Enantiomeric Steroids:  Synthesis, Physical, and Biological Properties

Biellmann, Jean‐François

doi:10.1021/cr020071b

Cited by 108 publications

(62 citation statements)

References 78 publications

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“…Other ent-steroids have been synthesized (58) and evaluated as probes of natural steroid interactions including ent-cholesterol (59,60), ent-progesterone (61), ent-estrogen (62), and enantiomeric neuroactive steroids (63,64). These reports illustrate that natural and enantiomeric steroids have distinctly different interactions with chiral environments, such as receptor-binding pockets.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Enantiomeric Bile Acid-induced Apoptosis in Colon Cancer Cell Lines

Katona

Anant

Covey

et al. 2009

Journal of Biological Chemistry

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Bile acids are steroid detergents that are toxic to mammalian cells at high concentrations; increased exposure to these steroids is pertinent in the pathogenesis of cholestatic disease and colon cancer. Understanding the mechanisms of bile acid toxicity and apoptosis, which could include nonspecific detergent effects and/or specific receptor activation, has potential therapeutic significance. In this report we investigate the ability of synthetic enantiomers of lithocholic acid (ent-LCA), chenodeoxycholic acid (ent-CDCA), and deoxycholic acid (ent-DCA) to induce toxicity and apoptosis in HT-29 and HCT-116 cells. Natural bile acids were found to induce more apoptotic nuclear morphology, cause increased cellular detachment, and lead to greater capase-3 and -9 cleavage compared with enantiomeric bile acids in both cell lines. In contrast, natural and enantiomeric bile acids showed similar effects on cellular proliferation. These data show that bile acid-induced apoptosis in HT-29 and HCT-116 cells is enantiospecific, hence correlated with the absolute configuration of the bile steroid rather than its detergent properties. The mechanism of LCA-and ent-LCA-induced apoptosis was also investigated in HT-29 and HCT-116 cells. These bile acids differentially activate initiator caspases-2 and -8 and induce cleavage of full-length Bid. LCA and ent-LCA mediated apoptosis was inhibited by both pan-caspase and selective caspase-8 inhibitors, whereas a selective caspase-2 inhibitor provided no protection. LCA also induced increased CD95 localization to the plasma membrane and generated increased reactive oxygen species compared with ent-LCA. This suggests that LCA/ ent-LCA induce apoptosis enantioselectively through CD95 activation, likely because of increased reactive oxygen species generation, with resulting procaspase-8 cleavage.Bile acids are physiologic steroids that are necessary for the proper absorption of fats and fat-soluble vitamins. Their ability to aid in these processes is largely due to their amphipathic nature and thus their ability to act as detergents. Despite the beneficial effects, high concentrations of bile acids are toxic to cells (1-11).High fat western diets induce extensive recirculation of the bile acid pool, resulting in increased exposure of the colonic epithelial cells to these toxic steroids (12, 13). A high fat diet is also a risk factor for colon carcinogenesis; increased bile acid exposure is responsible for some of this risk. Bile acids can contribute to both colon cancer formation and progression, and their effects on colonic proliferation and apoptosis aid this process by disrupting the balance between cell growth and cell death, as well as helping to select for bile acid-resistant cells (14,15).In colonocyte-derived cell lines bile acid-induced apoptosis is thought to proceed through mitochondrial destabilization with resulting mitochondrial permeability transition formation and cytochrome c release as well as generation of oxidative stress (1, 9 -11). Bile acid-induced apoptosis has also ...

