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Vaporization enthalpies and vapor pressures of 5α-androstane and 5α-cholestane are reported using correlation gas chromatography (CGC). The results for 5α-cholestane are compared to both estimated and experimental values reported previously for 5α-cholestane. The results are generally in agreement with the literature within the reported uncertainties. A simple method for reducing the amount of curvature in logarithm plots of vapor pressures as a function of K/T when using n-alkanes as standards in CGC experiments is also reported. This may prove useful in evaluating vapor pressures of rigid hydrocarbons at high temperatures. [ABSTRACT FROM AUTHOR]

Pregnane neuroactive steroids, notably allopregnanolone and pregnenolone, exhibit efficacy in mitigating inflammatory signals triggered by toll-like receptor (TLR) activation, thus attenuating the production of inflammatory factors. Clinical studies highlight their therapeutic potential, particularly in conditions like postpartum depression (PPD), where the FDA-approved compound brexanolone, an intravenous formulation of allopregnanolone, effectively suppresses TLR-mediated inflammatory pathways, predicting symptom improvement. Additionally, pregnane neurosteroids exhibit trophic and anti-inflammatory properties, stimulating the production of vital trophic proteins and anti-inflammatory factors. Androstane neuroactive steroids, including estrogens and androgens, along with dehydroepiandrosterone (DHEA), display diverse effects on TLR expression and activation. Notably, androstenediol (ADIOL), an androstane neurosteroid, emerges as a potent anti-inflammatory agent, promising for therapeutic interventions. The dysregulation of immune responses via TLR signaling alongside reduced levels of endogenous neurosteroids significantly contributes to symptom severity across various neuropsychiatric disorders. Neuroactive steroids, such as allopregnanolone, demonstrate efficacy in alleviating symptoms of various neuropsychiatric disorders and modulating neuroimmune responses, offering potential intervention avenues. This review emphasizes the significant therapeutic potential of neuroactive steroids in modulating TLR signaling pathways, particularly in addressing inflammatory processes associated with neuropsychiatric disorders. It advances our understanding of the complex interplay between neuroactive steroids and immune responses, paving the way for personalized treatment strategies tailored to individual needs and providing insights for future research aimed at unraveling the intricacies of neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Coronaviruses are continually evolving, as evidenced by the emergence of three closely related pathogenic variants over the past two decades: SARS (2002), MERS (2012), and SARS‐CoV‐2 (2019); and the appearance of many new SARS‐CoV‐2 strains during the COVID‐19 pandemic. Hence, COVID‐19 has now become a pandemic disease; with a real possibility for the emergence of new deadly SARS‐related coronaviruses. The SARS‐CoV‐2 main protease, Mpro is an attractive drug target for the development of inhibitors against SARS type and other coronaviruses because it is essential for the viral life cycle and highly conserved among a wide range of pathogenic coronaviruses. This motivated the synthesis of novel inhibitors of Mpro, which could be the basis for COVID‐19 drug development. The synthesis of new 5,6 : 16,17‐diseco and 6,7 : 16,17‐disecoandrostane 16,17a‐dinitriles is reported. In silico ADMET analyses suggest that the synthesized compounds possess drug‐like properties with no predicted toxicities. Structural similarity analyses indicates that synthesized B,D‐diseco 16,17a‐dinitrile derivatives have potential as protease inhibitors. Molecular docking simulations suggest that B,D‐diseco 16,17a‐dinitriles could inhibit substrate binding by Mpro. The present study suggests that newly synthesized androstane 5,6 : 16,17‐diseco‐5‐keto‐6‐oic acid and 6,7 : 16,17‐diseco‐6,7‐dioic acid 16,17a‐dinitriles 8 and 11 could represent a starting point for the design of Mpro inhibitors against SARS type coronaviruses. [ABSTRACT FROM AUTHOR]

The hydroxylation of steroids in the C7β position is one of the rare reactions that allow the production of value-added precursors in the synthesis of ursodeoxycholic acid and other pharmaceuticals. Recently, we discovered this activity in the ascomycete Curvularia sp. VKM F-3040. In this study, the novel gene of 7-hydroxylase (P450cur) was identified as being heterologously expressed and functionally characterized in Pichia pastoris. Transcriptome data mining and differential expression analysis revealed that 12 putative genes in Curvularia sp. mycelia significantly increased their expression in response to dehydroepiandrosterone (DHEA). The transcriptional level of the most up-regulated cytochrome P450cur gene was increased more than 300-fold. A two-gene construct with a candidate P450cur gene and the gene of its natural redox partner, NADPH-cytochrome P450 reductase (CPR), which is interconnected by a T2A element, was created. Using this construct, recombinant P. pastoris strains co-expressing fungal P450cur and CPR genes were obtained. The functional activity of the recombinant P450cur was studied in vivo during the bioconversion of androstane steroids. The fungal 7-monooxygenase predominantly catalyzed the 7β-hydroxylation of androstadienedione (ADD), DHEA, and androstenediol, whereas 1-dehydrotestosterone was hydroxylated by P450cur mainly at the C7-Hα position. To our knowledge, this is the first report of a recombinant yeast capable of catalyzing the 7α/β-hydroxylation of ADD and DHEA. [ABSTRACT FROM AUTHOR]

