• Open Access

High Cytotoxic Activity of Phosphonium Salts and Their Complementary Selectivity towards HeLa and K562 Cancer Cells: Identification of Tri-n-butyl-n-hexadecylphosphonium bromide as a Highly Potent Anti-HeLa Phosphonium Salt

Authors

  • Dr. Barbara Bachowska,

    1. Institute of Chemistry, Environmental Protection and Biotechnology, Jan Długosz University in Częstochowa, Armii Krajowej 13/15, 42-200 Częstochowa (Poland)
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  • Julia Kazmierczak-Baranska,

    1. Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łódź (Poland)
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  • Dr. Marcin Cieslak,

    1. Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łódź (Poland)
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  • Prof. Barbara Nawrot,

    1. Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łódź (Poland)
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  • Dorota Szczęsna,

    1. Department of Heteroorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łódź (Poland)
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  • Joanna Skalik,

    1. Department of Heteroorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łódź (Poland)
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  • Prof. Piotr Bałczewski

    Corresponding author
    1. Institute of Chemistry, Environmental Protection and Biotechnology, Jan Długosz University in Częstochowa, Armii Krajowej 13/15, 42-200 Częstochowa (Poland)
    2. Department of Heteroorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łódź (Poland)
    • Institute of Chemistry, Environmental Protection and Biotechnology, Jan Długosz University in Częstochowa, Armii Krajowej 13/15, 42-200 Częstochowa (Poland)
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Abstract

Quaternary ammonium and phosphonium salts have been screened for their toxic effect on HeLa and K562 cancer cell lines, as well as on normal HUVEC cells. Tri-n-butyl-n-hexadecylphosphonium bromide, the first phosphonium salt with a halogen anion tested against HeLa cells, was 12 times more potent (IC50 <5 μM after 24 and 48 h) than the clinically used reference compound cisplatin and 17 times more potent than tri-n-hexyltetradecylphosphonium bis(trifluoromethylsulfonyl)imide, which, to the best of our knowledge, is the first phosphonium salt to be evaluated in HeLa cells. However, it was inactive against K562 cells (24 and 48 h). According to a caspase-3/7 assay, its toxicity has not been connected with the induction of apoptosis. In contrast, triphenylalkylphosphonium iodides with shorter C1–5 alkyl chains were inactive against HeLa cells but very active against K562 cells (IC50=6–10 μM after 48 h). Phosphonium cations with halide counterions proved to be more potent than those with (CF3SO2)2N as the anion, as in the anticancer agent NSC 747251, or other anions in molecules with similar alkyl chain lengths. On the other hand, a series of ammonium salts containing a short methylthiomethyl or methoxymethyl side chain revealed low cytotoxicity (IC50 >500 μM after 24 and 48 h) against both HeLa and K562 cancer cell lines as well as normal HUVEC cells, showing that the nontoxic N+CH2YMe (Y=S, O) structural motif in ammonium salts could be suitable for further optimization and development, especially in transfection experiments.

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