Éva Frank

Efficient approach to androstene-fused arylpyrazolines as potent antiproliferative agents. Experimental and theoretical studies of substituent effects on BF3-catalyzed intramolecular [3 + 2] cycloadditions of olefinic phenylhydrazones

Highly diastereoselective Lewis acid induced intramolecular 1,3-dipolar cycloadditions of alkenyl phenylhydrazones (containing various substituents on the aromatic ring) obtained from a d-secopregnene aldehyde were carried out under fairly mild conditions to furnish androst-5-ene-fused arylpyrazolines in good to excellent yields. The ability of phenylhydrazones to undergo cyclization was found to be affected significantly by the electronic features of the substituents on the aromatic moiety. The rates of the ring-closure reactions were observed to be increased by electron-donating and decreased by electron-withdrawing groups. The experimental findings on the BF(3)-catalyzed transformations were supported by calculations of the proposed mechanism at the BLYP/6-31G(d) level of theory, indicating a noteworthy dependence, mainly of the initial complexation step, and hence of the whole process, on the character of the substituent. The cycloaddition was estimated to occur via a zwitterionic intermediate rather than involving a pure concerted mechanism. The antiproliferative activities of the structurally related pyrazoline derivatives were tested in vitro on three malignant human cell lines (HeLa, MCF7, and A431): the microculture tetrazolium assay revealed that several compounds exerted marked cell growth-inhibitory effects. The highest cytotoxic activities, displayed by the p-methoxyphenylpyrazoline derivative 7d (IC(50) values: 2.01, 2.16, and 1.41 microM on HeLa, MCF7, and A341 cells, respectively), were better than those of cisplatin (IC(50) values: 12.43, 9.63, and 2.84 microM, respectively).

Synthesis of novel steroidal 17α-triazolyl derivatives via Cu(I)-catalyzed azide-alkyne cycloaddition, and an evaluation of their cytotoxic activity in vitro.

Regioselective Cu(I)-catalyzed 1,3-dipolar cycloaddition of steroidal 17α-azides with different terminal alkynes afforded novel 1,4-disubstituted triazolyl derivatives in good yields in both the estrone and the androstane series. The antiproliferative activities of the structurally related triazoles were determined in vitro on three malignant human cell lines (HeLa, MCF7 and A431), with the microculture tetrazolium assay.

Stereoselective Synthesis of Some Novel Heterocyclic Estrone Derivatives by Intramolecular 1,3-Dipolar Cycloaddition

16,17-seco-3-Methoxyestra-1,3,5(10),16-tetraen-17-al undergoes intramolecular nitrone 1,3-dipolar cycloaddition with both hydroxylamine and N-methylhydroxylamine to produce a single isoxazolidine isomer in each case. The ring-closures of the hydrazones and the aldazine derived from the secoaldehyde lead to fused N-containing heterocycles via Lewis acid-induced cyclization of the intermediate azomethine imines.

Antiproliferative effects of some novel synthetic solanidine analogs on HL-60 human leukemia cells in vitro.

There is increasing evidence of the direct antiproliferative effects of various steroidal structures, including cardenolides, steroidal alkaloids and sexual hormones. The aim of the present study was to characterize the antiproliferative effects of three synthetic solanidine analogs (1-3) on HL-60 human leukemia cells. The three compounds exerted similar cytostatic effects (IC(50) values: 1.27-2.94 μM after a 72-h exposure) and the most effective (2) was selected for further investigations. Incubation with compound 2 resulted in a marked chromatin condensation followed by a gradual increase in cell membrane permeability detected by Hoechst dye 33258-propidium iodide double staining. A flow cytometric analysis revealed a marked decrease in the G1 phase and substantial increases in the S and G2/M phases after 24-h incubation, while after 48 h the proportion of cells in the subG1 phase was increased significantly with a concomitant decrease in cells in the G1 and G2/M phases. Compound 2 at 6.0 μM significantly decreased the activity of ribonucleotide reductase and proved to be a potent antioxidant in the lipid peroxidation and DPPH assays (IC(50) values: 2.0 and 13.1 μM, respectively). The antiproliferative effect of the test compound on the non-cancerous human lung fibroblast cell line (MRC-5) was significantly weaker than that on the leukemia cells. These results lead to the conclusion that compound 2 induces a marked disturbance in the cell cycle, which is, at least partially, a consequence of the inhibition of DNA synthesis.

