- Chemical synthesis of 7α-hydroxycholest-4-en-3-one, a biomarker for irritable bowel syndrome and bile acid malabsorption
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7α-Hydroxy-cholest-4-en-3-one is a biomarker for bile acid loss, irritable bowel syndrome, and other diseases associated with defective bile acid biosynthesis. Furthermore, 7α-hydroxy-cholest-4-en-3-one is the physiological substrate for cytochrome P450 8B1 (P450 8B1 or CYP8B1), the oxysterol 12α-hydroxylase enzyme implicated in obesity and cardiovascular health. We report the chemical synthesis of this physiologically important oxysterol beginning with cholesterol. The key feature of this synthesis involves a regioselective C3-allylic oxidation of a 3-desoxy-Δ4-7α-formate steroid precursor to form 7α-formyloxy-cholest-4-en-3-one, which was saponified to yield 7α-hydroxy-cholest-4-en-3-one.
- Offei, Samuel D.,Arman, Hadi D.,Yoshimoto, Francis K.
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- P -TsOH-Catalyzed one-pot transformation of di- and trihydroxy steroids towards diverse A/B-ring oxo-functionalization
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A solid support-mediated p-TsOH-catalyzed milder transformative protocol was developed to furnish diverse ring-A and/or ring-B oxo-functionalized steroids. To furnish interesting isomers involving the A/B-ring of biomolecules in a one-pot approach, only solid supports (and not solution!) were found to be effective. p-TsOH/SiO2-oxidation of 4β-hydroxycholesterol, the major oxysterol in human circulation, into a mixture of cholest-4-en-3-one, cholest-4-ene-3,6-dione, and 5α-cholestane-3,6-dione was the starting point for the investigations herein. The reaction protocol was optimized in detail, and efforts were carried out toward gaining an understanding of the mechanistic aspects favoring the solid support, and a possible synergetic catalytic system involving p-TsOH and SiO2 was expected to be a key part. Application of the novel methodology to 4β,7α-dihydroxy steroids resulted in the desired diverse ketosteroids through oxidation/oxidative dehydration, which generalized the process as a facile multi-oxo-functionalization steroidal transformation.
- Sarkar, Antara,Das, Jayanta,Ghosh, Pranab
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p. 9051 - 9060
(2017/08/29)
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- Oxysterols: Synthesis and anti-leishmanial activities
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Oxygenated sterols (2-16) were synthesized by skeletal rearrangement of steroidal allylic alcohols. All the derivatives were screened for their anti-leishmanial activities. Compounds 3, 11 and 12 showed potent activities. Compound 12 was found least toxic and induced highest nitric oxide (NO) at 48 h. Least toxicity of compound 12 on splenocytes validated its best anti-amastigote effect and induction of NO.
- Ghosh, Pranab,Ghosh, Ashim,Mandal, Amitava,Sultana, Sirin Salma,Dey, Somaditya,Pal, Chiranjib
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- Isomerization, but not oxidation, is suppressed by a single point mutation, E361Q, in the reaction catalyzed by cholesterol oxidase
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The putative active site base of cholesterol oxidase from Streptomyces has been removed by site-directed mutagenesis and the mutant enzyme characterized. When glutamate-361 is mutated to a glutamine, the isomerization chemistry catalyzed by cholesterol oxidase is suppressed and the intermediate cholest-5-ene-3-one is isolated. The specific activity for oxidation is 20-fold slower than the wild-type reaction, though the specific activity for isomerization is 10000-fold slower. Furthermore, incubation of cholest-5-ene-3-one with the E361Q cholesterol oxidase resulted in the production of cholest-4-ene-6β-hydroperoxy-3-one (6%), cholest-4-ene-3,6-dione (32%), cholest-4-ene-6β-ol-3-one (36%), and cholest-4-ene-6α-hydroperoxy-3-one/cholest-4-ene-6α-ol-3-one (13%), in addition to cholest-4-ene-3-one (13%). Measurement of reaction stoichiometry eliminated the possibility that H2O2 or the C4a-hydroperoxy flavin was the oxygenation agent. It is proposed that cholest-4-ene-6-hydroperoxy-3-one is the product of radical chain autoxidation and that cholest-4-ene-3,6-dione and cholest-4-ene-6-ol-3-one are decomposition products of the hydroperoxy steroid radical. The characterization of the E361Q mutant chemistry has illuminated the importance of intermediate sequestration in enzyme catalysis. The mutant enzyme will be used to obtain information about the structure of the enzyme in the presence of the reaction intermediate. Moreover, the altered activity of E361Q cholesterol oxidase will facilitate its application in studies of cell membranes.
