Synthesis of a 10-Oxo-Bilirubin:  Effects of the Oxo Group on Conformation, Transhepatic Transport, and Glucuronidation

Abstract

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 CO, 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.

The oxygen-independent coproporphyrinogen III oxidase HemN utilizes harderoporphyrinogen as a reaction intermediate during conversion of coproporphyrinogen III to protoporphyrinogen IX

“…Harderoporphyrin trimethyl ester 7 was synthesized by condensation of pyrromethanes 3 and 5 following a modified MacDonald approach that constructs the tetrapyrrole in a convergent approach from a northern and southern segment (Figure 3) (Arsenault et al, 1960;Carr et al, 1971;Cavaleiro et al, 1973Cavaleiro et al, , 1974Chen et al, 1999;Lash et al, 1999;Ludwig and Lehr, 2004). A slightly modified protocol was used for condensation of pyrromethanes 3 and 5 to avoid large amounts of self-condensation product 8 of the southern fragment 5.…”

“…Co-crystallization of HemN with coproporphyrinogen III would provide the necessary insight into the orientation of the substrate and its propionate side chains in the active site of the enzyme. Considering our findings that harderoporphyrinogen is a possible HemN reaction Harderoporphyrin trimethyl ester (7) was synthesized by condensation of pyrromethanes (3) and (5) following the modified MacDonald approach with some minor modifications as described in the text (Arsenault et al, 1960;Carr et al, 1971;Cavaleiro et al, 1973Cavaleiro et al, , 1974Chen et al, 1999;Lash et al, 1999;Ludwig and Lehr, 2004). intermediate, the ring A propionate side chain of coproporphyrinogen III is expected to be found in close proximity to the w4Fe-4Sx-bound S-adenosyl-L-methionine. Further biochemical and crystallographic studies are needed to understand how the reaction intermediate harderoporphyrinogen is further decarboxylated.…”

“…Pyrromethanes (1) and (4) were synthesized as previously described (Carr et al, 1971;Chen et al, 1999;Lash et al, 1999;Ludwig and Lehr, 2004).…”

Novel non-classical C9-methyl-5-substituted-2,4-diaminopyrrolo[2,3-d]pyrimidines as potential inhibitors of dihydrofolate reductase and as anti-opportunistic agents

“…This reaction was carried out under a variety of different reaction conditions using different bases (K 2 CO 3 , NaOEt, NaOMe, NaOH and KF), different solvents (MeOH, EtOH, THF, CHCl 3 and i-PrOH), and different temperatures (from room temperature to heating to reflux). [23][24][25][26] The optimized conditions in our hands involved using i-PrOH as the solvent, KF as a weak base and stirring at room temperature overnight to afford compounds 48-53 in >85% yield. 27 Under these conditions the product was readily purified via column chromatography.…”

Synthesis and Fungicidal Activity of New Pyrrolpyrazole Compounds

“…[20] , 其中选用三乙胺作为碱, 催化效果好, 缩短了反应时间, 后处理操作简便. 目标化合物 11 是碱性条件下制备的, 首先碱性条 件使化合物 4 亚甲基上的碳原子形成碳负离子, 而后与 化合物 10 上的碳碳双键发生 Michael 加成反应, 再发生 关环反应得到目标化合物 11 [21,22] , 实验过程中溶剂的类 别、碱和化合物 4 的用量对实验结果都有较大的影响. …”