Estrone oxidation

CYPl A2, CYP2C19, and CYP3A5 are responsible for estrone oxidation. These enzymes are all known to be genetically variant in the human population, and studies to asses the role of these CYP P450 enzymes in breast cancer risk are indicated [100]. 

Cribb A E, Knight M J, Dryer D, et al. (2006). Role of polymorphic human cytochrome P450 enzymes in estrone oxidation. Cancer Epidemiol. Biomarkers Prev. 15 551-558. 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

A carbonyl group cannot be protected as its ethylene ketal during the Birch reduction of an aromatic phenolic ether if one desires to regenerate the ketone and to retain the 1,4-dihydroaromatic system, since an enol ether is hydrolyzed by acid more rapidly than is an ethylene ketal. 1,4-Dihydro-estrone 3-methyl ether is usually prepared by the Birch reduction of estradiol 3-methyl ether followed by Oppenauer oxidation to reform the C-17 carbonyl function. However, the C-17 carbonyl group may be protected as its diethyl ketal and, following a Birch reduction of the A-ring, this ketal function may be hydrolyzed in preference to the 3-enol ether, provided carefully controlled conditions are employed. Conditions for such a selective hydrolysis are illustrated in Procedure 4. 

Estrone is rapidly oxidized by DDQ at room temperature to the A E om-pound (76) which can be obtained from the A" -3-ketone under more drastic conditions. The quinone methide (77) is suggested as an inter-... 

Finally, oxidative cleavage of the remaining aryl-silicon bond with lead tetrakis(trifluoroacetate), [Pb(OCOCF3)4]19, furnishes ( )-estrone [( )-1 ] in nearly quantitative yield. 

Eschenmoser reagent 784 Eschenmoser coupling -.oxidative 102 Eschenmoser sulfide contraction 102, 117ff 122, 474, 478 -.alkylative 119 -.oxidative 119 Eschenmoser-Claisen rearrangement 605 ff., 617 f.. estrone 153 ff. 

Iodine is enriched to a greater extent in chromatogram zones coated with lipophilic substances than it is in a hydrophilic environment. Hence, iodine is only physically dissolved or adsorbed. Occasionally a chemical reaction also takes place, such as, for example, with estrone [19] (cf. Iodine Reagents ). In general it may be said that the longer the iodine effect lasts the more oxidations, additions or electrophilic substitutions are to be expected. 

SCHEME 10.11 Estrone and estradiol are oxidized to catechols and o-quinones, which isomerizes to /j-QMs. 

Some steroid molecules (estrone, estradiol, and estriol) have phenolic hydroxyl in the ring A (Figure 29.12) and therefore, are able to react as free radical scavengers. In 1987, Japanese authors [264,265] showed that all these compounds inhibited iron adriamycin- or iron ADP-ascorbate-dependent phospholipid and liposomal lipid peroxidation. Later on, most attention was drawn to the study of antioxidative properties of estradiol-17(3 (estrogen E2) it has been proposed that E2 antioxidant activity may contribute to cardioprotection observed after estrogen therapy in postmenopausal women. The necessity for the phenolic hydroxyl has been shown by studying the effects of several estrogens on LDL oxidation. It was found [266]... 

Clinical trials of these orally active progestins showed that they were effective as contraceptives with a success rate that exceeded 99%. These compounds were then marketed as obtained from the reaction sequence after appropriate purification. As the analytical methodology improved it became apparent that a small amount of an impurity was present in all active samples. An examination of the reaction scheme allowed ready identification of that by-product. Any unreduced estradiol methyl ether (13-1) will go to estrone methyl ether on oxidation this will then afford the potent orally active estrogen mestranol (9-1) on ethynylation. Subsequent... 

Quercetin has been found to inhibit P-gp-mediated efflux of ritonavir in Caco-2 cells (47), to reduce the oxidation of acetaminophen in rat liver microsomes and HepG2 cells (48), and to inhibit the metabolism of midazolam and quinidine in human liver microsomes (49). It did not have an effect on CYP3A4-mediated metabolism and P-gp-mediated transport of saquinavir (41). Rutin was demonstrated to moderately increase the uptake of idar-ubicin in an isolated perfused rat lung model, and also the outflow recovery of the major metabolite idarubicinol, possibly by affecting P-gp (45). Nobe-litin and tangeretin were shown to inhibit OATP-B-mediated uptake of estrone-3-sulfate into human embryonic kidney cells (23). 

Reactions catalyzed by 11 (3-hydroxysteroid and 17(3-hydroxysteroid dehydrogenases, (a) 11 (3-hydroxysteroid dehydrogenase type 1, an NADPH-dependent enzyme, catalyzes the conversion of the inactive steroid, cortisone, to cortisol, which is the biologically active glucocorticoid. 11 (3-hydroxysteroid dehydrogenase type 2, an NAD+-dependent enzyme, catalyzes the reverse direction, (b) 17(3-hydroxysteroid dehy-drogenase type 1, an NADPH-dependent enzyme, catalyzes the reduction of estrone to estradiol. Type 2, an NAD+-dependent enzyme, catalyzes the oxidation of estradiol to estrone. Type 3, an NADPH-dependent enzyme, catalyzes the reduction of androstene dione to testosterone. Type 4, an NAD+-dependent enzyme, catalyzes the oxidation of estradiol to estrone, and androstenediol to dehydroepiandrosterone. 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolare (29) to the scalemic sulfoxide (30). Direct treatment of the crude Michael adduct with mew-chloroperbeuzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (31) X — a and ftH R = H in over 90% yield. 

Concerning the metabolism of triterpenes and steroids, quite a number of P450 catalyzed transformations are very important, namely the 14a-demethyla-tion of lanosterol [50], the side-chain cleavage of cholesterol [51]and pregnenes [52], and the desaturation of ring A of androgens with concomitant oxidative removal of C(19) [53]. The latter reaction is catalyzed by human placental aromatase, associated with a NADPH-dependent reductase, and requires three moles of oxygen and three moles of NADPH in order to oxidize andro-stenedione 45 to formic acid and estrone 46, Fig. 10. 

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