Gold(III) bis-thiosemicarbazonato complexes: synthesis, characterization, radiochemistry and X-ray crystal structure analysis

Introduction: A variety of (bis)thiosemicarbazone-based ligand systems have been investigated as chelating agents for Au(III) complexes with potential radiotherapeutic applications. Ligand systems containing an ethyl, propyl or butyl backbone between the two imine N donors have been synthesized to evaluate chelate ring size effects on the resultant Au(III) complex stability at the macroscopic and radiotracer levels. Methods: The Au(III) complexes were synthesized and characterized by NMR, electrospray ionization mass spectra, elemental analysis and X-ray crystallography. The ¹⁹⁸Au complexes were evaluated in vitro at the tracer level for stability in phosphate-buffered saline at pH 7.4 and 37°C. One of these complexes [¹⁹⁸Au(3,4-HxTSE)] showed high in vitro stability and was further evaluated in vivo in normal mice. Results: [Au(ATSM)]AuCl₄·2CH₃OH, (ATSM=diacetyl-bis(N⁴-methylthiosemicarbazone)) H₁₄C₈N₆O₂S₂Cl ₄Au₂·2CH₃OH, crystallized from methanol in the monoclinic space group P21/n with a=14.7293(13) Å, b=7.7432(7) Å, c=20.4363(18) Å, β=100.140(2)°, V=2294.4 (4) ų, Z=4; [Au(3,4-HxTSE)]Cl·CH₃CH₂OH/AuCl₂ , (3,4-HxTSE=3,4-hexanedione-bis(N⁴-ethylthiosemicarbazone)) H₂₆C_13.6N₆O_0.8S₂C l_1.2Au_1.2, crystallized from ethanol in the monoclinic space group P21/c with a=10.1990(10) Å, b=13.8833(14) Å, c=15.1752(15) Å, β=99.353(2)°, V=2120.2 (4) ų, Z=4. Conclusions: These studies revealed poor stability of the [¹⁹⁸Au][Au(3,4-HxTSE)]⁺ complex; however, crystal structure data suggest potential alterations to the ligand backbone may increase stability.