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Section: Discussionmentioning

confidence: 99%

Characterization of Enantiomeric Bile Acid-induced Apoptosis in Colon Cancer Cell Lines

Katona

Anant

Covey

et al. 2009

Journal of Biological Chemistry

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“…There is no possibility of racimization of ent -25-HC to nat -25-HC during the conversion of ent -testosterone to ent -25-HC and no known biochemical pathway to interconvert natural and enantiomeric steroids. ent -Steroids do not occur naturally in nature (Biellmann, 2003; Covey, 2009). All other compounds were obtained from Sigma-Aldrich (St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

Different oxysterols have opposing actions at N-methyl-d-aspartate receptors

et al. 2014

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Oxysterols have emerged as important biomarkers in disease and as signaling molecules. We recently showed that the oxysterol 24(S)-hydroxycholesterol, the major brain cholesterol metabolite, potently and selectively enhances NMDA receptor function at a site distinct from other modulators. Here we further characterize the pharmacological mechanisms of 24(S)-hydroxycholesterol and its synthetic analogue SGE201. We describe an oxysterol antagonist of this positive allosteric modulation, 25-hydroxycholesterol. We found that 24(S)-hydroxycholesterol and SGE201 primarily increased the efficacy of NMDAR agonists but did not directly gate the channel or increase functional receptor number. Rather than binding to a direct aqueous-accessible site, oxysterols may partition into the plasma membrane to access the NMDAR, likely explaining slow onset and offset kinetics of modulation. Interestingly, oxysterols were ineffective when applied to the cytosolic face of inside-out membrane patches or through a whole-cell pipette solution, suggesting a non-intracellular site. We also found that another natural oxysterol, 25-hydroxycholesterol, although exhibiting slight potentiation on its own, non-competitively and enantioselectively antagonized the effects of 24(S)-hydroxycholesterol analogues. In summary, we suggest two novel allosteric sites on NMDARs that separately modulate channel gating, but together oppose each other.

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“…The highest yield of (-)-methoxyestrone (11, 25 %) was obtained at -78°C. Interestingly, the application of other frequently utilized Lewis acids for the rearrangement of epoxides to carbonyl compounds such as Bi(OTf) 3 , [19] Cu(BF 4 ), [20] or IrCl 3 [21] did not give rise to the desired product; only complex mixtures of compounds were obtained.…”

Section: Resultsmentioning

confidence: 99%

“…Development of new synthetic pathways [1] for its enantioselective synthesis [2] has also been fuelled by a recent interest in ent-steroids (not produced by Nature), which are presumed to have biological activities different from those of the natural ones. [3] Recently, we reported two new procedures for the diastereoselective synthesis of an advanced steroid intermediate bearing the required tetracyclic skeleton including the correct relative stereochemistry. The first approach was based on threefold consecutive use of Cp 2 ZrBu 2 -mediated reactions (Negishi reagent) to construct the steroid A-C rings, and finally the D ring was assembled by a Ru complex catalyzed ring-closing metathesis.…”

Section: Introductionmentioning

confidence: 99%

Enantioselective Synthesis of (–)‐Methoxyestrone

Betík

Kotora

2011

Eur J Org Chem

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Enantioselective synthesis of unnatural (–)‐methoxyestrone in 12 steps from the commercially available tetralone based on the formation of a chiral bicyclic intermediate having the A–B steroid ring framework was accomplished. The crucial synthetic step comprised the enantioselective conjugate addition of vinylmagnesium bromide to a chiral imine formed from a trisubstituted cyclic α,β‐unsaturated aldehyde with >98 % ee, giving rise to the stereoselectively substituted building block possessing the A–B steroid rings. Further steps included the construction of the side chain containing the triple bond, and the obtained enyne was subjected to a Pauson–Khand reaction that furnished stereoselectively an intermediate tetracyclic ketone. Further functional group transformations yielded the target compound.

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Enantiomeric Steroids: Synthesis, Physical, and Biological Properties

Cited by 108 publications

References 78 publications

Characterization of Enantiomeric Bile Acid-induced Apoptosis in Colon Cancer Cell Lines

Characterization of Enantiomeric Bile Acid-induced Apoptosis in Colon Cancer Cell Lines

Different oxysterols have opposing actions at N-methyl-d-aspartate receptors

Enantioselective Synthesis of (–)‐Methoxyestrone

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