OXIDATION OF THE PHOSPHINE FROM THE AURANOFIN ANALOG, -O-ACETYL-1-THIO-BETA-D-GLUCOPYRANOSATO-S)GOLD(I), VIA A PROTEIN-BOUND PHOSPHONIUM INTERMEDIATE

The reactions of serum albumin, a blood carrier of gold(I), with the a uranofin analogue a-Q-acetyl-1-thio-beta-D-glucopyranosato-S)gold(I) ( i-Pr3PAuSATg) and free triisopropylphosphine have been studied in buff ered aqueous solution using {H-1}P-31 NMR and chromatographic methods. Triisopropylphosphine (i-Pr3P) is oxidized to i-Pr3PS Via an albumint hiolatotriisopropylphosphonium ion, i-Pr3p+SCH2(HSCH2)Alb, which is fo rmed by attack on a protein disulfide bond. This species is the key in termediate in the albumin-driven conversion of a phosphine ligand (e.g ., from auranofin or an analogue) into phosphine oxide or phosphine su lfide. i-Pr3p+SCH2-(HSCH2)Alb, which is characterized by a P-31 NMR ch emical shift of 75.4 ppm, forms quickly and then reacts slowly (k(obs) = (6.9 +/- 0.6) x 10(-5) s-1) to form i-Pr3PS and a small quantity of i-Pr3PO. The auranofin analogues i-Pr3PAuSATg and i-Pr3PAuCl, react w ith serum albumin at cysteine-34 to form AlbSAuPi-Pr3 via displacement of the anions. i-Pr3PAuCl reacts further at weak binding sites analog ous to the histidine binding sites of auranofin. In contrast to the di splacement of Et3P from AlbSAuPEt3 by thiols, cyanide is required to d isplace i-Pr3P from AlbSAuPi-Pr3. The liberated i-Pr3P also reacts via the alubminphosphonium intermediate described above to form i-P3PS an d traces of i-P3PO. In order to interpret the protein studies, a varie ty of potential reaction products (i-Pr3PAuX, X = CN, ATgS, Cl; i-Pr3P Y, Y = O, S) were prepared and characterized by P-31 NMR spectroscopy. Model reactions of i-Pr3PAuX (X = Cl, ATgS) with cyanide are also rep orted.