Synthesis and receptor-binding examinations of the normal and 13-epi-D-homoestrones and their 3-methyl ethers.

An effective epimerization of the normal estrone 3-methyl and 3-benzyl ethers by using o-phenylenediamine and AcOH made the possibility for facile entry into the 13alpha-estrone series. Combination of this synthetic methodology with an isolation step carried out by means of the Girard-P reagent, the corresponding ethers of 13-epi-estrone were obtained in excellent yields. The 3-hydroxy and 3-methoxy D-homoestrone derivatives in both the normal and the 13alpha-estrone series were then synthesized and tested in vitro in a radioligand-binding assay. The estrogen receptor recognizes these compounds, but their relative binding affinities (RBAs) are lower than that of the reference compound 3,17beta-estradiol. The progesterone receptor-binding affinities of the four D-homo derivatives were also tested showing low values for 13alpha-D-homoestrone and its 3-methyl ether. Pharmacologically, these 13alpha-D-homoestrone derivatives are estrogen receptor-selective molecules.

Efficient approach to novel 1α-triazolyl-5α-androstane derivatives as potent antiproliferative agents

Stereoselective 1,4-Michael addition of azoimide to 17β-acetoxy-5α-adrost-1-en-3-one was carried out to furnish a 1α-azido-3-ketone, which was reduced to give the 3β- and 3α-hydroxy epimers in a ratio of 5 : 2. The Cu(I)-catalyzed 1,3-dipolar cycloaddition of the major isomer to terminal alkynes afforded 1α-triazolyl derivatives, which were deacetylated to the corresponding 3β,17β-diols or oxidized to the analogous 3-ketones. However, the ability of the minor 1α,3α-azidoalcohol to undergo similar cyclization was found to be affected significantly by the steric bulk of the substituents on the alkyne reaction partner. All triazolyl compounds were tested in vitro on three malignant gynecological cell lines (HeLa, MCF7 and A2780).

Synthesis and in vitro antiproliferative activity of novel androst-5-ene triazolyl and tetrazolyl derivatives.

A straightforward and reliable method for the regioselective synthesis of steroidal 1,4-disubstituted triazoles and 1,5-disubstituted tetrazoles via copper(I)-catalyzed cycloadditions is reported. Heterocycle moieties were efficiently introduced onto the starting azide compound 3β-acetoxy-16β-azidomethylandrost-5-en-17β-ol through use of the “click” chemistry approach. The antiproliferative activities of the newly-synthesized triazoles were determined in vitro on three human gynecological cell lines (HeLa, MCF7 and A2780) using the microculture tetrazolium assay.

Synthesis of novel halogen-containing d-homoestrone and 13α-d-homoestrone derivatives by Lewis acid-induced intramolecular Prins reaction

Abstract A simple synthetic route has been developed for the synthesis of 16-halo- d -homosteroids in both the normal and 13-epiestrone series by the Lewis acid-catalyzed cyclization of an unsaturated secoestrone aldehyde and its 13α isomer.

Synthesis of novel steroid alkaloids by cyclization of arylimines from estrone

Intramolecular Lewis or Bronsted acid-catalyzed cyclization reactions of steroid arylimines 6 yielded either tetrahydroquinolines condensed to the estrane skeleton 9 or N-arylamino-D-homosteroids 12–16, depending on the substituent of the arylimino group.

Synthesis, characterization and biological evaluation of some novel 17-isoxazoles in the estrone series.

Regioselective 1,3-dipolar cycloadditions of different aryl nitrile oxides to mestranol were carried out to furnish novel steroidal 17α-isoxazoles in good to excellent yields. Copper(I) was found to be an efficient catalyst, accelerating the intermolecular ring-closures and leading exclusively to 3,5-disubstituted isoxazoles. The yields of the cycloadducts, however, were influenced by the substituents on the aromatic moiety of the 1,3-dipoles. Moreover, dehydration of the primary products resulted in the corresponding Δ(16,17)exo-heterocyclic derivatives. All the synthesized compounds were subjected to in vitro pharmacological studies of their antiproliferative effects relative to three human malignant cell lines (HeLa, MCF7 and A2780).