Imide Products from Photo-oxidation of Bilirubin and Mesobilirubin

Abstract

IN 1958 Cremer et al.¹ observed that the concentration of bilirubin (la) in the plasma could be reduced by exposing newborn infants to fluorescent light. Since that time phototherapy has come into wide use to lower elevated bilirubin levels associated with neonatal jaundice (hyperbilirubin-aemia)^{2, 3}. This condition in the newborn has been associated with retarded motor development, irreversible brain damage or even death. Phototherapy lowers bilirubin levels (by conversion of this lipid-soluble pigment to water-soluble products)⁴ and therefore presumably helps to prevent brain damage. But there are two possible dangers in this treatment: light may have other deleterious effects on the newborn and the photo-products of bilirubin may themselves be toxic. At present neither the structures of the bilirubin photo-products nor their toxicities have been established. Although the photo-destruction of bilirubin has been studied in vivo and in vitro by Ostrow^5–7, Schmid^{4, 7}, and others^{8, 9}, these authors investigated principally the visible-ultraviolet spectral changes during the course of bilirubin photo-oxidation and recorded paper chromatographic separations of the photo-products for comparison with the bile or urine of the congenitally jaundiced Gunn rat. More recently McDonagh has shown that singlet oxygen is involved in the self-sensitized photo-oxidation of bilirubin¹⁰. In view of the paucity of structural.information on the bilirubin photo-products, we wish to report preliminary findings on the in vitro photo-oxidation products from bilirubin IXa (1a), mesobilirubin IXa (1b) and 5′-oxo-3′,4,4′-triethyl-3,5-dimethyl-l′,5′-dihydro-(2.2′)-dipyrrylmethene (2). We synthesized and carried out our initial studies on 2, which serves as a simplified model for rings I and II of 1a and 1b because it lacks the vinyl group of 1a and the propionic acid β-substituent of 1a and 1b. The visible-ultraviolet spectrum of 2 is quite similar to that of either 1a or 1b^11–13.