Biological and structural studies of phosphonium ‘masked thiolate’ compounds

• Published in: European journal of medicinal chemistry Vol. 125; pp. 528 - 537
• Main Authors: Chen, Yu-Su, Allen, David W., Tizzard, Graham J., Pitak, Mateusz B., Coles, Simon J., Cross, Neil A., Bricklebank, Neil
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.01.2017; Elsevier
• Subjects: Cell Line, Tumor; Cell Survival - drug effects; Chemistry, Medicinal; Cytotoxicity; Humans; Hydrogen Bonding; Inhibitory Concentration 50; Life Sciences & Biomedicine; MALDI-TOF-MS; Male; Mitochondria; Models, Molecular; Molecular Structure; Organophosphorus Compounds - analysis; Organophosphorus Compounds - chemistry; Organophosphorus Compounds - pharmacokinetics; Organophosphorus Compounds - toxicity; Pharmacology & Pharmacy; Phosphonium; Prostatic Neoplasms; Science & Technology; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; X-ray crystallography; X-ray crystallography; Cytotoxicity; Mitochondria; MALDI-TOF-MS; Phosphonium; IN-VITRO; LIGANDS; TRIPHENYLPHOSPHONIUM CATIONS; NANOCARRIERS; FLUORINE; CHARGE; DERIVATIZATION
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.08.025

The ability of phosphonium cations to act as intracellular transport vectors is well-established. Phosphonioalkylthiosulfate zwitterions, and ω-thioacetylalkylphosphonium salts, which act as 'masked thiolate' ligands, are useful precursors for the formation of phosphonium-functionalised gold nanoparticles, enabling the nanoparticles to be transported into cells for diagnostic and therapeutic purposes. In this study we have completed cytotoxicity studies of ω-thioacetylpropylphosphonium salts derived from triphenylphosphine and tri(4-fluorophenyl)phosphine, which show that the compounds are only toxic towards PC3 prostate cancer cells at high concentrations and at prolonged incubation periods and display IC50 values of 67 μM and 252 μM respectively, significantly higher than those of other phosphonium salts. MALDI-TOF-MS has been used to investigate the uptake of the compounds by PC3 cells and to quantify detectable levels of the compounds inside the cells. The structures of ω-thioacetylpropyl(tri-4-fluorophenyl) phosphonium bromide and the corresponding tri(4-fluorophenyl)phosphoniopropylthiosulfate zwitterion have been investigated by single crystal X-ray crystallography. The results show that molecules of the zwitterion are held together through an extensive array of electrostatic and non-covalent interactions. The unit cell of ω-thioacetylpropyl(tri-4-fluorophenyl)phosphonium bromide contains eight cations together with eight bromide anions and two waters of crystallisation, all held together through a complex network of hydrogen bonds. The differences in the molecular packing of the two compounds may account for the lower solubility of the zwitterion in aqueous solutions, compared with that of the phosphonium salt. [Display omitted] •Phosphonium salts are synthetically useful intracellular transport vectors.•The cytotoxicity of ω-thioacetylpropylphosphonium salts is reported.•Cellular uptake of the phosphonium salts has been determined using MALDI-TOF-MS.•Crystal structures of tri(4-fluorophenyl)phosphonium compounds are described.