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), was synthesized from 8-(2-carboxyethyl)-2,3-diethyl-7-methyl-10H-dipyrrin-1-one in one step by reaction with sulfur dichloride. The thia-rubin exhibited the expected IR, UV-vis, and NMR spectroscopic properties, which are rather similar to those of mesobilirubin-XIIIalpha. Like bilirubin and mesobilirubin, 1 adopts an intramolecularly hydrogen-bonded conformation, shaped like a ridge-tile but with a steeper pitch. The longer C-S bond lengths and smaller bond angles at C-S-C, as compared to C-CH(2)-C, lead to an interplanar angle between the two dipyrrinones of only 74 degrees -or considerably less than that of bilirubin (approximately 100 degrees). On normal- and reversed-phase chromatography, 1 is substantially less polar than bilirubin. Despite this conformational distortion, 1 is metabolized in normal rats to acyl glucuronides, which are secreted into bile. In mutant (Gunn) rats lacking bilirubin glucuronosyl transferase, 1 (like bilirubin) was not excreted in bile.
Tipton
A K
AK
Department of Chemistry, University of Nevada, Reno, NV 89557-0020, USA.
Lightner
D A
DA
McDonagh
A F
AF
D000818:Animals; D001663:Bilirubin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D011911:Rats, Gunn; D012995:Solubility; D013057:Spectrum Analysis
C429064:8,12-bis(2-carboxyethyl)-2,3,17,18-tetraethyl-7,13-dimethyl-10-thia-(21H,23H,24H)-bilin-1,19-dione; D001663:Bilirubin