Bilirubin, the yellow pigment of jaundice, is a linear tetrapyrrole with a methylene group at its
center, C(10), a position of crucial importance to its conformation and metabolism. The presence of the central
methylene group allows the bilirubin to fold into an intramolecularly hydrogen-bonded conformation. This
paper describes the first synthesis of a bilirubin analogue with an oxo group at C(10). The change from CH2
to CO, from sp3 to sp2, is designed to stress the molecule at its hinge and relax its conformation. Such
compounds have been suggested as potential oxidative metabolites of bilirubin in vivo. 10-Oxo-mesobilirubin-XIIIα (1) is a red crystalline solid, unlike its parent, mesobilirubin-XIIIα, which is a bright yellow solid. It is
surprisingly polar, relative to the parent, yet it does not exhibit a significantly larger bicarbonate/chloroform
partition coefficient. Like the parent, 1 appears to adopt an intramolecularly hydrogen-bonded ridge-tile-like
conformation. In normal rats, 1 is metabolized to acylglucuronides, which are secreted into bile, but a portion
of the administered dose is secreted into bile intact. In mutant rats (Gunn rats) lacking bilirubin glucuronyl
transferase, 1 was excreted efficiently in bile in unchanged form, unlike the parent with a methylene group at
C(10). Thus, introduction of the oxygen function at C(10) has little effect on hepatic uptake but a dramatic
effect on canalicular secretion into bile.
(4Z)-9-(5-Carboxypentyl)-2,3,7,8-tetramethyl-(10H)-dipyrrin- 1-one (1, semirubin), a new dipyrrinone model for one-half of bilirubin, the yellow-orange neurotoxic pigment of jaundice, was synthesized following Friedel-Crafts acylation of 2,3,7, 8-tetramethyl-(10H)-dipyrrin-1-one (5) with the half-ester acid chloride of adipic acid. Unlike other dipyrrinone models for bilirubin, such as the xanthobilirubic acids, which engage only in intermolecular hydrogen bonding, 1 is unique in having been designed and found to engage in intramolecular hydrogen bonding, between the carboxylic acid and the dipyrrinone lactam and pyrrole. This important conformation-determining structural characteristic, shared by 1 and bilirubin, renders them less polar than their methyl esters and leaves them monomeric in nonpolar solvents, where their esters are dimeric. The corresponding 10-oxo analogue (3) of 1 serves as a model for 10-oxo-bilirubin, a presumed bilirubin metabolite in alternate pathways for bilirubin excretion. Like 1, 3 is found to engage in intramolecular hydrogen bonding. Unlike the methyl ester of 1, the ethyl ester of 3 is not intermolecularly hydrogen bonded in nonpolar solvents.
Reported here is the synthesis and characterization of a new class of macrocycle that represents a hybrid between texaphyrin and calixpyrrole. These polypyrrolic macrocycles were prepared in one step by the acid-catalyzed condensation between diformyl dipyrromethanes and ophenylenediamines in high yields. The X-ray crystal structure of one of these new "chimeras" was solved. It reveals that the diprotonated Schiff-base macrocycle has a V-shape in which one chloride anion is bound. Isothermal titration calorimetry (ITC) studies served to confirm the ability of the hybrid macrocycles to bind chloride anion in acetonitrile solution. These compounds may be useful as easy-to-make anion receptors.
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