IXα Dimethyl Ester Research Articles

Singlet oxygen oxidation products of biliverdin IXα dimethyl ester

Biliverdin IXα is a naturally occurring linear tetrapyrrolic product of the enzymatic oxidative ring cleavage of heme. Evidence is mounting that biliverdin possesses antioxidant properties in mammals but its mode of action is unclear. We present the single crystal X-ray structure analysis of two regioisomeric biladien-1,19-diones-ab that are derived from biliverdin IXα dimethyl ester by addition of two vicinal trans-methoxy groups to the 4,5- or 15,16-double bonds, respectively. The compounds were likely formed by photosensitized singlet oxygen addition, followed by Lewis acid-catalyzed methanol-induced ring-opening of the intermediate epoxide, and OH-to-OMe substitution. We thus present structural evidence for a possible reaction mechanism by which biliverdin can act as an antioxidant.

Phenyl biliverdin isomers obtained by chemical oxidation of iron(III) complex of 5-phenyl protoporphyrin IX

Oxidative cleavage of synthetic 5-phenyl protohemin IX in pyridine solution in the presence of ascorbic acid (coupled oxidation), followed by esterification of the products with boron trifluoride-methanol rendered mainly three isomeric biliverdins. These were identified by MS and 1D and 2D1H NMR as 15-phenyl biliverdin IXβ (1), 10-phenyl biliverdin IXγ (2) and 5-phenyl biliverdin IXδ (3) dimethyl esters. The fact that biliverdin IXα dimethyl ester derivative is not obtained indicates that oxidation fails to occur in the α-meso-carbon bearing the phenyl group.

Regioselective Deuteration and Resonance Raman Spectroscopic Characterization of Biliverdin and Phycocyanobilin

Abstract5‐Deuteriophycocyanobilin (4), 5,15,182,182‐tetradeuteriobiliverdin IXα dimethyl ester (6), and 5,15‐dideuteriomesobiliverdin IXα dimethyl ester (8) have been prepared and analyzed by resonance Raman spectroscopy in the C–H out‐of‐plane region, based on a previous normal‐mode analysis of biliverdin XI α dimethyl ester (5). In this way most of the modes containing out‐of‐plane vibrations of the methine bridges could be assigned unambiguously. These results are of special relevance with regard to the interpretation of the resonance Raman spectra of the chromoprotein phytochrome.

Reactivity of pyrrole pigments: Part 16. Mesobiliverdin IXα and mesobilirubin IXα bridged between the propionic acid substituents

Mesobiliverdin IXα diesters of α,ω-dialkanols were obtained by reaction of mesobiliverdin IXα dicesium salt with diiodomethane, 1,3-dibromopropane and 1,4-dibromobutane. Mesobiliverdin IXα methylene diester was tested and compared to mesobiliverdin IXα dimethyl ester, for their photoisomerization behaviour, addition of nucleophiles at C10, protonation, and deprotonation. The constriction imposed by the internal cycle to the flexibility around the two central rings has no appreciable effect on these reactions. In fact, the small pK a differences in the protonation indicate that previous results, on the protonation of biliverdins bridged between the end rings, can be explained through a stretched structure of the protonated bile pigment implying a change in the configuration or conformation of one end ring.

Syntheses of Bile Pigments. Part 16. Synthesis of a vinyl‐substituted 2,3‐Dihydrobilinedione: Possible role of this new class of bile pigments in phycobilin biosynthesis

AbstractThe total synthesis of racemic cis‐2,3,181, 182, ‐tetrahydroprotobiliverdin IXα dimethyl ester (19b), which is identical with the dimethyl ester of rac‐4, is described (Scheme 2). Under virtually neutral conditions, in solution, this bile pigment isomerized within a few min to racemic Z‐phycocyanobilin dimethyl ester (rac‐5b). Likewise, acid‐catalyzed allyl rearrangement of 3‐vinyl‐substituted cis‐ and trans‐2,3‐dihydrodipyrrin‐1(10H)‐ones 11c and 13c, respectively, yielded the corresponding ethylidene derivatives. In this case, however, the E‐isomer was formed stereo selectively from both substrates. The above results prove that, if protobiliverdin IXα (2) is transformed enzymatically to its 2,3,181, 182‐tetrahydro derivative, the latter would isomerize spontaneously to phycocyanobi‐lin. The biosynthesis of bacteriochlorophyll a and b from a common precursor bearing a vinyl group at C(8)may be straightforwardly explained in the same way.

Preparation of Mesoverdohemochrome IXα Dimethyl Ester and Mössbauer Spectra of Related Porphyrins

Abstract Mesobiliverdin IXα dimethyl ester (7) was obtained by hydrogenation of protobiliverdin IXα dimethyl ester (8). Zinc 5-oxamesoporphyrin IX dimethyl ester tetrafluoroborate (6) was prepared by the cyclization of 7 with zinc acetate in acetic anhydride followed by a treatment with aqueous sodium tetrafluoroborate. Bis(pyridine) mesoverdohemochrome IXα dimethyl ester (4) was obtained by the cyclization of 7 with both iron(II) sulfate and iron(III) chloride in acetic anhydride containing a small amount of pyridine. Bis(tosylmethyl isocyanide) mesoverdohemochrome IXα dimethyl ester (5) was prepared by the addition of excess tosylmethyl isocyanide (TsCH2NC) to 4. Both 4 and 5 reacted with ammonia to give iron(III) 5-azamesoporphyrin IX dimethyl ester (10). The Mössbauer spectra of bis(pyridine) verdohemochromes (4, 13, and 14) snowed doublet peaks having parameters of δ=0.41–0.43 mm s−1 and ΔEQ=1.24–1.26 mm s−1, indicating that the oxidation states of the central irons of these complexes are iron(II). Bis(TsCH2NC) verdohemochromes (5, 15, and 17) showed single peaks having parameters of δ=0.21–0.28 mm s−1. Unstable intermediate and stable final bis(TsCH2NC) octaethyl verdohemochromes, obtained by the addition of TsCH2NC to 4, were compared with the 1H NMR and Mössbauer spectra.

