Montmorillonite Catalyzed Synthesis of Novel Steroid Dimers.

The reactions of sterols (androst-5-en-3ß-ol-17-one, diosgenin, and cholesterol) and their tosylates with hydroquinone aimed at the synthesis of O,O-1,4-phenylene-linked steroid dimers were studied. The reaction course strongly depended on the conditions used. The study has shown that the major reaction products are the elimination products and unusual steroid dimers resulting from the nucleophilic attack of the hydroquinone C2 carbon atom on the steroid C3 position, followed by an intramolecular addition to the C5-C6 double bond. A different reaction course was observed when montmorillonite K10 was used as a catalyst. The reaction of androst-5-en-3ß-ol-17-one under the promotion of this catalyst afforded the O,O-1,4-phenylene-linked steroid dimer in addition to the disteroidal ether. The formation of the latter compound was suppressed by using 3-tosylate as a substrate instead of the free sterol. The reactions of androst-5-en-3ß-ol-17-one tosylate and cholesteryl tosylate with hydroquinone catalyzed by montmorillonite K10 carried out under optimized conditions afforded the desired dimers in 31% and 67% yield, respectively.

Cytotoxicity of Triterpene Seco-Acids from Betula pubescens Buds.

The present study investigated the magnitude and mechanism of the cytotoxic effect on selected cancer cell lines of 3,4-seco-urs-4(23),20(30)-dien-3-oic acid (1), 3,4-seco-olean-4(24)-en-19-oxo-3-oic acid (2), and 3,4-seco-urs-4(23),20(30)-dien-19-ol-3-oic acid (3) isolated from downy birch (Betula pubescens) buds by carbon dioxide supercritical fluid extraction and gradient column chromatography. Cell viability in six human cancer lines exposed to these compounds was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was quantified by annexin V/propidium iodide staining of gastric cancer AGS and colorectal cancer DLD-1 cells. To evaluate the mechanism of apoptosis, the expression of apoptosis-related proteins was analyzed by Western blot. Compound 1 exhibited non-specific toxicity, while compounds 2 and 3 were specifically toxic to colon and stomach cancer cells. The toxicity of compounds 2 and 3 against these two cell lines was greater than for compound 1. Cleavage of caspase-8, -9, and -3 was found in AGS and DLD-1 cells treated with all three seco-acids, indicating the induction of apoptosis via extrinsic and intrinsic pathways. Therefore, triterpene seco-acids (1-3) decreased cell viability by apoptosis induction. AGS and DLD-1 cells were more susceptible to seco-acids with an oxidized C19 than normal fibroblasts. Hence, it made them a new group of triterpenes with potential anticancer activity.

Synthesis of novel galeterone derivatives and evaluation of their in vitro activity against prostate cancer cell lines.

Prostate cancer is one of the main causes of male cancer-related deaths worldwide and the suppression of androgen receptor signalling is established as an effective strategy for the treatment. A series of galeterone analogues including several steroid-fused azacycles, as well as 17-(benzimidazol-1-ylimino), 16α-(benzimidazol-2-ylamino), and 16α-(benzothiazol-2-ylamino) steroid derivatives, were synthesized and tested against prostate cancer cell lines. Candidate compound 3f was shown to reduce AR-regulated transcription in a dose-dependent manner in nanomolar ranges and suppress expression of AR-regulated proteins Nkx3.1 and PSA in 22Rv1-ARE14 and VCaP cancer cell lines. Flexible docking study revealed similar position of 3f within AR binding site in comparison of galeterone even with stronger binding energy.

PhSeZnCl in the Synthesis of Steroidal ß-Hydroxy-Phenylselenides Having Antibacterial Activity.

We report here the reaction of in situ prepared PhSeZnCl with steroid derivatives having an epoxide as an electrophilic functionalization. The corresponding ring-opening reaction resulted to be regio- and stereoselective affording to novel phenylselenium-substituted steroids. Assessment of their antibacterial properties against multidrug-resistant bacteria, such as Pseudomonas aeruginosa Xen 5 strain, indicates an interesting bactericidal activity and their ability to prevent bacterial biofilm formation.

A study on the reaction of 16-dehydropregnenolone acetate with 2-aminobenzimidazole.