The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are nuclear receptors that are involved in the regulation of gene transcription of enzymes that are responsible for biotransformation and excretion of endo- and xenobiotics. The goal of the work was to study the effect of DL-butyonine sulfoximine (BSO, gamma-glutamylcysteine synthetase inhibitor) on the relative amounts of CAR and PXR in Caco-2 cells and to clarify its mechanisms. BSO was used at concentrations of 1‒500 μM for 24 and 72 h. The generation of reactive oxygen species (ROS) has been evaluated using the MitoTracker Red CM-H2 XRos fluorescent probes. Cytotoxicity was analyzed by the MTT test. The relative amount of CAR and PXR was assessed by the Western blot method. It has been shown that BSO caused an increase in ROS formation at concentrations of 10, 50, and 100 μM for 24 h and at concentrations of 50 and 100 μM for 72 h. However, 500 μM BSO reduced the viability of cells during all periods of exposure. The relative amount of CAR increased in 24 h at the BSO concentrations of 50 and 100 μM and in 72 h at its concentrations of 10 and 50 μM. The amount of PXR increased in 72 h during incubation with BSO at the concentration of 50 μM and in 24 and 72 h at its concentrations of 100 and 500 μM. The combined use of BSO (50 μM, 24 h; 10 and 50 μM, 72 h) and glutathione inhibited CAR induction, whereas 50 and 100 μM BSO inhibited PXR formation for 72 h. The addition of 1 mM glutathione to the nutrient medium with BSO (100 and 500 μM, 24 h; 500 μM, 72 h) did not affect the relative amount of PXR. No effect on CAR was observed when 1 mM glutathione was used together with BSO (100 μM, 24 h; 50 and 100 μM, 72 h). Thus, BSO can induce CAR and PXR formation by both increasing the production of free radicals, thus developing oxidative stress, and by acting independently as a xenobiotic. [ABSTRACT FROM AUTHOR]

Abstract Progesterone and its derivatives attracted widespread interest because of their applications in medicine, health care and birth control, which is the main active ingredient of contraceptive pills known as one of the five chemistry discoveries that changed human life. Although the research of pharmacological effects on contraceptive pill-related compounds has been around for decades, their ferroelectricity has long been overlooked. Here, we report that 4-androsten-3-one-5-ene-17-carboxylic acid, a derivative of progesterone, is an organic single-component ferroelectric, as confirmed by the polarization–electric field hysteresis loops. It crystallizes in the monoclinic space group P21 with a polar packing structure and undergoes a reversible structural phase transition at a high temperature of 489 K. Thermal analysis revealed that its ferroelectricity can persist up to 533 K, giving a wide working temperature range. As the first ferroelectric in steroid biomaterials, 4-androsten-3-one-5-ene-17-carboxylic acid shows great potential in applications for flexible devices, biomedical devices, bio-machines and so on.

The reaction of hydroxylamine and steroid obtained by the condensation of 16α,17α-epoxypregn-5-en-20-one with DMF dimethyl acetal proceeded through the involvement of the epoxide fragment and led to the formation of 3β-hydroxy-4′-hydroxylaminoandrost-5-eno[16,17-b]pyridine l′-N-oxide. [ABSTRACT FROM AUTHOR]

[Display omitted] • Late-stage C(sp3)–H oxyfunctionalization of saturated 5 α - and 5 β -steroids with gonane core. • Synthetic access to 20 oxidized metabolites, using H 2 O 2 as oxidant. • Preferential C–H hydroxylation of methylenic groups. • The oxidation regioselectivity is governed by steric effects. Herewith we report late-stage catalytic selective oxidative functionalization of several steroids with a common gonane core, namely androstane derivatives 5 α -androsterone-3-acetate, 5 β -androstan-17 β -ol-3-one (etiocholan-17 β -ol-3-one), 17 β -acetoxy-5 β -androstan-3-one, and 5 β -pregnane-3,20-dione, at C–H groups in the presence of chiral bis -amino- bis -pyridylmethyl and structurally related Mn complexes, using H 2 O 2 as terminal oxidant. Depending on the steric demand and absolute chirality of the catalyst, mono-hydroxylation at A, B, or C rings is achieved in up to 58% isolated yield. Strongly hydrogen-bond donating solvent hexafluoroisopropanol (HFIP) effectively protects the C17–OH group in etiocholan-17 β -ol-3-one from ketonization, thus providing an opportunity to obtain 6,17- and 12,17-dihydroxy androstane derivatives without using protecting groups. [ABSTRACT FROM AUTHOR]

Biotransformation of testosterone 1 and stanolone 2 has been investigated with fungus of Lignincola laevis. Biotransformaton of 1 gives 15α,17β-dihydroxyandrost-4-en-3-one 3. In the case of 2, two products, 5α-androstan-3α,17 β-diol 4 and 5α-androstane-3, 17-dione 5 have been obtained. [ABSTRACT FROM AUTHOR]

Most breast and prostate cancers are caused by abnormal production or action of steroidal hormones. Hormonal drugs based on steroid scaffolds represent a significant class of chemotherapeutics that are routinely used in chemotherapy. In this study, the synthesis of new 17a-homo lactone and 17α-(pyridine-2-ylmethyl) androstane derivatives with hydrazide and semicarbazone motifs is presented. All compounds were screened for their effect on cell viability against a panel of five cancer cell lines and one healthy cell line. Two compounds showed significant cytotoxicity against cancer cells, with low toxicity against healthy cells. The relative binding affinities of compounds for the ligand-binding domains of estrogen receptor α, estrogen receptor β, androgen receptor and glucocorticoid receptor were tested using a fluorescence screen in yeast. Potential for inhibition of aldo-keto reductase 1C3 and 1C4 activity was measured in vitro. Experimental results are analyzed in the context of molecular docking simulations. Our results could help guide design of steroid compounds with improved anticancer properties against androgen- and estrogen-dependent cancers. [Display omitted] • New androstane hydrazides and semicarbazones were synthesized. • One benzohydrazide and one hydrazine-1-carbothioamide derivative were cytotoxic. • Five compounds were identified as selective inhibitors of AKR1C3. • One acetohydrazide and one hydrazine-1-carboxamide were potent inhibitors of AKR1C4. • In silico studies support experimentally confirmed protein-ligand interactions. [ABSTRACT FROM AUTHOR]

