemistry, Silesian University of Technology, Krzywoustego 4, 44-100 Gliwice, Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Faculty of Chemistry, Silesian University of Technology, Krzywoustego 4, 44-100 Gliwice, Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Faculty of Chemistry, Silesian University of Technology, Krzywoustego 4, 44-100 Gliwice, Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Faculty of Chemistry, Silesian University of Technology, Krzywoustego 4, 44-100 Gliwice, Avantor Performance Materials Poland S.A., ul. Sowińskiego 11, 44-101 Gliwice, Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Faculty of Chemistry, Silesian University of Technology, Krzywoustego 4, 44-100 Gliwice



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