The condensation of 16-dehydropregnenolone acetate with 2-aminobenzimidazole was studied. The polycyclic aromatic product was formed as a single regioisomer in a cascade reaction comprising addition, cyclization, autoxidation, and aromatization, in addition to the rearranged D-homo product. The reaction mechanism based on DFT calculations is proposed.

Electrochemical cholesterylation of sugars with cholesteryl diphenylphosphate.

Electrochemical cholesterylation of various sugars with cholesteryl diphenylphosphate was studied. The reaction afforded mono-, di-, tri-, and tetra-cholesterylated products using equivalent amounts of the reagent. The reactions turned out to be completely stereoselective with respect to both sugar and steroid but only partially regioselective - primary and anomeric hydroxyl groups in sugars were the most reactive ones while no substantial differences in reactivity was found for different secondary hydroxyl groups.

Synthesis of Aromatic Retinoids and Curcuminoids and Evaluation of their Antiproliferative, Antiradical, and Anti-inflammatory Activities.

Natural retinoids and curcuminoids are known for their broad spectrum of biological properties, such as antioxidant, anti-inflammatory, antitumor, and so forth. In this work, a convenient synthesis of aromatic retinoids and curcuminoids from vinyl or allyl ketones, and the corresponding alcohols, using olefin metathesis as a key reaction, was elaborated. The best yields and diastereoselectivities were obtained from allylic or homoallylic alcohols by employing the two-step cross-metathesis/oxidation procedure. The synthesized analogues were tested for their antiproliferative activity on human cancer cell lines of various origin (leukemia CEM, adenocarcinoma MCF7, cervical carcinoma HeLa) as well as for their antioxidant and anti-inflammatory activity in vitro. All examined derivatives exhibited strong anti-inflammatory activity in vitro without affecting cell viability. They also showed strong cytotoxicity against leukemia cell line CEM, except for 18 and 35. The antioxidant activity of the tested compounds was rather weak.

Oxidation of Olefins with Benzeneseleninic Anhydride in the Presence of TMSOTf.

A new oxidizing system for olefins, consisting of benzeneseleninic anhydride and trimethylsilyl triflate, was studied. The highly reactive benzeneseleninyl cation is presumably formed under these conditions. It has been shown that different products are formed with this species depending on the specific structure of olefin. The 1,1-disubstituted olefins afforded mostly α,ß-unsaturated carbonyl compounds. The sterically encumbered tri- or tetrasubstituted olefins yielded 1,2- or 1,4-dihydroxylated products, presumably via four-membered cyclic intermediates.

Electrochemical synthesis of glycoconjugates from activated sterol derivatives.

Several derivatives of cholesterol and other 3ß-hydroxy-Δ(5)-steroids were prepared and tested as sterol donors in electrochemical reactions with sugar alcohols. The reactions afforded glycoconjugates with sugar linked to a steroid moiety by an ether bond. Readily available sterol diphenylphosphates yielding up to 54% of the desired glycoconjugate were found to be the best sterol donors.

Photoinduced isomerization of 23-oxosapogenins: conformational analysis and spectroscopic characterization of 22-isosapogenins.

The first synthesis of 22-isospirostane derivatives is described. They were obtained by photochemical isomerization of 23-oxosapogenins. The structure of 23-oxo-22-isotigogenin acetate (12) was proved by a single crystal X-ray diffraction, while structures of 23-oxo-22-isodiosgenin acetate (13) and 23-oxo-22-isosarsasapogenin acetate (14) were elucidated by spectroscopic methods. 22-Isodiosgenin acetate (17) was obtained by NaBH(4) reduction of the 23-oxo derivative 13 followed by the two-step Barton-McCombie deoxygenation procedure. Conformational analysis of 22-iso compounds was carried out with CD and NMR, as well as DFT calculations.

A selective electrochemical method of glycosylation of 3beta-hydroxy-Delta 5-steroids.

A new electrochemical glycosylation method is presented. According to the method cholesterol and other 3beta-hydroxy-Delta(5)-steroids can be selectively transformed to glycosides using non-activated sugars. The method is also useful for the synthesis of glycoconjugates with sugar linked to a steroid moiety by an ether bond.

Synthesis of "glycospirostanes" via ring-closing metathesis.