The synthesis of six dimeric spiroketals bearing an estradiol half fused to the 5α- or 5β-epimers of androstane, cholestane, and spirostane nuclei is described. The synthetic procedure comprises the Sonogashira- coupling of different steroid alkynes with 2-iodoestradiol 17-monoacetate, followed by Pd-catalyzed spiroketalization. The structural characterization of the obtained hybrid dimers was performed using a combination of 1D and 2D NMR techniques, and was assisted by DFT calculations. Single crystal X-ray diffraction of one of the obtained compounds confirmed the proposed structures. [ABSTRACT FROM AUTHOR]

Fungal strain Drechslera sp. Ph F-34 was shown to modify 3-oxo- and 3-hydroxy steroids of androstane series to form the corresponding allylic 7-alcohols and 17β-reduced derivatives thus evidencing the presence of 7α-, 7β-hydroxylase and 17β-hydroxysteroid dehydrogenase (17β-HSD) activities. The growing mycelium predominantly hydroxylated androsta-1,4-diene-3,17-dione (ADD) at the 7β-position, while much lower 7α-hydroxylation was observed. Along with 7β-hydroxy-ADD and its corresponding 7α-isomer, their respective 17β-alcohols were produced. In this study, transformation of ADD, androst-4-en-17β-ol-3-one (testosterone, TS) and 3β-hydroxyandrost-5-en-17-one (dehydroepiandrosterone, DHEA) by resting mycelium of Drechslera sp. have been estimated in different conditions with regard to the inducibility and functionality of the 17β-HSD and 7-hydroxylase enzyme systems. Steroids of androstane, pregnane and cholane series were evaluated as inducers. The inhibitory analysis was provided using cycloheximide (CHX). Steroids were assayed using TLC and HPLC methods, and the structures were confirmed by mass-spectrometry, 1H and 13C NMR spectroscopy data. 17β-HSD of the mycelium constitutively reduced 17-carbonyl group of ADD and DHEA to form the corresponding 17β-alcohols, namely, androsta-1,4-diene-17β-ol-3-one (1-dehydro-TS), and androst-5-ene-3β,17β-diol. Production of the 7α- and 7β-hydroxylated derivatives depended on the induction conditions. The inducer effect relied on the steroid structure and decreased in the order: DHEA > pregnenolone > lithocholic acid. β-Sitosterol did not induce hydroxylase activity in Drechslera sp. CHX fully inhibited the synthesis of 7-hydroxylase in Drechslera mycelium thus providing selective 17-keto reduction. Results contribute to the diversity of steroid modifying enzymes in fungi and can be used at the development of novel biocatalysts for production of valuable steroid 7(α/β)- and 17β-alcohols. [Display omitted] • Drechslera sp. actively modifies 3-oxo-4-ene and 3β-hydroxy-5-ene steroids. • Allylic 7-alcohols and 17β-reduced derivatives are the main metabolites. • The constitutive character was confirmed for fungal 17β-HSD activity. • 7-Hydroxylation is highly induced by steroids of androstane and pregnane series. • The maximum inducing effect was detected for DHEA. [ABSTRACT FROM AUTHOR]

5α,14α‐Androstane (C19H32) crystallizes in two different polymorphic forms in the same vapor diffusion experiment. The major form (Form I) crystallizes as thin plates in the space group P21, with Z = 4. These plates are twinned along a long c axis of length 43 Å and readily suffer from radiation damage when diffracted. The minor form (Form II) crystallizes as fine needles in the space group P212121, Z = 3. In the minor form, 5α,14α‐androstane cocrystallizes with 5α,14α‐androstan‐17‐one, an oxidation product of 5α,14α‐androstane. The presence of 5α,14α‐androstan‐17‐one in the minor form of the crystals was confirmed by HR‐MS. Form II can be crystallized as a pure form without the ketone impurity using a different solvent system. High level density functional theory (DFT) lattice free energy calculations were performed and show that both pure forms are isoergic within the estimated error of the calculations. [ABSTRACT FROM AUTHOR]

Switchable polarity solvents (reversible ionic liquids) have been used to replace conventional catalysts and solvents in Claisen‐Schmidt condensation reactions of 16‐formyl steroids and aromatic ketones. The primarily formed α,β‐unsaturated ketones may undergo a Michael addition with the aromatic ketone reaction partner. By the proper choice of the reaction conditions, either the α,β‐unsaturated ketone or the products of the domino Claisen‐Schmidt condensation ‐ Michael addition could be obtained with good selectivity. The catalyst could successfully be recovered and reused. The steroidal products with androstane and estrane skeleton were characterized by different spectroscopic methods (NMR, IR, MS). [ABSTRACT FROM AUTHOR]

[Display omitted] An unusual reaction of 16α,17α-epoxypregn-5-en-20-one with 3-amino-5-mercapto-1,2,4-triazole is accompanied by the heterocyclization involving epoxy ring opening and results in a mixture of new androstane derivatives fused with polyheterocycles at the D ring. Such polyheterocycles belong to 3-thia-1,2,8,8b-tetraazaacenaphthylene and 1,2a,7,7b-tetraazacyclopenta[ cd ]indene-2-thione families incorporating isomeric [1,2,4]triazolopyrimidine systems [ABSTRACT FROM AUTHOR]

