Aromatic congeners of bilirubin: synthesis, stereochemistry, glucuronidation and hepatic transport

A new synthetic analog (1) of the bile pigment bilirubin-IX alpha (bilirubi n, Fig. 1) with phenyl groups replacing vinyl was prepared by a constitutio nal scrambling reaction of a mixture of two new, symmetric phenylrubin anal ogs (2 and 3) of bilirubin-XIII alpha and III alpha. The former (2) with tw o endo-phenyls, and the latter (3) with two exo-phenyls were synthesized by condensation of a dipyrrylmethane dialdehyde with appropriate methylphenyl pyrrolinones, which were prepared in several steps from 4-methyl-3-phenyl-2 -(p-toluenesulfonyl)pyrrole, obtained by the Barton-Zard pyrrole synthesis. Nuclear Overhauser effect H-1 NMR studies of 1-3 confirm that, like their bilirubin equivalents, these yellow-orange pigments adopt an intramolecular ly hydrogen-bonded ridge-tile conformation. Reverse phase HPLC and TLC sugg est that 3 is less polar than 2, and that I has intermediate polarity. Larg e differences in the induced circular dichroism spectra of 1-3 were found i n pH 7.4 aqueous buffered solutions of human serum albumin. Despite the presence of bulky, lipophilic phenyl groups, 1-3 are metabolize d like natural bilirubin in rats and require glucuronidation by the same en zyme for canalicular secretion from the liver into bile. However, there are striking qualitative differences between the three pigments in the ratio o f mono- to diglucuronides formed. Phenyl substituents at the exo positions of the lactam rings diminish the proportion of diglucuronide more than phen yl substituents at the endo positions. (C) 2001 Elsevier Science Ltd. All r ights reserved.