Monatshefte für Chemie - Chemical Monthly

, Volume 141, Issue 1, pp 101–109 | Cite as

Lipid- and water-soluble bilirubins

  • Sanjeev K. Dey
  • David A. LightnerEmail author
Original Paper


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.

Graphical abstract


Tetrapyrrole Polyethyleneglycol NMR pKa 



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 14. 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.


  1. 1.
    Chowdhury JR, Wolkoff AW, Chowdhury NR, Arias IM (2001) Hereditary jaundice and disorders of bilirubin metabolism. In: Scriver CF, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, chap 125, McGraw-Hill, New York, pp 3063–3101Google Scholar
  2. 2.
    Lightner DA, McDonagh AF (1984) Acc Chem Res 17:417CrossRefGoogle Scholar
  3. 3.
    McDonagh AF, Lightner DA (1985) Pediatrics 75:443Google Scholar
  4. 4.
    McDonagh AF (1979) Bile pigments: Bilatrienes and 5,15-biladienes. In: Dolphin D (ed) The porphyrins, chap 6, vol VI, Academic Press, New YorkGoogle Scholar
  5. 5.
    Schmid R, McDonagh AF (1978) Hyperbilirubinemia. In: Stanbury JB, Wyngarden JB, Fredrickson DS (eds) Basis of inherited disease, 4th edn. McGraw-Hill, New YorkGoogle Scholar
  6. 6.
    Falk H (1989) The chemistry of linear oligopyrroles and bile pigments. Springer, WienGoogle Scholar
  7. 7.
    Person RV, Peterson BR, Lightner DA (1994) J Am Chem Soc 116:42CrossRefGoogle Scholar
  8. 8.
    Bonnett R, Davies JE, Hursthouse NB, Sheldrick GM (1978) Proc R Soc London Ser B 202:249CrossRefGoogle Scholar
  9. 9.
    LeBas G, Allegret A, Mauguen Y, DeRango C, Bailly M (1980) Acta Crystallogr Sect B 36:3007CrossRefGoogle Scholar
  10. 10.
    Becker W, Sheldrick WS (1978) Acta Crystallogr Sect B 34:1298CrossRefGoogle Scholar
  11. 11.
    Sheldrick WS (1983) Israel J Chem 23:55Google Scholar
  12. 12.
    Sheldrick WS (1976) J Chem Soc Perkin 2, 1457Google Scholar
  13. 13.
    Brodersen R (1986) Aqueous solubility, albumin binding, and tissue distribution of bilirubin. In: Ostrow JD (ed) Bile pigments and jaundice. Marcel Dekker, New York, pp 157–181Google Scholar
  14. 14.
    Brodersen R (1979) J Biol Chem 254:2364Google Scholar
  15. 15.
    Ghosh B, Lightner DA, McDonagh AF (2004) Monatsh Chem 135:1189Google Scholar
  16. 16.
    Xie M, Holmes DL, Lightner DA (1993) Tetrahedron 49:9235CrossRefGoogle Scholar
  17. 17.
    Brower JO, Lightner DA, McDonagh AF (2000) Tetrahedron 56:7869CrossRefGoogle Scholar
  18. 18.
    Boiadjiev SE, Watters K, Lai B, Wolf S, Welch W, McDonagh AF, Lightner DA (2004) Biochemistry 43:15617CrossRefGoogle Scholar
  19. 19.
    Dey SK, Lightner DA (2008) J Org Chem 73:2704CrossRefGoogle Scholar
  20. 20.
    Dey SK, Lightner DA (2009) Monatsh Chem 140:161CrossRefGoogle Scholar
  21. 21.
    Boiadjiev SE, Lightner DA (1994) Synlett 777Google Scholar
  22. 22.
    Boiadjiev SE, Lightner DA (2006) Org Prep Proced Int 38:347CrossRefGoogle Scholar
  23. 23.
    Brower JO, Lightner DA, McDonagh AF (2001) Tetrahedron 57:7813CrossRefGoogle Scholar
  24. 24.
    Brower JO, Lightner DA (2001) Monatsh Chem 132:1527CrossRefGoogle Scholar
  25. 25.
    Brower JO, Huggins MT, Boiadjiev SE, Lightner DA (2000) Monatsh Chem 131:1047CrossRefGoogle Scholar
  26. 26.
    Huggins MT, Lightner DA (2000) J Org Chem 65:6001CrossRefGoogle Scholar
  27. 27.
    Boiadjiev SE, Anstine DT, Lightner DA (1995) J Am Chem Soc 117:8727CrossRefGoogle Scholar
  28. 28.
    Boiadjiev SE, Anstine DT, Maverick E, Lightner DA (1995) Tetrahedron Asymmetry 6:2253CrossRefGoogle Scholar
  29. 29.
    Nogales DF, Ma J-S, Lightner DA (1993) Tetrahedron 49:2361CrossRefGoogle Scholar
  30. 30.
    Navon G, Frank S, Kaplan D (1984) J Chem Soc Perkin 2, 1145Google Scholar
  31. 31.
    Tipton AK, Lightner DA, McDonagh AF (2001) J Org Chem 66:1832CrossRefGoogle Scholar
  32. 32.
    Ghosh B, Lightner DA (2003) J Heterocycl Chem 40:1113CrossRefGoogle Scholar
  33. 33.
    Kasha M, El-Bayoumi MA, Rhodes W (1961) J Chim Phys Chim Biol 58:916Google Scholar
  34. 34.
    Falk H, Vormayr G, Margulies L, Metz S, Mazur Y (1986) Monatsh Chem 117:849CrossRefGoogle Scholar
  35. 35.
    Falk H, Grubmayr K, Höllbacher G, Hofer O, Leodolter A, Neufingerl F, Ribó JM (1977) Monatsh Chem 108:1113CrossRefGoogle Scholar
  36. 36.
    Lightner DA, Gawroński JK, Wijekoon WMD (1987) J Am Chem Soc 109:6354CrossRefGoogle Scholar
  37. 37.
    Lightner DA, Wijekoon WMD, Zhang MH (1988) J Biol Chem 263:16669Google Scholar
  38. 38.
    Pu Y-M, McDonagh AF, Lightner DA (1993) J Am Chem Soc 115:377CrossRefGoogle Scholar
  39. 39.
    Shalaeva M, Kenseth J, Lombardo F, Bastin A (2008) J Pharm Sci 97:2581CrossRefGoogle Scholar
  40. 40.
    Yesuda M (1959) Bull Chem Soc Jpn 32:429CrossRefGoogle Scholar
  41. 41.
    Shedlovsky T (1962) In: Pesce B (ed) Electrolytes. Pergamon, New YorkGoogle Scholar
  42. 42.
    Avdeef A, Box KJ, Comer JEA, Gilges M, Hadley M, Hibbert C, Patterson W, Tam KY (1999) J Pharm Biomed Anal 20:632CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Department of ChemistryUniversity of NevadaRenoUSA

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