Synthesis and metabolism of the first thia-bilirubin

A symmetrical C(10)-thiabilirubin analogue, 8,12-bis(2-carboxyethyl)-2,3,17 ,18-tetraethyl-7,13-dimethyl-10-thia-(21H,23H,24H)-bilin-1,19-dione (1), wa s synthesized from 8-(2-carboxyethyl)-2,3-diethyl-7-methyl-10H-dipyrrin-1-o ne in one step by reaction with sulfur dichloride. The thia-rubin exhibited the expected IR, W-vis, and NMR spectroscopic properties, which are rather similar to those of mesobilirubin-XIII alpha. Like bilirubin and mesobilir ubin, 1 adopts an intramolecularly hydrogen-bonded conformation, shaped lik e a ridge-tile but with a steeper pitch. The longer C-S bond lengths and sm aller bond angles at C-S-C, as compared to C-CH2-C, lead to an interplanar angle between the two dipyrrinones of only 74 degrees -or considerably less than that of bilirubin (similar to 100 degrees). On normal- and reversed-p hase chromatography, 1 is substantially less polar than bilirubin. Despite this conformational distortion, 1 is metabolized in normal rats to acyl glu curonides, which are secreted into bile. In mutant (Gunn) rats lacking bili rubin glucuronosyl transferase, 1 (like bilirubin) was not excreted in bile .