Absolute configuration of bilirubin conformational enantiomers

Boiadjiev, Stefan E.; Person, Richard V.; Puzicha, Gisbert; Knobler, Carolyn B.; Maverick, Emily F.; Trueblood, K. N.; Lightner, David A.

doi:10.1021/ja00052a006

Cited by 99 publications

(112 citation statements)

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“…1) and correlations between pigment propeller stereochemistry (M and P) and CD spectroscopy have been drawn on the basis of exciton coupling theory. 8,9,12,18,22 …”

Section: Exciton Chiralitymentioning

confidence: 99%

“…6,7,8 The ridge-tile conformation is dissymmetric and bilirubin can adopt either of two nonsuperimposible mirror-image conformations. Both enantiomers occur both in the crystal 6,7 and in solution, 9 interconverting rapidly 10 in the latter via a succession of nonplanar intermediates in which the hydrogen bonding network is never completely broken. 8 The energetically most favored ridge-tile conformation (with interplanar angle, ∼100°) is not rigid; however, it is flexible.…”

mentioning

confidence: 99%

“…Displacement of the equilibrium toward the M or P can be achieved by enantioselective complexation with a chiral compound such as quinine, 12 serum albumin, 13,14 or by the action of intramolecular nonbonded steric repulsions, as has been observed when stereogenic centers are created by methyl substitution at either the ␣ or the ␤ carbons of the propionic acid chains. 9,15 It is this latter phenomenon that has attracted our interest because such "intramolecular resolution" can be observed by circular dichroism spectroscopy. 9,[15][16][17][18][19] The optically active compound of particular interest in the current work is an analog of bilirubin: (␤R,␤ЈR)-dimethylmesobilirubin-XIII␣ (1).…”

mentioning

confidence: 99%

“…9,15 It is this latter phenomenon that has attracted our interest because such "intramolecular resolution" can be observed by circular dichroism spectroscopy. 9,[15][16][17][18][19] The optically active compound of particular interest in the current work is an analog of bilirubin: (␤R,␤ЈR)-dimethylmesobilirubin-XIII␣ (1). 9 Mesobilirubins differ from bilirubin in having ethyl rather than vinyl groups (cf.…”

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confidence: 99%

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Chirality inversion in the bilirubin molecular exciton

Boiadjiev

Lightner

2001

Chirality

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The bichromophoric pigment bilirubin acts as a molecular exciton in its UV-visible and circular dichroism (CD) spectroscopy. In both polar and nonpolar solvents, an optically active analog, (beta R,beta 'R)-dimethylmesobilirubin-XIII alpha (1), exhibits intense bisignate CD Cotton effects in the region of its long wavelength UV-vis absorption near 400 nm: Delta epsilon(434)(max) + 337, Delta epsilon(389)(max) - 186 (CHCl(3)), and Delta epsilon(431)(max) + 285, Delta epsilon(386)(max) - 177 (CH(3)OH). However, introduction of an amine into a CHCl(3) solution of 1 causes the Cotton effect signs to become inverted, e.g., after addition of NH(3), Delta epsilon(433)(max) - 345, Delta epsilon(389)(max) + 243, and after addition of ethylene diamine, Delta epsilon(435)(max) - 420, Delta epsilon(390)(max) + 299. The sign inversions imply inversion of molecular chirality of the bilirubin and the phenomenon appears to be general for amines, including alpha,omega-diamines. 1,8-Diaminooctane was found to be more effective than longer or shorter chain analogs in producing CD sign inversion.

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“…1) and correlations between pigment propeller stereochemistry (M and P) and CD spectroscopy have been drawn on the basis of exciton coupling theory. 8,9,12,18,22 …”

Section: Exciton Chiralitymentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Chirality inversion in the bilirubin molecular exciton

Boiadjiev

Lightner

2001

Chirality

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“…For dimethylformamide, there is little evidence to show whether this is true or not, but for dimethyl sulfoxide there is extensive NMR and spectroscopic evidence that intramolecular hydrogen bonding is maintained, albeit slightly altered (34,35,53). This evidence indicates that the ridge tile structure prevails, although somewhat flattened, and that, at high sulfoxide concentrations in organic solvents or in pure anhydrous dimethyl sulfoxide, a sulfoxide group intercalates between each propionic carboxyl and its apposite dipyrrinone NH groups (35,54,55).…”

