Chemical Synthesis of Rare Natural Bile Acids: 11α‐Hydroxy Derivatives of Lithocholic and Chenodeoxycholic Acids

Namegawa, Kazunari; Iida, Kei; Omura, Kaoru; Ogawa, Shoujiro; Hofmann, Alan F.; Iida, Takashi

doi:10.1002/lipd.12013

Cited by 4 publications

(6 citation statements)

References 25 publications

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“…The organic layer was concentrated to dryness to afford the title compound 13 (319.8 g, 98%). 1 H and 13 C NMR spectra matched that previously reported [ 46 ].…”

Section: Methodssupporting

confidence: 88%

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Synthesis of Novel C/D Ring Modified Bile Acids

et al. 2022

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Bile acid receptors have been identified as important targets for the development of new therapeutics to treat various metabolic and inflammatory diseases. The synthesis of new bile acid analogues can help elucidate structure–activity relationships and define compounds that activate these receptors selectively. Towards this, access to large quantities of a chenodeoxycholic acid derivative bearing a C-12 methyl and a C-13 to C-14 double bond provided an interesting scaffold to investigate the chemical manipulation of the C/D ring junction in bile acids. The reactivity of this alkene substrate with various zinc carbenoid species showed that those generated using the Furukawa methodology achieved selective α-cyclopropanation, whereas those generated using the Shi methodology reacted in an unexpected manner giving rise to a rearranged skeleton whereby the C ring has undergone contraction to form a novel spiro–furan ring system. Further derivatization of the cyclopropanated steroid included O-7 oxidation and epimerization to afford new bile acid derivatives for biological evaluation.

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“…The organic layer was concentrated to dryness to afford the title compound 13 (319.8 g, 98%). 1 H and 13 C NMR spectra matched that previously reported [ 46 ].…”

Section: Methodssupporting

confidence: 88%

“…Methyl 3α,7α-diacetoxy-12α-[(methylsulfonyl)oxy]-5β-cholan-24-oate ( 13 ) [ 46 ]. A solution of 12 (283.4 g, 559 mmol) in pyridine (1.7 L) was concentrated to approx.…”

Section: Methodsmentioning

confidence: 99%

Synthesis of Novel C/D Ring Modified Bile Acids

et al. 2022

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“…Following established methods, our synthetic efforts began by converting CA ( 1 ) into its corresponding methyl ester 21a . This was followed by selective acetylation of the 3- and 7-hydroxy groups and the subsequent reaction of 22a with methanesulfonyl chloride to furnish the desired precursor 23a . , …”

Section: Results and Discussionmentioning

confidence: 99%

“… a Reagents and conditions: (a) MeOH, p -TsOH·H 2 O, Δ or rt; 21b–c : 83–84%; (b) for 22a : Ac 2 O, DMAP, py (2.5 equiv), toluene; 90%; for 22b–c : DCM, DMAP, NEt 3 , Ac 2 O, 0 °C–rt; 2–6 h; 76–86%; (c) for 23a / 23c : MsCl, py, 0 °C–rt, o/n; 83–97%; for 23b : McCl, py, 0 °C, 45 min; (d) 24a / c // 25a / c : HOAc, NaOAc, 100 °C, 2–3 h; 83–86%; 24b / 25b : HOAc, Zn(OAc) 2 , 100 °C, 1.5 h; 84%. Abbreviations: DCM: dichloromethane; DMAP: N , N -dimethylaminopyridine; o/n: overnight; rt: room temperature; Ts: para -toluenesulfonate. …”

Section: Results and Discussionmentioning

confidence: 99%

Synthesis of 12β-Methyl-18-nor-bile Acids

et al. 2021

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Decoupling the roles of the farnesoid X nuclear receptor and Takeda G-protein-coupled bile acid receptor 5 is essential for the development of novel bile acid therapeutics targeting metabolic and neurodegenerative diseases. Herein, we describe the synthesis of 12β-methyl-18-nor-bile acids which may serve as probes in the search for new bile acid analogues with clinical applicability. A Nametkin-type rearrangement was applied to protected cholic acid derivatives, giving rise to tetra-substituted Δ13,14- and Δ13,17-unsaturated 12β-methyl-18-nor-bile acid intermediates (24a and 25a). Subsequent catalytic hydrogenation and deprotection yielded 12β-methyl-18-nor-chenodeoxycholic acid (27a) and its 17-epi-epimer (28a) as the two major reaction products. Optimization of the synthetic sequence enabled a chromatography-free route to prepare these bile acids at a multi-gram scale. In addition, the first cis-C-D ring-junctured bile acid and a new 14(13 → 12)-abeo-bile acid are described. Furthermore, deuteration experiments were performed to provide mechanistic insights into the formation of the formal anti-hydrogenation product 12β-methyl-18-nor-chenodeoxycholic acid (27a).

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“…With the widespread application of bile acids in the pharmaceutical industry, the demand for animal bile has increased. The preparation of bile acids is mainly obtained by natural bile extraction ( Chanquia et al, 2018 ; Namegawa et al, 2018 ). However, bile from different animals is difficult to distinguish, and the major bile acids present in each bile as well as the biological activities of bile acids are not yet clear, which greatly limits the processing and reuse of bile.…”

Section: Introductionmentioning

confidence: 99%

An integrated strategy combining metabolomics and machine learning for the evaluation of bioactive markers that differentiate various bile

Liang²,

Su³

et al. 2022

Front. Chem.

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Animal bile is an important component of natural medicine and is widely used in clinical treatment. However, it is easy to cause mixed applications during processing, resulting in uneven quality, which seriously affects and harms the interests and health of consumers. Bile acids are the major bioactive constituents of bile and contain a variety of isomeric constituents. Although the components are structurally similar, they exhibit different pharmacological activities. Identifying the characteristics of each animal bile is particularly important for processing and reuse. It is necessary to establish an accurate analysis method to distinguish different types of animal bile. We evaluated the biological activity of key feature markers from various animal bile samples. In this study, a strategy combining metabolomics and machine learning was used to compare the bile of three different animals, and four key markers were screened. Quantitative analysis of the key markers showed that the levels of Glycochenodeoxycholic acid (GCDCA) and Taurodeoxycholic acid (TDCA) were highest in pig bile; Glycocholic acid (GCA) and Cholic acid (CA) were the most abundant in bovine and sheep bile, respectively. In addition, four key feature markers significantly inhibited the production of NO in LPS-stimulated RAW264.7 macrophage cells. These findings will contribute to the targeted development of bile in various animals and provide a basis for its rational application.

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Chemical Synthesis of Rare Natural Bile Acids: 11α‐Hydroxy Derivatives of Lithocholic and Chenodeoxycholic Acids

Cited by 4 publications

References 25 publications

Synthesis of Novel C/D Ring Modified Bile Acids

Synthesis of Novel C/D Ring Modified Bile Acids

Synthesis of 12β-Methyl-18-nor-bile Acids

An integrated strategy combining metabolomics and machine learning for the evaluation of bioactive markers that differentiate various bile

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