Boronated phosphonium salts containing arylboronic acid, closo-carborane, or nido-carborane: synthesis, X-ray diffraction, in vitro cytotoxicity, and cellular uptake

• Published in: Journal of biological inorganic chemistry 2010-11, Vol.15 (8), p.1305-1318
• Main Authors: Morrison, Daniel E, Issa, Fatiah, Bhadbhade, Mohan, Groebler, Ludwig, Witting, Paul K, Kassiou, Michael, Rutledge, Peter J, Rendina, Louis M
• Format: Article
• Language: English
• Subjects: Animals; Biochemistry; Biomedical and Life Sciences; Boron Compounds - chemical synthesis; Boron Compounds - chemistry; Boron Compounds - pharmacology; Boron neutron capture therapy; Boronic acid; Carborane; Cell Line; Cell Survival - drug effects; Crystallography, X-Ray; Dogs; Dose-Response Relationship, Drug; Epithelial Cells - drug effects; Humans; Kidney - cytology; Life Sciences; Microbiology; mitochondria; Models, Molecular; Molecular Conformation; Organophosphorus Compounds - chemical synthesis; Organophosphorus Compounds - chemistry; Organophosphorus Compounds - pharmacology; Original Paper; Phosphonium salt; Salts - chemical synthesis; Salts - chemistry; Salts - pharmacology; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0949-8257; 1432-1327
• DOI: 10.1007/s00775-010-0690-6

The preparation of boronated triaryl and tetraaryl phosphonium salts of the type [PPh₃CH₂R]Br [R is 4-boronophenyl (1), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-yl)phenyl (2), 3-boronophenyl (3), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-yl)phenyl (4), 2-boronophenyl (5), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-yl)phenyl (6), and closo-1,2-carboran-1-yl (7)] is described. These compounds were prepared by the reaction of triphenylphosphine with benzylic bromides or 1-bromomethyl-closo-1,2-carborane in acetonitrile solution at 85 °C. The zwitterionic nido-7,8-carborane derivative PPh₃CH₂C₂B₉H₁₁ (8) was prepared by treatment of 7 with cesium fluoride in refluxing ethanol. All compounds were fully characterized by multinuclear (¹H, ¹¹B, ¹³C, and ³¹P) 1D- and 2D-NMR spectroscopy, electrospray ionization mass spectrometry, and elemental analysis, and single-crystal X-ray structures were determined for compounds 1, 3, 7, and 8. The cytotoxicities and boron uptake of selected derivatives were investigated in vitro using human glioblastoma (T98G) and canine kidney tubule (MDCK II) cells. The zwitterionic species 8 was found to be the least cytotoxic agent while also delivering the greatest amount of boron to the T98G cells, peaking at 9.15 ± 2.65 μg B/mg protein.