Synthesis and interaction with human serum albumin of the first 3,18-disubstituted derivative of bilirubin
Addition of excess (>500 equiv.) of p-fluorothiophenol to bilirubin in the presence of toluene-p-sulfonic acid catalyst afforded 3,18-didevinyl-3,18-bis[2-(p-fluorothiophenyl)ethyl] bilirubin 2 from anti-Markovnikov addition to both the exo and endo vinyl groups of bilirubin. Toluene-p-sulfonic acid is not essential as p-fluorothiophenol acts as the acid and nucleophile in the reaction. In contrast, in the presence of toluene-p-sulfonic acid, regioselective Markovnikov addition of thioacetic S-acid to the exo vinyl group occurs, in agreement with previous studies of the addition of a range of oxygen and sulfur nucleophiles to bilirubin (P. Manitto and D. Monti, Experientia, 1973, 29, 137). Binding of 2 to human serum albumin was measured by circular dichroism. The two bulky p-fluorothiophenyl groups do not appear to impede interaction with the protein. This result supports a model in which the reactive methylene bridge of bilirubin, that connects rings B and C, points into the binding pocket of human serum albumin.