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.

Tuning the Hydrophobicity of a Mitochondria‐Targeted NO Photodonor

“…Reference 2 did not show any toxicity in the dark, unlike 13 , which was not significantly toxic up to a concentration of 5 μ m and then showed enhanced toxicity with increasing concentration (data not shown). This is in keeping with the finding that phosphonium salts can display toxic activity toward cancer cell lines . When irradiated at 5 μ m , 2 did not show any toxicity, unlike 13 , which was markedly more toxic, in keeping with its accumulation into mitochondria (Figure ).…”

“…This is in keeping with the finding that phosphonium salts can display toxic activity toward cancerc ell lines. [33] When irradiated at 5 mm, 2 did not show any toxicity, unlike 13,w hichw as markedlym ore toxic, in keepingw ith its accumulationi nto mitochondria ( Figure 5).…”

An Amphiphilic Ruthenium Polymetallodrug for Combined Photodynamic Therapy and Photochemotherapy In Vivo

“…These cancer cell lines are commonly used as models to evaluate anticancer activities of new anticancer materials . We observed that the half‐maximal inhibitory concentration (IC 50 ) of 2 for HeLa cells was 25 µg mL −1 , which is comparable with the IC 50 of the commercial metallodrug cisplatin (16.5 µg mL −1 ). Red light irradiation enhanced the anticancer effect of 2 : the IC 50 value of 2 for HeLa cells after irradiation was as low as 2.5 µg mL −1 .…”

Mechanisms of action of ionic liquids on living cells: the state of the art

“…Apart from few very ad hoc “system biology” studies, as the one just mentioned, there are several studies highlighting the specificity of ILs towards cancer cells and their ability to kill those cells, leaving healthy cells almost unaffected (Kumar and Malhotra 2009 ; Malhotra and Kumar 2010 ; Wang et al 2015 ; Stromyer et al 2020 ). In this context, it has been shown, for example, that tri- n -butyl- n -hexadecyl-phosphonium bromide—a phosphonium-based IL with a halogen anion and balanced lengths of C 4 and C 16 alkyl chains—is approximately 100 times more toxic against HeLa cells than several ammonium-based ILs, but it remains inactive against human chronic myelogenous leukemia K562 cells; complementarily, triphenyl-alkyl-phosphonium iodides, with shorter C 1 and C 5 alkyl chains, resulted to be inactive against HeLa cells, but very active against K562 cells (Bachowska et al 2012 ). More recently, (i) a novel betulinic acid–derived IL, i.e., [P 6,6,6,14 ][BA], has shown a specific cytotoxicity against human hepatocellular carcinoma HepG2 and human lung carcinoma A459 tumor cell lines (Silva et al 2019 ), and (ii) a new imidazolium IL with a triphenylphosphonium substituent, applied intravesically to mouse, has selectively killed bladder cancer cells, leaving adjacent healthy cells unaffected (Stromyer et al 2020 ).…”