Seleno-Auranofin (Et3PAuSe-tagl): Synthesis, Spectroscopic (EXAFS, 197Au Mössbauer, 31P, 1H, 13C, and 77Se NMR, ESI-MS) Characterization, Biological Activity, and Rapid Serum Albumin-Induced Triethylphosphine Oxide Generation

• Published in: Inorganic chemistry Vol. 49; no. 17; pp. 7663 - 7675
• Main Authors: Hill, David T, Isab, Anvarhusein A, Griswold, Don E, DiMartino, Michael J, Matz, Elizabeth D, Figueroa, Angel L, Wawro, Joyce E, DeBrosse, Charles, Reiff, William M, Elder, Richard C, Jones, Benjamin, Webb, James W, Shaw, C. Frank
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 06.09.2010
• Subjects: Animals; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Antirheumatic Agents - chemical synthesis; Antirheumatic Agents - chemistry; Antirheumatic Agents - pharmacology; Antirheumatic Agents - therapeutic use; Auranofin - chemical synthesis; Auranofin - chemistry; Auranofin - pharmacology; Auranofin - therapeutic use; Edema - drug therapy; Inflammation - drug therapy; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred BALB C; Rats; Selenium - chemistry; Selenium - pharmacology; Selenium - therapeutic use; Serum Albumin - metabolism; Spectrometry, Mass, Electrospray Ionization; Spectroscopy, Mossbauer
• ISSN: 0020-1669; 1520-510X
• DOI: 10.1021/ic902335z

Seleno-auranofin (SeAF), an analogue of auranofin (AF), the orally active antiarthritic gold drug in clinical use, was synthesized and has been characterized by an array of physical techniques and biological assays. The Mössbauer and extended X-ray absorption fine structure (EXAFS) parameters of the solid compound demonstrate a linear P−Au−Se coordination environment at a gold(I) center, analogous to the structure of auranofin. The 31P, 13C, and 1H NMR spectra of SeAF in chloroform solution closely resemble those of auranofin. The 77Se spectrum consists of a singlet at 481 ppm, consistent with a metal-bound selenolate ligand. The absence of 2JPSe coupling in the 31P and 77Se spectra may arise from dynamic processes occurring in solution or because the 2JPSe coupling constants are smaller than the observed bandwidths. Electrospray ionization mass spectrometry (ESI-MS) spectra of SeAF in 50:50 methanol−water exhibited strong signals for [(Et3P)2Au]+, [(Et3PAu)2-μ-Se-tagl]+, and [Au(Se-tagl)2]−, which arise from ligand scrambling reactions. Three assays of the anti-inflammatory activity of SeAF allowed comparison to AF. SeAF exhibited comparable activity in the topically administered murine arachadonic acid-induced and phorbol ester-induced anti-inflammatory assays but was inactive in the orally administered carragenan-induced assay in rats. However, in vivo serum gold levels were comparable in the rat, suggesting that differences between the in vivo metabolism of the two compounds, leading to differences in transport to the inflamed site, may account for the differential activity in the carrageenan-induced assay. Reactions of serum albumin, the principal transport protein of gold in the serum, demonstrated formation of AlbSAuPEt3 at cysteine 34 and provided evidence for facile reduction of disulfide bonds at cysteine 34 and very rapid formation of Et3PO, a known metabolite of auranofin.