- Sampson, Nicole S.,Kass, Ignatius J.
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p. 855 - 862
(2007/10/03)
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- Stereospecific oxidation of 3β-hydroxysteroids by persolvent fermentation with Pseudomonas sp. ST-200
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Pseudomonas sp. strain ST-200 isolated from a humus soil effectively oxidizes cholesterol dissolved in organic solvents but not that suspended in the growth medium. The organism does not assimilate cholesterol. This organism oxidized a variety of 5α- or 5-ene-steroids dissolved in organic solvent. First, the 3β-OH group was oxidized to a ketone group. The 3α-OH group was scarcely oxidized. Successively, C-6 position of 5-ene-steroids was hydroxylated, and a double bond of 5-ene-steroids was transferred from Δ5 to Δ4. Then, the 6-OH group was oxidized to a ketone group. Persolvent fermentation with ST-200 would provide an effective, convenient, and stereospecific method to oxidize the C-3 and C-6 positions of steroids.
- Aono, Rikizo,Doukyu, Noriyuki
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p. 1146 - 1151
(2007/10/03)
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- Oxidation of homoallylic steroidal alcohols with pyridinium chlorochromate. The synthesis of steroidal 4-en-3,6-diones
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Prolonged oxidation of steroidal homoallylic Δ5-3-alcohols with pyridinium chlorochromate (PCC) in dichloromethane affords the corresponding Δ4-3,6-diones via the intermediate Δ5-3-one and not a Δ4-3-one.
- Blaszczyk,Paryzek
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p. 3255 - 3259
(2007/10/02)
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- Allylic Hydroperoxides Formed by Singlet Oxygenation of Cholest-5-en-3-one
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Cholest-5-en-3-one (I) reacts with singlet oxygen to give the hemiperketal (II) (ca. 55percent), the epimeric 6β- and 6α-hydroperoxides (III) and (IV) (ca. 30 and 8percent respectively), and the dione (V) (ca 7percent).The hemiperketal (II) does not undergo an allylic rearrangement in solution, but the hydroperoxides (III) and (IV) epimerise by a radical chain mechanism. .Stereochemical problems connected with this system have been probed by carrying out parallel experiments and molecular mechanics calculations on the corresponding derivatives of methyloctahydronaphthalenone as model compounds.
- Dang, Hai-Shan,Davies, Alwyn G.,Schiesser, Carl H.
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p. 789 - 794
(2007/10/02)
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- Catalytic Oxygenation of Cholesterol with a Platinum Catalyst under Moderate Pressure of Oxygen
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The catalytic oxigenation of cholesterol 1 with a platinum black catalyst under moderate pressure (20-25 atm) of oxygen yielded eleven oxidation products, 3-13a.The reaction pathway of the catalytic oxygenation is discussed on the basis of the results for several reaction conditions.
- Sakamaki, Hiroshi,Take, Masa-aki,Akihisa, Toshihiro,Matsumoto, Taro,Ichinohe, Yoshiyuki
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p. 3023 - 3025
(2007/10/02)
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- SYNTHESIS OF UNSATURATED CARBONYL COMPOUNDS VIA A CHROMIUM-MEDIATED ALLYLIC OXIDATION BY 70percent TERT.BUTYLHYDROPEROXIDE
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Alkenes were converted into α,β-unsaturated carbonyl compounds using excess of tert.butylhydroperoxide and catalytic amounts of chromiumVI oxide at room temperature.Fair yields and conversions were obtained from Δ5-steroids while allylic oxidation of acyclic alkenes was less efficient.Epoxidation of the double bond, sometimes observed, remained a minor reaction pathway.
- Muzart, Jacques
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p. 4665 - 4668
(2007/10/02)
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- Peroxide oxidation of Δ4-3-ketosteroids
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Treatment of Δ4-3-ketosteroids with tert-butyl hydroperoxide in the presence of lithium hydroxide leads to the formation of the corresponding 4β,5β epoxides stereospecifically and in good yield.The stereospecificity of this reaction is explicable in terms of the accepted mechanism for the hydrogen peroxide epoxidation of Δ4-3-ketosteroids.The use of aqueous sodium peroxide as oxidant leads to the production of the corresponding Δ4-3,6-diones.A mechanism for this reaction is proposed in which the key step is autooxidation of the corresponding deconjugated Δ5-3-ketone, produced from the starting material in situ by the action of the reagents.Lithium peroxide does not oxidize androst-4-ene-3,17-dione at C-6, but produces the 4,5-epoxides in low yield together with an A-nor-3,5-secoacid.
- Holland, Herbert L.,Riemland, Elly,Ulrich, Daum
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p. 1919 - 1923
(2007/10/02)
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