Synthesis, characterization, and estrogen receptor binding affinity of flavone-, indole-, and furan-estradiol conjugates.

Different flavone-, indole-, and furan-17beta-estradiol conjugates, linked via alkyl spacer chains extending from the 17alpha-position of the estradiol moiety, were synthesized by Pd-catalyzed cross-coupling reactions. Structures were assigned based on spectroscopic data. In vitro competitive binding assays for the estrogen receptor (alpha-ER), using [(3)H]estradiol (RBA=100) as a competitor, revealed that a two-carbon alkyl linker combined with a flavone conjugate provided the highest binding affinity (RBA approximately 9), warranting further studies on their potential use as selective estrogen-receptor modulators (SERMs) for hormone-replacement therapies.

Estradiol derivatives bearing sulfur-containing substituents at the 11beta or 7alpha positions: versatile reagents for the preparation of estrogen conjugates.

Estradiol derivatives bearing HS-, HSCH(2)-, HSCH(2)CH(2)-, MeS-, MeSCH(2)-, MeSCH(2)CH(2)-, or PhCH(2)SCH(2)CH(2)-groups at the 11beta position or an HS-group at the 7alpha position have been synthesized, and their binding affinity to the estrogen receptor (ER) determined. Nearly all of these substituted estrogens retain high binding affinity, and at the 11beta position, the sulfur atom has an effect on ER binding that is similar to that of a carbon atom. These thiol derivatives are promising intermediates for the preparation of a variety of estradiol conjugates. The methyl sulfides, in particular, might potentially be developed as (11)C-labeled agents for imaging ER-positive tumors by positron emission tomography.

Vascular effects of synthetic or natural progestagen combined with conjugated equine estrogen in healthy postmenopausal women.

BACKGROUND: Synthetic, not natural, progestagen may negate the favorable effects of estrogen. Nonetheless, observational studies report no differences in risk for clinical cardiovascular events between users of unopposed estrogen and users of estrogen combined with synthetic progestin. METHODS AND RESULTS: In a double-blind study, we randomly assigned 20 healthy postmenopausal women to micronized progesterone (MP) 200 mg or medroxyprogesterone acetate (MPA) 10 mg for 10 days with conjugated equine estrogen (CEE) 0.625 mg for 25 days and the remaining 5 days off cyclically during 2 months, followed by crossover to the alternate therapy. CEE+MP and CEE+MPA significantly improved the percent flow-mediated dilator response to hyperemia relative to baseline measurements (P=0.004 by ANOVA) by a similar degree (P=0.863). Both therapies significantly decreased E-selectin, intercellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1 levels from baseline values (P<0.001, P=0.048, and P=0.016 by ANOVA, respectively) by a similar degree (P=0.977 for ICAM-1 and P=0.541 for VCAM-1, respectively). CEE+MPA decreased E-selectin levels more than CEE+MP did (P=0.040). Both therapies significantly decreased monocyte chemoattractant protein-1 levels from baseline values (P<0.005 by ANOVA) by a similar degree (P=0.194). Both therapies significantly decreased tissue factor antigen and increased tissue factor activity levels from baseline values (P=0.003 and P<0.001 by ANOVA, respectively) by a similar degree (P=0.652 for antigen and P=0.173 for activity). Both therapies significantly lowered plasma plasminogen activator inhibitor-1 levels from baseline values (P<0.001 by ANOVA) by a similar degree (P=0.533). CONCLUSIONS: CEE+MP and CEE+MPA provide similar improvement in endothelium-dependent vasodilator responsiveness and effects on markers of inflammation, hemostasis, and fibrinolysis inhibition in healthy postmenopausal women.

[Synthesis of new test reagents for the estrogen receptor in human breast cancer tissues].

According to the character of structure and activity of the test reagents I-IV, two new reagents V and VI for detecting estrogen receptor of human mammary cancer cells were synthesized. This simplifies the route of synthesis and increases activity. Key intermediates VIII and IX were confirmed by IR, MS, UV and elemental analysis. The quantification of the final products V and VI were determined by UV. The result of preliminary clinico-pathological test shows compound V to be effective on estrogen receptor.

Synthesis of immunogenic C-6 derivatives of 2-methoxyestrone and 2-methoxyestradiol-17 beta and characterization of the corresponding antisera.

The synthesis, purification and structural confirmation of the 6-(carboxymethoxyimino) derivatives of 2-methoxyestrone and 2-methoxyestradiol-17 beta are described. These derivatives were coupled to bovine serum albumin by the mixed anhydride method, and rabbits were immunized with the product. The resulting antisera showed high affinity and specificity for 2-methoxyestrone and 2-methoxyestradiol-17 beta, respectively, with low cross reactivities to structurally related estrogens.

A short efficient synthesis of 16-oxygenated estratriene 3-sulfates.

A novel synthesis of sodium 17-oxo-16 alpha-hydroxy-1,3,5(10)-estratrien-3-yl sulfate (4), sodium 16 alpha, 16 beta-dihydroxy-1,3,5(10)-estratrien-3-yl sulfate (5) and sodium 16-oxo-17 beta-hydroxy-1,3,5(10)-estratrien-3-yl sulfate (6) is described. 16 alpha-Bromo-3-hydroxy-1,3,5(10)-estratrien-17-one (1) was efficiently synthesized in one step with 70-97% yield by bromination of 3-hydroxy-1,3,5(10)-estratrien-17-one with cupric bromide. 3,16 alpha-Dihydroxy-1,3,5(10)-estratrien-17-one (3) was quantitatively obtained by controlled stereospecific hydrolysis of the bromoketone 1 with sodium hydroxide in aqueous pyridine. The bromoketone 1 was converted to the 16 alpha-hydroxy-17-ketone 3-sulfate 4 by sulfation with chlorosulfonic acid in pyridine and a subsequent controlled hydrolysis in a high yield without formation of the other ketols. Treatment of the sulfate 4 with sodium borohydride have the triol sulfate 5. The sulfate 4 was also rearranged to the 17 beta-hydroxy-16-ketone 6 with sodium hydroxide in water in a quantitative yield.

Determination of estrogens by radioimmunoassay with antibodies to estrogen-C6-conjugates. I. Synthesis of estrone-, estradiol-17 -, and estriol-6-albumin conjugates.

PIP: 6-oxoestriol 6-carboxymethoxime, 6-oxoestradiol-17beta 6-carboxymethoxime, and 6-oxoestrone 6-carboxymethoxime were prepared and each was coupled to bovine serum albumin by means of the mixed anhydride technique. Standard methods were used to characterize the reaction products and intermediates. The results indicate that the estrone-, estradiol-17beta-, and estriol-6-albumin conjugates, as prepared in this study, can be used as antigens which induce specific antibodies to the corresponding haptens.^ieng