16-Keto estradiol

Figure 43. MIKE spectra of isomeric molecular ions m/z 286 for 16-keto estradiol (d) and 16-hydroxy-estrone (e) [196],...

The transformation of estradiol-17/3 to estriol has been postulated to proceed by dehydrogenation of estradiol to yield the enolic form of estrone followed by hydration to estriol (Fig. 20). Another hypothesis is that estrone is first oxidized to 16-ketoestrone and thence reduced to 16-keto-estradiol-17/8 and estriol. There is no experimental evidence in favor of... 

The application of the Birch reduction to ethers of estradiol by A. J. Birch opened up the area of 19-norsteroids to intensive research. The major Birch reduction product is an enol ether which affords either a 3-keto-A -or a 3-keto-A -19-norsteroid depending upon the hydrolysis conditions. Various 19-norsteroids have been found to have useful clinical activity compounds (30), (31), and (32) are oral contraceptive agents and compound (33) has been used as an oral anabolic agent. Several of these compounds were prepared on an industrial scale for a number of years by the Birch reduction of estradiol derivatives. 

Treatment of A 8(9)-dehydroestradiol with trifhioroacetic acid and triethylsilane gives estradiol in 96% yield (Eq. 86).239 The 3-methyl ether is similarly reduced to the 3-methyl ether of estradiol in >50% yield.239 The structurally related 18-ethyl and 18-propyl 17-keto compounds experience reduction of the A8(9) function in excess of 70% yield without concomitant reduction of the 17-keto... 

Estradiol Estradiol, estra-l,3,5(10)-trien-3,17)3-diol (28.1.17), is most easily made by reducing the keto-group of estrone by various reducing agents, in particular potassium borohydride [23,24]. 

Oxcarbazepine is a keto derivative of carbamazepine but offers several advantages over carbamazepine. Oxcarbazepine does not require blood cell count, hepatic, or serum drug level monitoring. It causes less cytochrome P450 enzyme induction than does carbamazepine (but may decrease effectiveness of oral contraceptives containing ethinyl estradiol and levonorgestrel). As opposed to carbamazepine, oxcarbazepine does not induce its own metabolism. These properties, combined with its similarity to carbamazepine, led many clinicians to use this medication for the treatment of bipolar disorder. Randomized controlled trials suggested efficacy in the treatment of acute mania compared with lithium and haloperidol, but these trials were quite small and did not include a placebo control (Emrich 1990). 

Absorption of orally administered, relatively lipophilic compounds, such as estrone or estradiol, occurs mainly in the intestine. The bacteria that colonize the gut are, however, particularly adept at converting those compounds by attack at the 17 position to very water-soluble derivatives that defy absorption. Alkylation of that position avoids this catabolic pathway and consequently enhances bioavailability on oral administration. The reaction of 17-keto steroids with nucleophiles illustrates the high degree of stereospecifity that is maintained in many steroid reactions approach of that carbonyl group from the (3 face is virtually forbidden by the presence of the adjacent 18 methyl. The reaction products consequently consist of almost pure isomers from attack at the a face. Reaction of estradiol with lithium acetylide thus gives ethynylestradiol (9-2) [9] the corresponding alkylation of estradiol 3-methyl ether (9-1) leads to mestranol (9-3) [10]. Both compounds are potent orally active... 

Double dehydrogenation and even complete aiomatization of the A-ring of 34iydroxy or 3-keto steroids can also be etiected the latter is of special interest in the preparation of estrogens, for example the conversion of the diene (60) to the a-estradiol derivative (61 equation 19) by Proactinomyces glob-erulaP ... 

Ruthenium hydrogenation of estrone, estradiol, or related steroids 7 gives 3 )3-hydroxy-5 a,10 a-estranes 8 as the major products [equation (e)]. Reaction proceeds through a 3-keto intermediate and the stereochemistry of the product at all three new asymmetric centers follows the pattern of cfr-rear attack. ... 

J -3-Keto isomerase catalyzes the isomerization of J -3-ketosteroids to zl -3-ketosteroids by stereospecific transfer of a hydrogen atom from C(4) to C(6). There is considerable evidence that it is the 40- and 6/5-hydrogens that are involved and that the reaction proceeds via an enolic intermediate. A low resolution (6 A) crystal structure determination has been published and the probable steroid-binding site identified via a bound inhibitor, 4-acetoxy-mercuric estradiol. The results of a higher resolution study (2.5 A) combined with the results of NMR studies and analysis of activity of mutant forms of the enzyme have helped to further define the probable active site of the enzyme [64]. 

Eollowing oral administration, at least 75% of a dose of estramustine is absorbed from the gastrointestinal tract and rapidly dephosphorylated. Estramustine is found in the body mainly as its oxidized 17-keto analog isomer, estro-mustine both forms accumulate in the prostate. Some hydrolysis of the carbamate linkage occurs in the liver, releasing estradiol, estrone, and the normustine group. Estramustine and estromustine have plasma half-lives of... 

Simultaneous metabolites, desogestrel, 3-hydroxydesogestrel, 3-ketodesogestrel, 6-ketoe-thinyl estradiol... 

We have studied the reaction of the potential afiSnity label, 3-bromo-acetoxyestrone, with human placental estradiol dehydrogenase and have found that it satisfies the first four criteria for an afiSnity label. Furthermore, the 17-keto group of this compound offers an opportunity to determine whether, after reaction with the enzyme, the covalently bound steroid is suitably positioned to serve as a substrate in the dehydrogenase reaction. We provide evidence that such is indeed the case. 

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