Background. Metformin, as a first-line treatment for diabetes, interacts with many protein kinases and transcription factors which affect the expression of downstream target genes governing drug metabolism. Sulfotransferase, SULT2A1, one phase II metabolic enzyme, sulfonates both xenobiotic and endobiotic compounds to accelerate drug excretion. Herein, we designed experiments to investigate the effects and mechanisms of metformin on SULT2A1 expression in vitro. Methods. The hepatocellular carcinoma cell line, HepaRG, was cultured with different concentrations of metformin. The cell viability was measured using CCK8 kit. HepaRG was used to evaluate the protein expression of pregnane X receptor (PXR), the constitutive androstane receptor (CAR), SULT2A1, AMP-activated protein kinase (AMPK), and phosphorylation of AMPK (p-AMPK), respectively, at different concentrations of metformin with or without rifampin (human PXR activator) and CITCO (human CAR activator). The coregulators with CAR on SULT2A1 promoter response elements have also been characterized. Results. We showed that metformin did not affect the basic expression of SULT2A1 but could suppress the expression of SULT2A1 induced by the activator of human CAR. Investigations revealed that metformin which could block CAR nuclear translocation further suppress SULT2A1. In addition, we found that the prevented CAR transfer into the nucleus by metformin was partially an AMPK-dependent event. Conclusion. The present study indicated that the activation of AMPK-CAR pathway mediated the suppression of SULT2A1 by metformin. Metformin may affect the metabolism and clearance of drugs which are SULT2A1 substrates. The results that emerged from this work provide substantial insights into an appropriate medication in the treatment of diabetes patients. [ABSTRACT FROM AUTHOR]

The combination of an androstane-3,17-diol nucleus and a 2β-N-alkylamidopiperazino sidechain is important for the anticancer activity of a new family of steroid derivatives. As the structure-activity relationship studies have so far been limited to the beta orientation of the substituent at position 2 of the steroid nucleus, a series of analogs (compounds 1-4) were synthesized to investigate the impact on biological activity of A-ring substitution. Nuclear magnetic resonance (NMR) analysis, especially using a series of 2D experiments, such as correlation spectroscopy (COSY), homonuclear Overhauser effect spectroscopy (NOESY), heteronuclear single-quantum correlation (HSQC), and heteronuclear multiple-bond correlation (HMBC) provided crucial information that was found essential in confirming the sidechain position and orientation of compounds 1-4. Assessment of their antiproliferative activity on leukemia HL-60 cells confirmed the best efficiency of the 2β-sidechain/3α-OH orientation (compound 1) compared to the other configurations tested (compounds 2-4). [ABSTRACT FROM AUTHOR]

The ability of androstane and androstene neurosteroids with modifications at C-17, C-5, and C-3 (compounds 1-9) to influence the functional activity of inhibitory glycine and γ-aminobutyric acid (GABA) receptors was estimated. The glycine- and GABA-induced chloride current (IGly and IGABA) were measured in isolated pyramidal neurons of the rat hippocampus and isolated rat cerebellar Purkinje cells, correspondingly, using the patch-clamp technique. Our results demonstrate that all the nine neurosteroids display similar biological activity, namely, they strongly inhibited IGly and weakly inhibited IGABA. The threshold concentration of neurosteroids inducing effects on IGly was 0.1 μM, and for effects on IGABA was 10–50 μM. Moreover, our compounds accelerated desensitization of the IGly with the IC50 values varying from 0.12 to 0.49 μM and decreased the peak amplitude with IC50 values varying from 16 to 22 μM. Interestingly, our study revealed that only compounds 4 (epiandrosterone) and 8 (dehydroepiandrosterone) were able to cause a significant change in IGABA in 10 μM concentration. Moreover, compounds 3 (testosterone), 5 (epitestosterone), 6 (dihydroandrostenedione), and 9 (etiocholanedione) did not modulate IGABA up to the concentration of 50 μM. Thus, we conclude that compounds 3, 5, 6, and 9 may be identified as selective modulators of IGly. Our results offer new avenues of investigation in the field of drug-like selective modulators of IGly.

The ability of androstane and androstene neurosteroids with modifications at C-17, C-5, and C-3 (compounds 1 - 9) to influence the functional activity of inhibitory glycine and γ-aminobutyric acid (GABA) receptors was estimated. The glycine- and GABA-induced chloride current (I Gly and I GABA) were measured in isolated pyramidal neurons of the rat hippocampus and isolated rat cerebellar Purkinje cells, correspondingly, using the patch-clamp technique. Our results demonstrate that all the nine neurosteroids display similar biological activity, namely, they strongly inhibited I Gly and weakly inhibited I GABA. The threshold concentration of neurosteroids inducing effects on I Gly was 0.1 μM, and for effects on I GABA was 10–50 μM. Moreover, our compounds accelerated desensitization of the I Gly with the IC50 values varying from 0.12 to 0.49 μM and decreased the peak amplitude with IC50 values varying from 16 to 22 μM. Interestingly, our study revealed that only compounds 4 (epiandrosterone) and 8 (dehydroepiandrosterone) were able to cause a significant change in I GABA in 10 μM concentration. Moreover, compounds 3 (testosterone), 5 (epitestosterone), 6 (dihydroandrostenedione), and 9 (etiocholanedione) did not modulate I GABA up to the concentration of 50 μM. Thus, we conclude that compounds 3 , 5 , 6 , and 9 may be identified as selective modulators of I Gly. Our results offer new avenues of investigation in the field of drug-like selective modulators of I Gly. [ABSTRACT FROM AUTHOR]

