Synthesis of a new lipophilic bilirubin. Conformation, transhepatic transport and glucuronidation

Analogs of symmetrical bilirubin isomers with vinyl groups replaced by n-bu tyls (1 and 2) were synthesized and found to be much more soluble in nonpol ar solvents than either bilirubin itself or its analogs with ethyls in plac e of vinyls (3 and 4). The increased Lipophilicity of 1 and 2 allowed, for the first time, vapor pressure osmometric molecular wt, determinations of a bilirubin acid, showing in CHCl3 solvent: MWobs=632+/-10 for 1, and 637+/- 10 for 2 (both formula weight 644)-data that clearly indicate monomers and no dimers. The induced circular dichroism (ICD) spectra of 1 and 2, with ne gative exciton chirality Cotton effects, are quite like those of 3 and 4 in chloroform containing quinine, but the ICDs in aqueous buffer containing h uman serum albumin differ considerably. Rubins 1, 3 and 4 exhibit dissimila r but positive exciton chirality Cotton effects, while 2 shows a negative e xciton chirality Cotton effect. The metabolism of the n-butyl rubins in the rat is highly dependent on the specific endo or exo location of the n-buty l groups. Rubin 2, with two endo n-butyl groups was metabolized rather like the corresponding mesobilirubin (4) or natural bilirubin itself, being con verted to a mono and diglucuronide that were excreted promptly in bile. The presence of the bulky endo-n-butyl groups and the high lipophilicity of th e compound seemed to interfere with glucuronidation in the liver only sligh tly. In contrast, the similar, yet even more lipophilic n-butyl rubin 1, wh ich has two exo n-butyl groups, was glucuronidated and excreted in bile in the rat rather poorly. (C) 2000 Elsevier Science Ltd. All rights reserved.