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Phosphorus–nitrogen compounds part 33: in vitro cytotoxic and antimicrobial activities, DNA interactions, syntheses, and structural investigations of new mono(4-nitrobenzyl)spirocyclotriphosphazenes

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Abstract

The condensation reactions of hexachlorocyclotriphosphazene, N3P3Cl6, with N-alkyl-N′-mono(4-nitrobenzyl)diamines (1–3), NO2PhCH2NH(CH2) n NHR1 (R1 = CH3 or C2H5), led to the formation of the mono(4-nitrobenzyl)spirocyclotriphosphazenes (4–6). The tetra-pyrrolidino (4a–6a), piperidino (4b–6b), and 1,4-dioxa-8-azaspiro[4,5]decaphosphazenes (4c–6c) were prepared from(for) the reactions of partly substituted compounds (4, 5, and 6) with excess pyrrolidine, piperidine, and 1,4-dioxa-8-azaspiro[4,5]decane (DASD), respectively. The partly substituted geminal (4d and 5d) and cis-morpholino (6d) phosphazenes were isolated from the reactions of excess morpholine in boiling THF and o-xylene, but the expected fully substituted compounds were not obtained. The structures of all the phosphazene derivatives were determined by elemental analyses, MS, FTIR, 1H, 13C{1H}, 31P{1H} NMR, HSQC, and HMBC techniques. The crystal structures of 4, 6, 4a, and 5a were verified by X-ray diffraction analysis. In addition, in vitro cytotoxic activities of fully substituted phosphazenes (4a–6c) against HeLa cervical cancer cell lines (ATCC CCL-2) and the compounds 4a and 4c against breast cancer cell lines (MDA-MB-231) and L929 fibroblast cells were evaluated, respectively. Apoptosis effect was determined by MDA-MB-231 cancer cell lines and fibroblast cells. The MIC values of the compounds were in the ranges of 9.8–19.5 µM. The compounds 6, 5a, 6a, 5b, and 6d have greater MIC activity against bacterial and yeast strain. The investigation of DNA binding with the phosphazenes was studied using plasmid DNA. The phosphazene derivatives inhibit the restriction endonuclease cleavage of plasmid DNA by BamHI and HindIII enzymes. BamHI and HindIII digestion results demonstrate that the compounds bind with G/G and A/A nucleotides.

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Acknowledgments

The authors acknowledge the “Ankara University, Scientific Research Unit” Grant No. 09B4240006. T. H. is grateful to Hacettepe University Scientific Research Project Unit (Grant No. 013 D04 602 004) and Z. K. thanks the Turkish Academy of Sciences (TÜBA) for partial support of this work.

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Authors and Affiliations

  1. Department of Chemistry, Ankara University, 06100, Ankara, Turkey

    Aytuğ Okumuş & Zeynel Kılıç

  2. Department of Chemistry, Gaziosmanpaşa University, 60150, Tokat, Turkey

    Hüseyin Akbaş

  3. The Turkish Sugar Authority, 06510, Ankara, Turkey

    L. Yasemin Koç

  4. Department of Biology, Gazi University, 06500, Ankara, Turkey

    Leyla Açık & Betül Aydın

  5. Department of Bioengineering, Kırıkkale University, Kirikkale, Turkey

    Mustafa Türk

  6. Department of Physics, Hacettepe University, 06800, Ankara, Turkey

    Tuncer Hökelek

  7. Department of Chemistry, Anadolu University, 26470, Eskisehir, Turkey

    Hakan Dal

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  1. Aytuğ Okumuş
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Correspondence to Zeynel Kılıç.

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Okumuş, A., Akbaş, H., Kılıç, Z. et al. Phosphorus–nitrogen compounds part 33: in vitro cytotoxic and antimicrobial activities, DNA interactions, syntheses, and structural investigations of new mono(4-nitrobenzyl)spirocyclotriphosphazenes. Res Chem Intermed 42, 4221–4251 (2016). https://doi.org/10.1007/s11164-015-2271-3

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