A facile total synthesis of ent-17beta-estradiol and structurally related analogues

A facile six-step synthesis (15.2% yield) of ent-17beta-estradiol from readily accessible precursors is described. The preparation of analogues with 2-alkyl substituents, double bond unsaturation in the C-ring, a cis C,D-ring fusion and modified substituents at C(17) is also reported.     

A facile synthesis of D-ribo-C(20)-phytosphingosine and its C2 epimer from D-ribose

A facile synthetic route to d-ribo-C(20)-phytosphingosine 31 and its C2 epimer 32 is described. The Overman rearrangement of allylic trichloroacetimidates derived from the known ribose derivative 7 has been used as the key step. The subsequent functional group interconversions in rearranged products 14 and 15 followed by Wittig olefination, Pd/C-mediated reduction and the removal of protecting groups successfully constructed the final molecules.     

An efficient synthesis of C2-symmetric chiral binaphthyl ketone catalysts

An efficient synthesis of C2-symmetric chiral binaphthyl ketones 1a and b, effective catalysts for asymmetric epoxidation, is reported. The key features of this synthesis are Co(salen)-catalyzed macrolactonization of racemic 1,1'-binaphthyl-2,2'-dicarboxylic acid monoglycidyl esters 3a and b and lipase-catalyzed enantioselective acylation of resulting 11-membered cyclic binaphthyl alcohols 4a and b.     

A facile synthesis of [14C] epicholesterol

A facile procedure is described for the preparation of [14C]epicholesterol from [14C]cholesterol. Cholesterol is first converted to cholesteryl mesylate, which is treated with cesium acetate and 18-crown-6 in refluxing toluene to give epicholesteryl acetate. The latter is hydrolyzed, without isolation, with potassium hydroxide in tetrahydrofuran-methanol to give epicholesterol, which is obtained in pure form by preparative thin-layer chromatography.     

A facile one-pot synthesis of 4,5-diaryl-2,2-dimethyl-3(2H)-furanones

An efficient and practical one-pot synthesis of 4,5-diaryl-2,2-dimethyl-3(2H)-furanones has been achieved from 1,2-diarylethanones and 2-bromoisobutyryl cyanide in the presence of excess base, by employing the 'hard soft acid base' principle. The reaction scope of 2-bromoisobutyryl cyanide could be expanded to prepare a variety of 2,2-dimethyl-3(2H)-furanone derivatives other than 4,5-diaryl-2,2-dimethyl-3(2H)-furanones.     

A facile synthesis of 5-(perfluoroalkyl)-pyrimidines.

In the paper a synthetic two stage procedure is described for the preparation of perfluoroalkylated derivatives of uracil and its nucleosides. Using copper bronze a perfluoroalkyl-copper-complex is formed from perfluoralkyl iodides in polar aprotic solvents, such as DMSO, and under inert conditions. The reaction of this complex with uracil, uridine and 2-deoxyuridine leads to the corresponding 5-substituted perfluoralkyl derivatives. It is shown by mass spectra that the substitution always takes place at the 5-position of the pyrimidine. The chemical and physical properties of the formed compounds are described.     

C2-symmetric inhibitors of Plasmodium falciparum plasmepsin II: synthesis and theoretical predictions

A series of C(2)-symmetric compounds with a mannitol-based scaffold has been investigated, both theoretically and experimentally, as Plm II inhibitors. Four different stereoisomers with either benzyloxy or allyloxy P1/P1' side chains were studied. Computational ranking of the binding affinities of the eight compounds was carried out using the linear interaction energy (LIE) method relying on a complex previously determined by crystallography. Within both series of isomers the theoretical binding energies were in agreement with the enzymatic measurements, illustrating the power of the LIE method for the prediction of ligand affinities prior to synthesis. The structural models of the enzyme-inhibitor complexes obtained from the MD simulations provided a basis for interpretation of further structure-activity relationships. Hence, the affinity of a structurally similar ligand, but with a different P2/P2' substituent was examined using the same procedure. The predicted improvement in binding constant agreed well with experimental results.     

