Oxidation of the Phosphine from the Auranofin Analog, Triisopropylphosphine(2, 3, 4, 6-tetra-O-acetyl-1-thio-β-D-glucopyranosato-S)gold(I), via a Protein-Bound Phosphonium Intermediate

The reactions of serum albumin, a blood carrier of gold(I), with the auranofin analogue triisopropylphosphine-(2, 3, 4, 6-tetra-Q-acetyl-l-thio-β-D-glucopyranosato-S)gold(I) (i-Pr₃PAuSATg) and free triisopropylphosphine have been studied in buffered aqueous solution using {₁H}³¹P NMR and chromatographic methods. Triisopropylphosphine (i-Pr₃P) is oxidized to i-Pr₃PS via an albuminthiolatotriisopropylphosphonium ion, i-Pr₃P⁺SCH₂(HSCH₂)Alb, which is formed by attack on a protein disulfide bond. This species is the key intermediate in the albumin-driven conversion of a phosphine ligand (e.g., from auranofin or an analogue) into phosphine oxide or phosphine sulfide. i-Pr₃P⁺SCH₂- (HSCH₂)Alb, which is characterized by a ³¹P NMR chemical shift of 75.4 ppm, forms quickly and then reacts slowly (K_obs= (6.9 ± 0.6) X 10^-5s^-1) to form i-Pr₃PS and a small quantity of i-Pr₃PO. The auranofin analogues i-Pr₃PAuSATg and i-Pr₃PAuCl, react with serum albumin at cysteine-34 to form AlbSAuPi-Pr₃via displacement of the anions. i-Pr₃PAuCl reacts further at weak binding sites analogous to the histidine binding sites of auranofin. In contrast to the displacement of Et₃P from AlbSAuPEt₃by thiols, cyanide is required to displace i-Pr₃P from AlbSAuPz-Pr₃. The liberated i-Pr₃P also reacts via the alubminphosphonium intermediate described above to form i-P₃PS and traces of i-P₃P0. In order to interpret the protein studies, a variety of potential reaction products (i-Pr₃PAuX, X = CN, ATgS, CI; i-Pr₃PY, Y = O, S) were prepared and characterized by ²²P NMR spectroscopy. Model reactions of i-Pr₃PAuX (X = CI, ATgS) with cyanide are also reported.