Chemical Studies on Products Obtained from Verdohemochrome IXα Dimethyl Ester by Treatment with Ammonia under Air

Abstract Verdohemochrome IXα dimethyl ester [bis(pyridine)iron(II) 5-oxaprotoporphyrin IX dimethyl ester] gave 5-azaprotohemin IX dimethyl ester (2) and six tripyrrin derivatives upon treatment with ammonia under air, followed by methylation. The reaction of 2 with coned HCl in acetic acid in the presence of ferrous sulfate, followed by methylation gave demetallated product, 5-azaprotoporphyrin IX dimethyl ester (8), accompanied by products obtained by the hydration and reduction of both or one of the vinyl groups of 8. 8,12-Bis[2-(methoxycarbonyl)ethyl]-3,7,13-trimethyl-1-oxo-2-vinyltripyrrin-14-carbaldehyde, obtained as a major tripyrrin product by an oxidative degradation of 1, gave a pyrromethene derivative, 3,7-bis[2-(methoxycarbonyl)ethyl]-2,8-dimethyl-l-methoxy-5-pyrromethene-9-carbaldehyde by the reaction with Tl(OAc)3 under air. The structures of all products obtained in the present study were determined by spectral measurements.

Cyclization of biliverdins to verdohaemochromes

Iron(II) octaethylverdohaemochrome was obtained both by cyclization of octaethylbiliverdin in the presence of FeSO4 and pyridine, and by coupled oxidation of octaethylhaemin and ascorbic acid with O2 in the presence of pyridine. The compound obtained by cyclization of biliverdin IXα dimethyl ester was, however, different from that obtained by the methylation of iron(II) protoverdohaemochrome IXα, the product of coupled oxidation of the protohaem in myoglobin. The electronic absorption spectra of the pyridine and tosylmethyl isocyanide (TsCH2NC) complexes, (14) and (15), of the product of cyclization were different from the spectra of the same complexes, (11) and (12), of the product of coupled oxidation. The product of cyclization was reduced to the product of coupled oxidation by sodium dithionite. It is postulated that compounds (14) and (15) are bis(pyridine) and bis(isocyanide) co-ordination complexes of iron (III) protoverdohaemochrome dimethyl ester. The positions of the maxima in the absorption spectra of compounds (16) and (17), the pyridine and TsCH2NC complexes of both the product of coupled oxidation of mesohaemin dimethyl ester and the product of cyclization of mesobiliverdin dimethyl ester, indicated that these compounds are analogues, not of (11) and (12), but of (14) and (15). Iron(II) azaporphyrins (7) and (13) were prepared by treatment of the corresponding iron(II) oxaporphyrins (5) and (11) with ammonia.

Picosecond Kinetics of Excited State Relaxation in Biliverdin Dimethyl Ester

AbstractThe relaxation processes of biliverdin IXα dimethyl ester have been studied by time‐resolved absorption and fluorescence detection, using pump‐probe and single‐photon timing techniques, respectively. The results complement and extend those of earlier investigations.1,3–5 In 2‐methyltetrahydrofuran, chloroform, ethanol, and ethyl lactate, four emitting species, two short‐lived (picosecond) and two long‐lived ones (nanosecond), have been detected. In methanol, the number of emitters is possibly reduced to three. In the cases of four emitters, these can be attributed to either three or four ground state forms. We conclude that the radiationless relaxation of the short‐lived excited states is simultaneously induced both by proton transfer processes and by conformational changes, as previously discussed.3 The spectroscopic properties of the long‐lived species point to the presence of relatively rigid conformations of the bilatriene in liquid solutions at room temperature. The possible relevance of this observation with regard to the influence of protein interactions on the conformational equilibrium of tetrapyrroles in phycobiliproteins is discussed.

Singlet oxygen reactivity of bilirubin and related tetrapyrroles

The rates of chemical reactivity (kR) and physical quenching (kQ) of singlet oxygen by bilirubin IXα, mesobilirubin IXα, bilirubin IXα dimethyl ester, aetiobilirubin IVγ, biliverdin IXα, biliverdin IXα dimethyl ester, aetiobiliverdin IVγ and an oxodipyrromethene have been determined. The kR and kQ values approach the diffusion threshold for the bilirubin-like substrates, but kR<kQ by about a factor of 103 for the verdins. A reaction mechanism involving superoxide ion is suggested. Bilirubin appears to quench singlet oxygen by an electron-transfer mechanism.

Evidence for singlet oxygen quenching by biliverdin IX-α dimethyl ester and its relevance to bilirubin photo-oxidation

Summary Biliverdin IX-α dimethyl ester inhibits the sensitized and unsensitized photo-oxidation of bilirubin IX-α. Biliverdin IX-α is probably not an intermediate in the main pathway of bilirubin photo-oxidation in vitro .