Syntheses of "glycospirostanes" from 3beta-hydroxy-23,24-dinor-5alpha-cholano-22,16-lactone and 3alpha-hydroxy-23,24-dinor-5beta-cholano-22,16-lactone were performed. The key step of these syntheses was ring-closing metathesis of the corresponding C,O-diallyl derivative. Further elaboration of the six-membered ring F consisted of allylic hydroxylation with SeO(2) followed by OsO(4) dihydroxylation of the C24-C25 double bond. The obtained final products proved to be simultaneously O- and C-l-arabinopyranosides.

On reactions of steroidal 23-oxo and 23,24-epoxysapogenins with Lewis acids.

The reaction of 23-oxotigogenin acetate with TMSOTf in THF afforded the corresponding bisnorcholanic lactone in 60% yield. The analogous reactions carried out in dichloromethane or benzene gave the rearranged products--the isomeric spirostanic ketone (10-15%) and bisfuran (40-42%). Similar products were also obtained upon treatment of 23,24-epoxysapogenins with BF(3). The epoxides treated with TiCl(4) afforded mostly chlorohydrins and no rearranged products were detected.

Relationship between frontal N-acetylaspartate and cognitive deficits in first-episode schizophrenia.

BACKGROUND: The aim of this study was to evaluate the relationship between N-acetylaspartate (NAA) levels in selected brain regions and cognitive performance in patients with first-episode schizophrenia. MATERIAL/METHODS: Thirty patients (20 male, 10 female; mean age: 22.5 years) with the diagnosis of first-episode schizophrenia and 19 comparable healthy controls were studied. The Wisconsin Card Sorting Test (WCST) was used to assess cognitive functions. MR imaging and MR spectroscopy examinations were performed on a 1.5 T scanner. Voxels of 8 cm3 were positioned in the left frontal lobe, left temporal lobe, and left thalamus. The ratio of NAA to creatine and the ratio of NAA to unsuppressed water signal were analyzed. RESULTS: Patients performed significantly worse than controls on measures of the WCST. In the patient group, NAA levels in the frontal lobe were significantly related to poorer WCST performance. CONCLUSIONS: Cognitive impairment related to dysfunction of the prefrontal cortex in first-episode schizophrenia is associated with NAA level in the frontal lobe.

13C-NMR study of 4-azasteroids in solution and solid state.

A group of biologically active 4-azasteroids was studied by 13C-NMR spectroscopy in solution and in the solid phase. A full assignment of signals in the spectra of samples in chloroform was performed for thirteen 4-azasteroids using two-dimensional techniques. Substituent and steric effects of a nitrogen atom, and their influence on chemical shifts of the neighboring carbon atoms are discussed. CP MAS spectra were obtained for five 4-azasteroids including finasteride. The spectra confirmed polymorphism of the latter compound. In addition to the polymorphic forms that are already known, a new molecular complex of finasteride with dioxane is reported.

MR proton spectroscopy in liver examinations of healthy individuals in vivo.

BACKGROUND: Magnetic resonance proton spectroscopy ((1)H MRS) is a non-invasive method that provides in vivo measurement of metabolic concentrations in body tissue. However, relatively little is known about the potential of 1H MR spectroscopy for the quantification of liver metabolites. The aim of this study was to determine the usefulness of (1)H MRS in establishing the metabolic pattern of normal human liver. MATERIAL/METHODS: Proton spectroscopy of the liver, using the Picker system, Edge Eclipse 1.5T, with whole-body coil and PRESS 35 sequence, was conducted in a group of 24 healthy volunteers. In all subjects we also evaluated the thickness of the subcutaneous fat tissue in MR images and body mass index. RESULTS: The presence of lipid resonances, phosphoesters (Pe), glycogen/glucose (Glc), and glutamine/glutamate (Gln) were observed in the spectra. Total lipid concentration, CH3 and (CH2)n of the lipid resonances were higher in the men than in the women, while the metabolite contents in the CH2=CH-CH2 groups of lipids, Pe, Glc and Gln peaks were similar in both genders. We observed statistically significant positive correlation, more apparent in the group of men, between TL concentration and BMI. There was no statistically significant correlation between lipid total concentration and age. CONCLUSIONS: Proton spectroscopy enables the quantitative evaluation of lipid contents in the liver. The correlation between liver triglyceride contents and body mass index shows that the tendency to obesity is also connected with lipid accumulation in the liver.