Estradiol derivatives

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. 

RU 58668. This is a 17/J-estradiol derivative compound, substituted in the 11/9-position with a long hydrophobic side chain, producing a spatial arrangement similar to the 7a-substituted compounds in relation to the plane of steroid nucleus (Van de Velde et al. 1994,1996). 

The estradiol derivative 588 was obtained in 91% yield via oxy-Cope rearrangement, which proceeded smoothly when the tertiary alcohol 587 was exposed to potassium hydride/18-crown-6 in THF at ambient temperature under an inert atmosphere... 

M. E. Brewster, K. S. Estes, N. Bodor, Improved Debvery through Biological Membranes. 32. Synthesis and Biological Activity of Brain-Targeted Debvery Systems for Various Estradiol Derivatives , J. Med. Chem. 1988, 31, 244-249. 

Other authors have described the lipase-catalyzed chemoselective acylation of alcohols in the presence of phenolic moities [14], the protease-catalyzed acylation of the 17-amino moiety of an estradiol derivative [15], the chemoselectivity in the aminolysis reaction of methyl acrylate (amide formation vs the favored Michael addition) catalyzed by Candida antarctica lipase (Novozym 435) [16], and the lipase preference for the O-esterification in the presence of thiol moieties, as, for instance, in 2-mercaptoethanol and dithiotreitol [17]. This last finding was recently exploited for the synthesis of thiol end-functionalized polyesters by enzymatic polymerization of e-caprolactone initiated by 2-mercaptoethanol (Figure 6.2)... 

When there is a substituent on the benzene ring, a benzylic methylene proton at the meta position is more activated than the para position. Reaction of formaldehyde on the complexed estradiol derivative 246 occurred regioselectively and stereoselectively from the opposite side of Cr(CO)3 to give 247 [62],... 

Here, C is the mole fraction solubility of the drug, S is the mole fractioR of the drug, X is the mole fraction of the poiymer, and Y is the activity coeffic ent of the drug in the polymer. This relationship is equivalent to equation 8, in assuming that aH rather than AS is constant. The correlation was tested using the solubility of steroids in silicone rubber (Figure 7). The relationships in List I, for families of testosterone, progesterone, and estradiol derivatives, were observed. 

Vessieres A, Jaouen G, Gruselle M, Rossignol JL, Savignac M, Top S, Greenfield S (1988) Synthesis and receptor binding of polynuclear organometallic estradiol derivatives. J Steroid Biochem 30 301-306... 

Top S, El Hafa H, Vessieres A, Huche M, Vaissermann J, Jaouen G (2002) Novel estradiol derivatives labeled with Ru, W, and Co complexes. Influence on hormone receptor affinity of several organometallic groups at the 170 position. Chem Eur J 8 5241-5249... 

Top S, El Hafa H, Vessieres A, Quivy J, Vaissermann J, Huges DW, McGlinchey MJ, Momon JP, Thoreau E, Jaouen G (1995) Rhenium carbonyl complexes of 0-estradiol derivatives with high affinity for the estradiol receptor an approach to selective organometallic radiopharmaceuticals. J Am Chem Soc 117 8372-8380... 

El Amouri H, Vessieres A, Vichard D, Top S, Gruselle M, Jaouen G (1992) Syntheses and affinities of novel organometallic-labeled estradiol derivatives a structure-affinity relationship. J Med Chem 35 3130-3135... 

An extension to this work appeared recently when pyridin-2-yl hydrazine based classical chelators were introduced through an ethinyl or ethenyl moiety at position 17. Although still model complexes, this type of derivatization and complexation can easily be transferred to the corresponding 99mTc chemistry. It could be shown that the relative binding affinity was essentially retained and compared favourably with other reported estradiol-derived carbonyl complexes [106]. 

Diastereomeric complexes (4) of estradiol derivatives can be separated by chromatography. These differ in the location of the metal, which may be on the a- or 3-side of the ring system. Both complexes undergo regiospecific alkylation at the meta Cs-position, but with opposite stereospecificities. Decomplexation by exposure to sunlight and air furnishes 6-substituted estradiol derivatives. 

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 ... 

Gantchev, T.G., Ali, H. and Vanlier, J.E. (1994). Quantitative Structure-Activity Relationships Comparative Molecular Field Analysis (QSAR/CoMFA) for Receptor Binding Properties of Halogenated Estradiol Derivatives. J.Med.Chem., 37,4164-4176. 

Gantchev TG, Ali H, van Lier JE. Quantitative structure-activity relationships/ comparative molecular field analysis (QSAR/CoMFA) for receptor-binding properties of halogenated estradiol derivatives. J Med Chem 1994 37 4164-76. 

Type II hyperlipoproteinemia were given 2 mg/day of an estradiol derivative for 6 months. LDL-C declined by an average of 18% and HDL-C rose by 30%, while serum triglycerides were unaltered the data demonstrate another indication for estrogen therapy in postmenopausal women. ... 

Gomparison of electrotopological-state indices versus atomic charge and superdelocalisability indices in a QSAR study of the receptor binding properties of halogenated estradiol derivatives. Mol. Div., 8, 343-355. 

Sun, L, Zhou, Y, Genrong, L. and Li, S.Z. (2004) Molecular electronegativity-distance vector (MEDV-4) a two-dimensional QSAR method for the estimation and prediction of biological activities of estradiol derivatives. J. Mol. Struct. (Theochem), 679, 107—113. 

LX Tiefenauer, RY Andres. Biotinyl-estradiol derivatives in enzyme immunoassays Structural requirements for optimal antibody binding. J Steroid Biochem 35 633, 1990. 

A stereoselective Prins reaction of the estradiol derivative leads exclusively to the 7 -hydroxy-methyl products36. 

Based on the use of 4-methoxybenzocyclobutene-1-carboxylic acid, racemic homoestrone has been synthesised (ref. 124). A strategy based on boron annulation led not directly to estrone but to a synthesis of norpregnenolone which was then degraded by standard procedures to afford estradiol derivatives (ref. 125). 

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