Two-dimensional NMR spectroscopy was used to assign the signals of the hydrogen and carbon atoms in the spectra of 15-substituted androstane and pregnane steroid compounds. [ABSTRACT FROM AUTHOR]

Abstract The present study is aimed to analyze lipophilicity and ADMET profiles, and to develop field based 3D-QSAR and ligand-based pharmacophore hypothesis for a series of 17α-picolyl and 17(E)-picolinylidene androstane derivatives in order to give detailed structural insights and to highlight important binding features of novel androstane derivatives, as compounds with antiproliferative activity toward breast adenocarcinoma cells. This study can provide guidelines for the rational design of novel potent compounds. Sum of ranking differences (SRD), as a non-parametric method, was applied for compounds ranking. 3D-QSAR methods, including comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), were applied to predict the antiproliferative effect on breast adenocarcinoma cells and provide the regions in space where interactive fields may influence the activity. The compounds are ranked so the compounds with the most favorable ADME and lipophilicity features together with significant anticancer activity can be distinguished. The established 3D-QSAR model could be used for design of new compounds with antiproliferative activity on the human ER– breast adenocarcinoma cells. The pharmacophore model is able to accurately predict antiproliferative activity. Generally, the present study provides significant guidelines for further selection, synthesis and rational design of new highly potential androstane derivatives as anticancer drugs. Graphical abstract Image 1 Highlights • The androstane derivatives have been ranked by SRD method based on their ADME and logP features. • The field based 3D-QSAR and ligand-based pharmacophore hypothesis have been developed. • The 3D-QSAR model is applicable in design of new cytotoxic androstanes on the human ER– breast adenocarcinoma cells. [ABSTRACT FROM AUTHOR]

Glucose 6-phosphate dehydrogenase (G6PDH) fulfills an essential role in cell physiology by catalyzing the production of NADPH+ and of a precursor for the de novo synthesis of ribose 5-phosphate. In trypanosomatids, G6PDH is essential for in vitro proliferation, antioxidant defense and, thereby, drug resistance mechanisms. So far, 16α-brominated epiandrosterone represents the most potent hit targeting trypanosomal G6PDH. Here, we extended the investigations on this important drug target and its inhibition by using a small subset of androstane derivatives. In Trypanosoma cruzi, immunofluorescence revealed a cytoplasmic distribution of G6PDH and the absence of signal in major organelles. Cytochemical assays confirmed parasitic G6PDH as the molecular target of epiandrosterone. Structure-activity analysis for a set of new (dehydro)epiandrosterone derivatives revealed that bromination at position 16α of the cyclopentane moiety yielded more potent T. cruzi G6PDH inhibitors than the corresponding β-substituted analogues. For the 16α brominated compounds, the inclusion of an acetoxy group at position 3 either proved detrimental or enhanced the activity of the epiandrosterone or the dehydroepiandrosterone derivatives, respectively. Most derivatives presented single digit μM EC50 against infective T. brucei and the killing mechanism involved an early thiol-redox unbalance. This data suggests that infective African trypanosomes lack efficient NADPH+-synthesizing pathways, beyond the Pentose Phosphate, to maintain thiol-redox homeostasis.

Cancer remains a major health concern worldwide. The most frequently diagnosed types of cancer are caused by abnormal production or action of steroid hormones. In the present study, the synthesis and structural characterization of new heterocyclic androstane derivatives with D -homo lactone, 17α-(pyridine-2′′-ylmethyl) or 17(E)-(pyridine-2′′-ylmethylidene) moiety are presented. All compounds were evaluated for their anti-proliferative activity against HeLa cervical cancer cell line and non-cancerous kidney MDCK cells, where A-homo lactam compound 9A showed the greatest selectivity. Based on in vitro binding assays, N -formyl lactam compound 18 appeared to be the strong and isoform-selective ligand for ERα, while compound 9A displayed binding affinity for the GR-LBD, but also inhibited aldo-keto reductase 1C4 enzyme. Out of four selected compounds, methylpyrazolo derivative 13 showed potential for aromatase binding, while in silico studies provided insight into experimentally confirmed protein-ligand interactions. [Display omitted] • New A-homo lactam and A-ring fused pyrazole androstanes were synthesized. • A-Homo lactam derivative appeared to be the most selective for cancer HeLa cells. • N -Formyl lactam compound showed strong and selective binding affinity for ERα. • Only one derivative with pyrazole moiety showed potential as an aromatase inhibitor. • In silico studies support experimentally confirmed protein-ligand interactions. [ABSTRACT FROM AUTHOR]

The combination of an androstane-3,17-diol nucleus and a 2β-N-alkylamidopiperazino sidechain is important for the anticancer activity of a new family of steroid derivatives. As the structure-activity relationship studies have so far been limited to the beta orientation of the substituent at position 2 of the steroid nucleus, a series of analogs (compounds 1–4) were synthesized to investigate the impact on biological activity of A-ring substitution. Nuclear magnetic resonance (NMR) analysis, especially using a series of 2D experiments, such as correlation spectroscopy (COSY), homonuclear Overhauser effect spectroscopy (NOESY), heteronuclear single-quantum correlation (HSQC), and heteronuclear multiple-bond correlation (HMBC) provided crucial information that was found essential in confirming the sidechain position and orientation of compounds 1–4. Assessment of their antiproliferative activity on leukemia HL-60 cells confirmed the best efficiency of the 2β-sidechain/3α-OH orientation (compound 1) compared to the other configurations tested (compounds 2–4).

