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Lipid- and water-soluble bilirubins

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Abstract

Novel bilirubin analogs with two nonionic, water-solubilizing polyethyleneglycol (PEG) β-substituents of varying chain length on the lactam ring of each dipyrrinone were synthesized. In contrast to bilirubin, which is insoluble in CH3OH and in H2O at pH 7 but somewhat soluble in CHCl3 (~1 mM), the PEGylated rubins are soluble in all three solvents, with H2O solubility increasing with increasing number of ethyleneglycol units in the PEG chain(s). Vapor pressure osmometry indicates that, like bilirubin, they are monomeric in CHCl3 and in CH3OH. Nuclear magnetic resonance (NMR) studies indicate that their most stable structure in these solvents and in H2O has the 4Z,15Z configuration that is bent into a ridge-tile shape with the pigment’s dipyrrinones engaged in intramolecular hydrogen bonding to the propionic acid carboxyl groups. Aqueous pK a values for the intramolecularly hydrogen-bonded carboxyl groups of these compounds, determined by vacuum-assisted multiplexed capillary electrophoresis in H2O–CH3OH mixtures followed by Yesuda-Shedlovsky extrapolations to pure H2O, were found to be 4.9, as previously determined by NMR titrations for mesobilirubin-XIIIα.

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Acknowledgments

We thank the US National Institutes of Health (HD 17779) for generous support of this work and the National Science Foundation (CHE-0521191) for providing funding for acquisition of a 400-MHz NMR spectrometer and upgrade of our 500-MHz NMR. We thank Prof. A.F. McDonagh (Univ. California, San Francisco) for running the HPLCs of 1–4. We also thank Prof. T.W. Bell for use of the VPO apparatus and Dr. Stephen Spain for assistance with the water-suppression NMR experiments. We thank Ms. Jolanta Plewa and Dr. Christopher Welch of Merck Research Labs for the VAMCE measurements of pK a.

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  1. Department of Chemistry, University of Nevada, Reno, NV, 89557-0216, USA

    Sanjeev K. Dey & David A. Lightner

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  1. Sanjeev K. Dey
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  2. David A. Lightner
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Correspondence to David A. Lightner.

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Dey, S.K., Lightner, D.A. Lipid- and water-soluble bilirubins. Monatsh Chem 141, 101–109 (2010). https://doi.org/10.1007/s00706-009-0232-5

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