title: 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.
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.
authors.affiliation: Institute of Chemistry, Environmental Protection and Biotechnology, Jan Długosz University in Częstochowa Armii Krajowej 13/15, 42-200 Częstochowa (Poland) E-mail: pbalczew@bilbo.cbmm.lodz.pl.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bachowska
authors.affiliation: Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences Sienkiewicza 112, 90-363 Łódź (Poland).
authors.forename: Julia
authors.initials: J
authors.lastname: Kazmierczak-Baranska
authors.affiliation: Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences Sienkiewicza 112, 90-363 Łódź (Poland).
authors.forename: Marcin
authors.initials: M
authors.lastname: Cieslak
authors.affiliation: Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences Sienkiewicza 112, 90-363 Łódź (Poland).
authors.forename: Barbara
authors.initials: B
authors.lastname: Nawrot
authors.affiliation: Department of Heteroorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences Sienkiewicza 112, 90-363 Łódź (Poland).
authors.forename: Dorota
authors.initials: D
authors.lastname: Szczęsna
authors.affiliation: Department of Heteroorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences Sienkiewicza 112, 90-363 Łódź (Poland).
authors.forename: Joanna
authors.initials: J
authors.lastname: Skalik
authors.affiliation: Institute of Chemistry, Environmental Protection and Biotechnology, Jan Długosz University in Częstochowa Armii Krajowej 13/15, 42-200 Częstochowa (Poland) E-mail: pbalczew@bilbo.cbmm.lodz.pl ; Department of Heteroorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences Sienkiewicza 112, 90-363 Łódź (Poland).
authors.forename: Piotr
authors.initials: P
authors.lastname: Bałczewski
keywords: cancer cells; cytotoxicity; gene delivery; phosphonium cations; transfection