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On the Acid Dissociation Constants of Bilirubin and Biliverdin

Lightner

Holmes

McDonagh

1996

Journal of Biological Chemistry

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Biliverdin and bilirubin are naturally-occurring tetrapyrrolic bile pigments containing two propionic acid side chains. These side chains, and their propensity for ionization, are critical in the biological disposition of the pigments. Surprisingly, accurate dissociation constants for the propionic acid groups of biliverdin are unknown, and a wide range of values, extending over some 4 orders of magnitude, has been suggested for the K a values of the propionic acid groups of bilirubin in aqueous solutions. Recently, pK a values of 6.7-9.3 have been reported for bilirubin-values much greater than the value of ϳ5 typical of propionic acid groups. These curiously high values, currently being used to explain the biological transport and metabolism of bilirubin and related compounds, have been attributed to intramolecular hydrogen bonding. We have determined the pK a values of 99% Bilirubin and biliverdin are blue-green and yellow-orange pigments formed from heme during normal metabolism in humans and other animals (1, 2). Like heme, biliverdin and bilirubin have two propionic acid groups and low solubility in water (1-3). The acidity constants of bilirubin have been determined many times during the past 40 years (4 -13), but those of heme and biliverdin have not been measured (3). A mean pK a of ϳ5.3 has been predicted for porphyrin dicarboxylic acids (14), and pK a values of ϳ5.0 and ϳ7.2 have been estimated for biliverdin (3). A wide range of pK a values has been reported for bilirubin, with most investigators favoring a pK a of 6.2 to 6.5 (15), but recent determinations suggest that the true pK a values are even higher (6.8 to Ն 9.3) because of intramolecular hydrogen bonding (11,12). Since most carboxylic acid pK a values are ϳ5 and values Ͼ6 are seldom encountered (16 -18), these recent determinations imply a remarkable and unprecedented effect of intramolecular hydrogen bonding on proton dissociation. To investigate this effect, we have used 13 C NMR to study the dissociation of hydrogen-bonded and non-hydrogen-bonded pyrrolic acids and to determine the pK a values of mesobilirubin-XIII␣ (1) and mesobiliverdin-XIII␣ (2), two synthetic surrogates that differ from bilirubin and biliverdin, respectively, only by trivial differences in the nature, i.e. vinyl groups reduced to ethyl, and sequence of alkyl side chains on the lactam rings. Being remote from the propionic acid side chains, the alkyl substituents on the lactam rings are expected

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Ab initio relative stability of a few conformers of bilirubinin vacuo and in aqueous solution (PCM)

Alagona¹,

Ghio²,

Agresti

et al. 1998

Int. J. Quant. Chem.

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ABSTRACT:The conformational properties of bilirubin present a considerable interest from the medical and biological points of view, because of the toxic pigment peculiar solubility features. Therefore, ab initio geometry optimizations at the 3-21GrSCF level were carried out on a few model-built structures of bilirubin, after substituting the methyl groups on the heteroaromatic rings with H atoms. The structures obtained show a varied network of H bonds, ranging from 0 to 6 H bonds for the lowest-energy conformer in vacuo. This conformer assumes a ''ridge-tile'' shape previously found in w Ž . .x 1992 , but at the ab initio level, its computed H-bond geometrical parameters are fairly consistent with the X-ray observed ones. The relative stability of all the structures is compared in vacuo and in aqueous solution using the polarizable continuum model Ž . PCM of the solvent, whose stabilizing effect, however, is not sufficient to fill the large energy gap between the less lipophilic conformers and the most stable one in vacuo, in agreement with previous CD measurements. The energetic cost imposed to the solvent effect by each intramolecular H bond is almost constant if the other structural features do not change appreciably. The trend of the purely electrostatic results obtained employing a partial charge model of bilirubin is analogous to that produced by its polarized ab initio charge distribution.

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Absolute configuration of bilirubin conformational enantiomers

Cited by 99 publications

References 1 publication

Chirality inversion in the bilirubin molecular exciton

Chirality inversion in the bilirubin molecular exciton

On the Acid Dissociation Constants of Bilirubin and Biliverdin

Ab initio relative stability of a few conformers of bilirubinin vacuo and in aqueous solution (PCM)

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