On the basis of GC-MS analysis, a suite of 97 lacustrine and coal measure rocks from the Songliao Basin, Ordos Basin and Tarim Basin were found to contain abundant rearranged hopanes. Except for peak ratios, the absolute concentrations of rearranged hopanes were determined based on addition of an internal standard (5α-androstane) normalized to bitumen “A”, which in lacustrine source rocks are far more than those in coal measure rocks. To examine the effects of depositional environment on relative abundance and absolute concentration of rearranged hopanes, the clay content, redox condition and water salinity of sedimentary rocks from two sample sets were analyzed. The results reveal that the acidic clay acted as clay-mediated acidic catalysis in the formation and degradation of rearranged hopanes, but there is no positive correlation between clay content and rearranged hopanes in lacustrine source rocks. In contrast, the absolute concentrations of rearranged hopanes in coal measure rocks, show a general increase with clay content. Some molecular parameters, such as pristane/phytane (Pr/Ph), C 35 homohopane index and gammacerane index, were found to change as a function of depositional environment. With increasing Pr/Ph, C 35 homohopane index and gammacerane index, the ratios of C 30 diahopane/C 30 hopane and C 29 Ts/C 29 hopane display an initial increase and subsequent decrease trend. The absolute concentrations of C 30 diahopane and C 29 Ts in lacustrine source rocks also increase at first, followed by a decrease at the largest value. Whereas the absolute concentrations of rearranged hopanes in coal measure rocks show an apparent positive correlation with some depositional environmental parameters. On the whole, abundant rearranged hopanes in lacustrine source rocks appear to be distributed in suboxic-weak reduction and fresh-brackish condition, while abundant rearranged hopanes in coal measure rocks appear to be present in oxic and fresh condition. [ABSTRACT FROM AUTHOR]

The crystal structures and Hirshfeld surface analyses of two hemi-solvates of 3α-hydroxy-16α-bromoandrostan-17-one, 3 , namely [(3) 2 .(H 2 O) ] and [(3) 2 .(MeOH) ], are reported. Both solvates crystallize in the monoclinic space group, P 2 1 , with Z = 4. . The asymmetric unit of the hemi-hydrate [(3) 2 .(H 2 O) ] contains two independent but similar steroid molecules and a water molecule, while that of the hemi-methanoate [(3) 2 .(MeOH) ] has four similar but independent steroid molecules and two methanol molecules. Very similar conformations are found for the steroid molecules in both solvates. In both solvates, the strongest intermolecular interactions are O H···O hydrogen bonds, involving hydroxyl groups of the steroid and the solvate molecule, which result in head-to-head directly linked steroid molecules and solvate separated steroid molecules. In both cases, the oxygen atoms of the carbonyl groups of the steroids are involved in weaker C H···O hydrogen bonds which directly link steroid molecules in tail-to-tail fashions. Combinations of the hydrogen bonds, both O H···O and C H···O, result in two-molecule wide sheets in the hemi-hydrate, which are further weakly linked in the hemi--methanoate into a 3-dimensional array. Very different hydrogen bonded chains are found in the two solvates. There is a higher proportion of C H···O to O H···O hydrogen bonds in the hemi-methanoate, [8–6], compared to that in the hemi-hydrate [1–4]: this is an indication of the weaker solvating influence of methanol compared to water. [ABSTRACT FROM AUTHOR]

An androstane (17β-hydroxy-17α-picolyl-androst-5-en-3β-yl-acetate (derivative A)) cancer inhibitor was successfully captured in a carrier made of nano-sized hydroxyapatite (HAp) coated with chitosan-PLGA polymer blends (Ch-PLGA). In our previous studies, we demonstrated that it was convenient to use spherical HAp/Ch-PLGA carriers as vehicles to target the lungs following intravenous administration. In this study, we used emulsification and subsequent freeze-drying to load the spherical HAp/Ch-PLGA carriers with varying contents of the derivative A, in order to examine the selective toxicity towards cancerous/healthy lung cells. The XRD and FT-IR techniques confirmed the drug loading process, and the content of the poorly water soluble derivative A was estimated directly via the DSC technique. The particles were spherical in shape with the d 50 distribution varying between 167 and 231 nm, whereas the content of the derivative A ranged from 6.5 to 19.3 wt%. Cell-selective cytotoxicity was examined simultaneously on two cell lines: human lung carcinoma (A549 ATCC CCL 185) and human lung fibroblasts (MRC-5 ATCC CCL 171). All particles exhibited nearly three times larger cytotoxicity towards cancer cells (A549) than towards healthy cells (MRC5), where the particles with the derivative A content of 6.5 wt% allowed for the viability of healthy cells >80%. Ninety-six hours after the treatment of cells with particles with different contents of derivative A (after incubation and recovery), recovery was faster in damaged healthy cells than in cancerous cells. [ABSTRACT FROM AUTHOR]

Androst-5-ene-triols are metabolites of dehydroepiandrosterone, the most abundant steroid hormone in human circulation. Many observations in rodents have demonstrated the anti-inflammatory and immune modulating activity of 7β-hydroxy-androst-5-enes, and on the basis of these experiments androst-5-ene-3β,7β,17β-triol is considered as a potential agent in the treatment of autoimmune diseases. In contrast to the fairly abundant information on the levels and effects of androst-5-ene-triols in experimental animals and of their the pharmacological perspective, little is known about androst-5-ene-3β,7α/β,17β-triols circulating in human blood, their regulation by the hypothalamo–pituitary–adrenal axis, or their daily concentration variability. Here we provide some data on androst-5-ene-3β,7α/β,17β-triol concentrations under various conditions in men and women. [ABSTRACT FROM AUTHOR]