Vitellogenin induction by 17beta-estradiol and 17alpha-ethinylestradiol in male zebrafish (Danio rerio)

Adult male zebrafish (Danio rerio) were exposed to 17beta-estradiol (E2) or 17alpha-ethinylestradiol (EE2) in flow-through systems for 8 days. This was done to compare the sensitivity of the estrogen inducible vitellogenin (Vtg) biomarker system of this proposed OECD test guideline species to other relevant test species. Vtg was quantified in whole body homogenate by a species-specific ELISA. Actual water concentrations of E2 and EE2 were quantified by LC-MS, with detection limits of 1.0 and 0.6 ng/l, respectively. Vtg induction (LOEC) occurred in whole body homogenate at actual water concentrations of 21 ng E2/l and 3.0 ng EE2/l, respectively. As an alternative to the ANOVA approach, the relationship between the percentage of responding fish (Vtg) and the external E2 or EE2 concentration was determined by logistic regression analysis. Based on the regression analysis, EC-values could be determined: EC10, EC50 and EC90 were 15.4, 41.2 and 67.1 ng E2/l, respectively and 0.92, 2.51 and 4.09 ng EE2/l, respectively. Comparisons of these response limits to corresponding values for rainbow trout (Oncorhynchus mykiss), fathead minnow (Pimephales promelas) and Japanese medaka (Oryzias latipes) revealed the zebrafish as a sensitive test species.     

A facile synthesis of 1-O-alkyl-2-(R)-hydroxypropane-3-phosphonocholine (lyso-phosphono-platelet activating factor).

The synthesis of 1-O-alkyl-2-(R)-hydroxypropane-3-phosphonocholine is described. An efficient alkylation procedure using (NaH/DMSO) catalysis is also described and applied to the synthetic scheme. The key intermediate 1-O-alkyl-2-(R)-O-benzyl-3-bromopropane was phosphonylated using tris(methylsilyl)phosphite; the resulting phosphonic acid was coupled to choline using trichloroacetonitrile/pyridine or triisopropylbenzenesulfonyl chloride/pyridine followed by catalytic hydrogenation to yield 1-O-alkyl-2(R)-hydroxypropane-3-phosphonocholine.     

Mitochondria play an important role in 17beta-estradiol attenuation of H(2)O(2)-induced rat endothelial cell apoptosis

Studies have shown salutary effects of 17beta-estradiol following trauma-hemorrhage on different cell types. 17beta-Estradiol also induces improved circulation via relaxation of the aorta and has an anti-apoptotic effect on endothelial cells. Because mitochondria play a pivotal role in apoptosis, we hypothesized that 17beta-estradiol will maintain mitochondrial function and will have protective effects against H(2)O(2)-induced apoptosis in endothelial cells. Endothelial cells were isolated from rats' aorta and cultured in the presence or absence of H(2)O(2), a potent inducer of apoptosis. In additional studies, endothelial cells were pretreated with 17beta-estradiol. Flow cytometry analysis revealed H(2)O(2)-induced apoptosis in 80.9% of endothelial cells; however, prior treatment of endothelial cells with 17beta-estradiol resulted in an approximately 40% reduction in apoptosis. This protective effect of 17beta-estradiol was abrogated when endothelial cells were cultured in the presence ICI-182780, indicating the involvement of estrogen receptor (ER). Fluorescence microscopy revealed a 17beta-estradiol-mediated attenuation of H(2)O(2)-induced mitochondrial condensation. Western blot analysis demonstrated that H(2)O(2)-induced cytochrome c release from mitochondrion to cytosol and the activation of caspase-9 and -3 were decreased by 17beta-estradiol. These findings suggest that 17beta-estradiol attenuated H(2)O(2)-induced apoptosis via ER-dependent activation of caspase-9 and -3 in rat endothelial cells through mitochondria.     

