Strategy in drug reseabch. Synthesis and study of the psogestational and ovulation inhibitory activity of a series of 11β-substituted-17α-ethynyl-4-estren-17β-ols

Broek, Albert; Broess, A. I. A.; Heuvel, Marianne J. van den; Jongh, H. P. De; Leemhuis, J.; Schönemann, K. H.; Smits, J.; Visser, J. de; Vliet, N. P. Van; Zeelen, F. J.

doi:10.1016/0039-128x(77)90095-2

Cited by 26 publications

(4 citation statements)

References 15 publications

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“…Estradiol was protected with 3- and 17-benzyl ether groups and oxidized with DDQ in methanol and dioxane to give 24 . Hydroboration and oxidation followed by further oxidation with PCC with methodology used previously , gave the 11-ketone 26 , which was converted to the 11-methylene compound 27 by Peterson olefination. , Hydroboration/oxidation of 11-methylene-substituted steroids occurs with delivery of the reagent to the less stearically hindered α-face giving the 11β-hydroxymethyl substituent. − Olefin 27 was converted to 28 in this manner. Tosylation of the hydroxyl group followed by displacement with cyanide gave the nitrile 30 , which was hydrolyzed to the acid 31 .…”

Section: Chemistrymentioning

confidence: 98%

“…21,22 Hydroboration/oxidation of 11-methylene-substituted steroids occurs with delivery of the reagent to the less stearically hindered R-face giving the 11β-hydroxymethyl substituent. [23][24][25] Olefin 27 was converted to 28 in this manner. Tosylation of the hydroxyl group followed by displacement with cyanide gave the nitrile 30, which was hydrolyzed to the acid 31.…”

Section: Chemistrymentioning

confidence: 99%

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Synthesis and Evaluation of B-, C-, and D-Ring-Substituted Estradiol Carboxylic Acid Esters as Locally Active Estrogens

et al. 2003

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We have synthesized derivatives of estradiol that are structurally modified to serve as "soft" estrogens and act within a geographically limited area of the body; estrogens without systemic action. We have previously shown with 16alpha-substituted analogues of estradiol that carboxylates proximal to the steroid ring neither bind to the estrogen receptor nor activate estrogen-responsive genes. However, when the carboxylic acid is masked as an ester, they bind to the receptor and stimulate estrogenic responses. Enzymatic hydrolysis through nonspecific esterases can inactivate these estrogens and thereby limit their area of action. Here, we describe our continued studies to design "soft" estrogens by synthesizing carboxylic acid esters of estradiol at the 7alpha-, 11beta-, and 15alpha-positions in the steroid nucleus at which bulky substituents are accommodated by the estrogen receptor. These compounds were tested for estrogen receptor binding (estrogen receptors alpha and beta), stimulation of an estrogen sensitive gene in Ishikawa cells in culture, and as substrates for enzymatic hydrolysis. Likely candidates were tested in in vivo assays for systemic and local estrogenic action. The biological studies showed that regardless of the point of attachment, all of the short-chain carboxylic acids, C-1 to C-3, were devoid of hormonal action, while many of the esters were estrogenic. The site on the steroid nucleus had great influence on hormonal activity and esterase hydrolysis. Formate esters at 7alpha and 15alpha were good estrogens, but lengthening the chain to acetate dramatically decreased hormonal activity. However, the 7alpha-formate esters were not enzymatically hydrolyzed. At 11beta, the acetate (methyl ester) was an effective estrogen, but increasing the chain length to propionate dramatically reduced hormonal activity. In general, the length of the alcohol from methyl to butyl had only a small effect on receptor binding, and as the size of the alcohol increased, so did esterase hydrolysis. One exception was the 11beta-acetate esters where increasing the alcohol moiety from methyl to ethyl eliminated estrogenic activity (Ishikawa cells) without affecting estrogen receptor binding. Several of the esters were tested in vivo, and two, the methyl and ethyl esters of estradiol-15alpha-formate, appeared to have the requisite properties (high local and low systemic activity) of superior "soft" estrogens.

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Section: Chemistrymentioning

confidence: 98%

Section: Chemistrymentioning

confidence: 99%

Synthesis and Evaluation of B-, C-, and D-Ring-Substituted Estradiol Carboxylic Acid Esters as Locally Active Estrogens

et al. 2003

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“…A correlation between the steric size of the 1 l fl substituent and the progestational activity of lynestrenol derivatives has been proposed (van der Broek et al, 1977) and the variation in activity appears related to changes in the overall conformation of the molecule caused by the introduction of the 1 l fl substituent rather than to the direct interaction of the 1 lfl substituent with the receptor site. Because the progestational activity of the title compound is only slightly enhanced by 1 lfl-fluoro substitution, it is of interest to compare its conformation with that of lynestrenol.…”

Section: Introductionmentioning

confidence: 99%

Conformational analysis of progestational agents: 11β-fluoro-19-nor-17α-pregn-4-en-20-yn-17β-ol

Rohrer¹,

Duax²,

Zeelen³

1978

Acta Crystallogr Sect B

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Successive cross-linking would form polymer molecules with chain axes parallel to a. There is sufficient freedom for the diacetylene segments of 3,5-octadiyne-l,8-diol to be rearranged during polymerization without the series of hydrogen bonds (illustrated by the broken lines in Fig. 3) being disrupted. This contrasts significantly with the behaviour of 2,4-hexadiyn-1-ol (Fisher, Batchelder & Hursthouse, 1978) where rather severe hydrogen-bonding restrictions at one end of each monomer molecule affect the polymerization process. Crystallographic studies of polymeric 3,5-octadiyne-1,8-diol are in progress.We thank C. Galiotis for his help in synthesizing the octadiyne-diol and Dr D. Bloor for useful discussions. This work was supported by grants from the SRC and The Royal Society. Abstract. C20H27FO, M r = 302.4, monoclinic, P2~, a = 10.2844 (7), b = I1.2118 (6), c = 7.2248(4) A, fl= 94.604 (5) ° (2 = 1.5418 A, T = room temperature), V= 830.4 A 3, Z = 2, px= 1.210g cm -3.The llflfluoro substituent places about the same steric strain on the molecule as H. The result in overall conformation is essentially the same as the unsubstituted compound without the bowing caused by other 11 fl substituents.

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“…lynestrenol (Rohrer, Lauffenburger, Duax & Zeelen, 1976) and have been reviewed by Griffin, Duax & Weeks (1984). A study concerning the biological activity of 11/3-substituted lynestrenol derivatives has been published by van der Broek et al (1977).…”

mentioning

confidence: 99%

Diphenylphosphino-N-methylthioformamid

Hiller¹,

Wurst²,

Kunze³

1987

Acta Crystallogr C

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Strategy in drug reseabch. Synthesis and study of the psogestational and ovulation inhibitory activity of a series of 11β-substituted-17α-ethynyl-4-estren-17β-ols

Cited by 26 publications

References 15 publications

Synthesis and Evaluation of B-, C-, and D-Ring-Substituted Estradiol Carboxylic Acid Esters as Locally Active Estrogens

Synthesis and Evaluation of B-, C-, and D-Ring-Substituted Estradiol Carboxylic Acid Esters as Locally Active Estrogens

Conformational analysis of progestational agents: 11β-fluoro-19-nor-17α-pregn-4-en-20-yn-17β-ol

Diphenylphosphino-N-methylthioformamid

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