A sensitive, specific, selective and rapid LC-ESI–MS/MS method has been developed and validated for the quantification of apalutamide in mice plasma using apalutamide- d 3 as an internal standard (I.S.). Sample preparation was accomplished through a simple protein precipitation process. Chromatography of apalutamide and the I.S. was achieved on an Atlantis dC 18 column using an isocratic mobile phase comprising 0.2% formic acid in water and acetonitrile (20:80, v/v) delivered at a flow rate of 0.8 mL/min. LC–MS/MS was operated under the multiple reaction-monitoring mode (MRM) using the electrospray ionization technique in positive ion mode and the transitions of m / z 478 → 450 and m / z 481 → 453 were used to measure the derivative of apalutamide and the I.S, respectively. The total chromatographic run time was 2.5 min and the elution of apalutamide and I.S. occurred at 1.10 and 1.09 min, respectively. Method validation was performed as per regulatory guidelines and the results met the acceptance criteria. Linearity was established in the concentration range of 1.02–2030 ng/mL ( r  > 0.995) for apalutamide. The intra- and inter-day accuracy and precision for apalutamide in mice plasma were in the range of 2.11–8.44 and 2.51–6.09%, respectively. Apalutamide was found to be stable under various stability conditions. This novel method has been applied to a pharmacokinetic study in mice. [ABSTRACT FROM AUTHOR]

Neurosteroids, comprising pregnane, androstane, and sulfated steroids can alter neuronal excitability through interaction with ligand-gated ion channels and other receptors and have therefore a therapeutic potential in several brain disorders. They can be formed in brain cells or are synthesized by an endocrine gland and reach the brain by penetrating the blood-brain barrier (BBB). Especially sulfated steroids such as pregnenolone sulfate (PregS) and dehydroepiandrosterone sulfate (DHEAS) depend on transporter proteins to cross membranes. In this review, we discuss the involvement of ATP-binding cassette (ABC)- and solute carrier (SLC)-type membrane proteins in the transport of these compounds at the BBB and in the choroid plexus (CP), but also in the secretion from neurons and glial cells. Among the ABC transporters, especially BCRP (ABCG2) and several MRP/ABCC subfamily members (MRP1, MRP4, MRP8) are expressed in the brain and known to efflux conjugated steroids. Furthermore, several SLC transporters have been shown to mediate cellular uptake of steroid sulfates. These include members of the OATP/SLCO subfamily, namely OATP1A2 and OATP2B1, as well as OAT3 (SLC22A3), which have been reported to be expressed at the BBB, in the CP and in part in neurons. Furthermore, a role of the organic solute transporter OSTα-OSTβ (SLC51A/B) in brain DHEAS/PregS homeostasis has been proposed. This transporter was reported to be localized especially in steroidogenic cells of the cerebellum and hippocampus. To date, the impact of transporters on neurosteroid homeostasis is still poorly understood. Further insights are desirable also with regard to the therapeutic potential of these compounds. [ABSTRACT FROM AUTHOR]

Background: While loteprednol etabonate (LE) suspension 0.5% is approved for the treatment of postoperative ocular inflammation, there have been no reported studies of its use in glaucoma patients undergoing canaloplasty. Methods: This was a retrospective medical chart review conducted at a single US center. Data were collected on patients with glaucoma who underwent canaloplasty with or without cataract surgery, and were prescribed LE suspension 0.5% postoperatively. Outcomes evaluated included postsurgical inflammation (anterior chamber [AC] cells and flare), intraocular pressure (IOP), number of IOP-lowering medications, and postsurgical complications. Results: Data were collected on 204 patients (262 eyes) with a mean (SD) age of 71.6 (11.3) years. The most frequent LE dosing regimens at day 1, week 1, and month 1 postsurgery were QID (92.3%; 241/261), TID (52.6%; 133/253), and QD (65.5%; 78/119), respectively. Inflammation (AC flare and cells), mostly mild, was noted in 33.2% (86/259) of eyes on postoperative day 1 and 8.6% (21/244) of eyes at month 1. Mean IOP and mean number of IOP-lowering medications were significantly reduced from baseline (P<0.001) at all time points postoperatively. Complete (no IOP-lowering medication) or qualified (use of #2 IOP-lowering medications) surgical success was achieved in 78.8% and 90.6% of eyes, respectively, at month 6 and 63.4% and 92.7% of eyes at month 36. The most frequently observed postoperative complication was hyphema in 48.7% (126/259) eyes at day 1, which decreased to 0.4% (1/244) of eyes by month 1. IOP $30 mmHg was noted in 13 (5.3%) eyes at postoperative week 1 and rarely thereafter, and no patient discontinued therapy because of an IOP increase. Conclusion: These real-world data suggest that canaloplasty with or without cataract surgery managed postoperatively with LE suspension 0.5% is effective and safe in the glaucoma patient. [ABSTRACT FROM AUTHOR]

Abstract: Aromatase catalyzes the biosynthesis of estrogens from androgens. Owing to the physiological importance of this conversion of lipophilic substrates, the interaction with the lipid bilayer for this cytochrome P450 is crucial for its dynamics that must allow an easy access to substrates and inhibitors. Here, the aromatase–anastrozole interaction is studied by combining computational methods to identify possible access/egress routes with the protein inserted in the membrane and experimental tools aimed at the investigation of the effect of the inhibitor on the protein conformation. By means of molecular dynamics simulations of the protein inserted in the membrane, two channels, not detected in the starting crystal structure, are found after a 20‐nSec simulation. Trypsin digestion on the recombinant protein shows that the enzyme is strongly protected by the presence of the substrate and even more by the inhibitor. DSC experiments show an increase in the melting temperature of the protein in complex with the substrate (49.3 °C) and the inhibitor (58.7 °C) compared to the ligand‐free enzyme (45.9 °C), consistent with a decrease of flexibility of the protein. The inhibitor anastrozole enters the active site of the protein through a channel different from that used from the substrate and promotes a conformational change that stiffens the protein conformation and decreases the protein–protein interaction between different aromatase molecules. [ABSTRACT FROM AUTHOR]