Vitellogenic effects of 17beta-estradiol in male Chinese loach (Misgurnus anguillicaudatus)

Male Chinese loaches (Misgurnus anguillicaudatus) were exposed to 17beta-estradiol (E2) in the ambient water at nominal concentrations of 0.5, 1, 5 and 10 mug/L continuously for 8 weeks using a semi-static system. The gonadosomatic index (GSI), total plasma protein, total plasma calcium, magnesium and zinc, and plasma vitellogenin (Vtg) were determined as test endpoints. Our results indicate no significant changes in the GSI between exposed and control groups (P<0.05). All exposure concentrations of E2 dramatically induced the production of Vtg within 7 days. The vitellogenic response of male loach was time- and dose-dependent. At higher concentrations of E2 (5 and 10 microg/L), total plasma protein, total plasma calcium, and total plasma magnesium presented a significant time- and dose-dependent increase, and the three parameters were significantly correlated with plasma Vtg. We conclude that Chinese loaches are sensitive to estrogenic compounds and may be chosen as potential sentinel species in field and laboratory studies. In addition, total plasma protein, total plasma calcium, and total plasma magnesium can be used as indirect indicators to predict Vtg levels in estrogenized Chinese loach.     

Synthesis and C(2) -symmetric structure of a cyclotetrapeptide composed of anthranilic acid and leucine

A chiral cyclotetrapeptide (1) was synthesized from 2-nitrobenzoic acid and leucine. A single-crystal X-ray of the compound revealed a C(2) -symmetric bowl-shaped structure. The cyclic compound had a unique hydrogen-bonding network composed of three-centered hydrogen bonds and bifurcated hydrogen bonds between NH and CO of anthranilic residue. The NMR spectra and molecular modeling of 1 also suggested the chiral bowl structure.     

Requirement for prostaglandin F2 alpha in 17 beta-estradiol stimulation of DNA synthesis in rabbit endometrial cultures

We have hypothesized that two of the endogenously synthesized endometrial prostaglandins (PGs), prostaglandin F2 alpha (PGF2 alpha), and prostaglandin E1 (PGE1), play a regulatory role in growth control of the rabbit endometrium. PGF2 alpha increases DNA synthesis and PGE1 inhibits that effect. Primary cultures of rabbit endometrial cells were used to examine the possible role of these PGs in the mechanism of action of 17 beta-estradiol on DNA synthesis. Towards this end, binding, second messenger and DNA synthesis experiments were performed. 17 beta-estradiol stimulation resulted in a time dependent (optimal: approximately 6 h) and 17 beta-estradiol concentration dependent (optimal: approximately 10(-7) M 17 beta-estradiol in phenol red-containing medium) increase in [3H]PGF2 alpha binding. Scatchard type analysis of the binding data revealed an increase in receptor number while the receptor affinity for [3H]PGF2 alpha remained the same as in the control treated cultures. This 17 beta-estradiol stimulated increase in PGF2 alpha receptor allowed a suboptimal concentration of PGF2 alpha (10(-9) M) to increase intracellular levels of inositol polyphosphates, while by itself this concentration of PGF2 alpha caused no significant change in intracellular inositol polyphosphate levels. 17 beta-estradiol, alone among the several studied steroid hormones, could increase [3H]PGF2 alpha binding. Proliferation studies revealed that, in these primary cultures of rabbit endometrium, 17 beta-estradiol could increase DNA synthesis but not in the presence of indomethacin, unless PGF2 alpha was added to the medium at a concentration (10(-10) M) near or above what is normally accumulated in the medium by these cultures. In the absence of 17 beta-estradiol stimulation, addition of these same low concentrations of PGF2 alpha had no effect on DNA synthesis. Apparently, through its effect on the PGF2 alpha receptor, 17 beta-estradiol enhances the PGF2 alpha stimulated DNA synthesis response approximately 100 fold. The DNA synthesis induced by 17 beta-estradiol can be inhibited by PGE1, as can PGF2 alpha-induced DNA synthesis. We propose that 17 beta-estradiol may be mediating its mitogenic effect through an alteration of the prostaglandin agonist:antagonist control of proliferation in rabbit endometrial cultures. In addition we suggest that, if 17 beta-estradiol acts to increase PGF2 alpha, receptors as part of its mode of action, this may be of importance in other tissues possessing both prostaglandin and 17 beta-estradiol receptors.