• Cytotoxic activity of new androstane 3-oximes was modeled by QSAR approach. • The statistically reliable linear and non-linear QSARs were obtained. • Molecular docking and molecular dynamics pointed out a high binding potential of novel compounds. As one of the deadliest forms of skin cancers, malignant melanoma is the most common cause of death from this type of cancer. Malignant melanoma has a steadily increasing incidence and the medical treatment options are still quite limited. One of the possible options for malignant melanoma treatment is medication therapy. The present study is focused on the development of new compounds that can be possibly used for malignant melanoma treatment. A newly synthesized series of alkylaminoethyl derivatives of androstane 3-oximes expressed significant cytotoxic activity towards malignant melanoma cells. This was an excellent basis for the development of quantitative structure-activity relationship (QSAR) models for the prediction of cytotoxic activity of not yet synthesized compounds. Also, on the basis of the cytotoxic activity data the molecular docking and molecular dynamics analysis were carried out. This local QSAR modeling, which is based on a limited set of structurally similar compounds, resulted in one univariate linear regression model, four multiple linear regression models and five support vector machines models. All of the models were confirmed to be statistically reliable with quite good prediction ability. The results of comparative molecular docking and molecular dynamics analysis indicated a high binding potential of novel compounds in regards to cisplatin as well-known chemotherapy drug. The established QSAR models and the results of molecular docking and molecular dynamics can be considered to be the guidelines for the design of new compounds worth synthesizing as potential lead compounds for malignant melanoma treatment. [ABSTRACT FROM AUTHOR]

Atrazine is an herbicide with several known toxicologically relevant effects, including interactions with other chemicals. Atrazine increases the toxicity of several organophosphates and has been shown to reduce the toxicity of triclosan to D. magna in a concentration dependent manner. Atrazine is a potent activator in vitro of the xenobiotic-sensing nuclear receptor, HR96, related to vertebrate constitutive androstane receptor (CAR) and pregnane X-receptor (PXR). RNA sequencing (RNAseq) was performed to determine if atrazine is inducing phase I-III detoxification enzymes in vivo, and estimate its potential for mixture interactions. RNAseq analysis demonstrates induction of glutathione S-transferases (GSTs), cytochrome P450s (CYPs), glucosyltransferases (UDPGTs), and xenobiotic transporters, of which several are verified by qPCR. Pathway analysis demonstrates changes in drug, glutathione, and sphingolipid metabolism, indicative of HR96 activation. Based on our RNAseq data, we hypothesized as to which environmentally relevant chemicals may show altered toxicity with co-exposure to atrazine. Acute toxicity tests were performed to determine individual LC 50 and Hillslope values as were toxicity tests with binary mixtures containing atrazine. The observed mixture toxicity was compared with modeled mixture toxicity using the Computational Approach to the Toxicity Assessment of Mixtures (CATAM) to assess whether atrazine is exerting antagonism, additivity, or synergistic toxicity in accordance with our hypothesis. Atrazine-triclosan mixtures showed decreased toxicity as expected; atrazine-parathion, atrazine-endosulfan, and to a lesser extent atrazine- p -nonylphenol mixtures showed increased toxicity. In summary, exposure to atrazine activates HR96, and induces phase I-III detoxification genes that are likely responsible for mixture interactions. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that 5ɑ-androst-3β,5,6β-triol (Triol), a synthesized steroid compound, showed notable neuroprotective effect in cultured cortical neurons. In the present study, we explored whether and how Triol have neuroprotective effect on retinal ganglion cells (RGCs) in a chronic ocular hypertension (COH) rat model. COH model was produced by injecting superparamagnetic iron oxide micro-beads into the anterior chamber, and Triol was administrated (4.8 μg/100 g, i.p., once daily for 4 weeks). Immunohistochemistry experiments showed that in whole flat-mounted COH retinas, the number of CTB-labeled survival RGCs was progressively reduced, while TUNEL-positive signals were significantly increased from 1 to 4 weeks after the micro-bead injection. Triol administration significantly attenuated the reduction in the number of CTB-labeled RGCs, and partially reduced the increased number of TUNEL-positive signals in COH retinas. Furthermore, Triol administration partially reduced the levels of malondialdehyde (MDA) and reactive oxygen species (ROS), and significantly rescued the activities of mitochondrial respiratory chain complex (MRCC) I/II/III in COH retinas. Our results suggest that Triol prevents RGCs from apoptotic death in COH retinas by reducing the lipid peroxidation and enhancing the activities of MRCCs. [ABSTRACT FROM AUTHOR]

An effective method of dehydrating 9_-hydroxyandrost-4-ene-3,17-dione by mineral acids in organic solvents, producing essentially quantitative formation of androsta-4,9(11)-diene-3,17-dione is proposed. Quantitative isomerization of the side product androsta-4,8(9)-diene-3,17-dione to target product was shown to be pssible. [ABSTRACT FROM AUTHOR]

Rates of intramolecular electron transfer from a 1,1'-biphenylyl radical anion to six different acceptors on an androstane scaffold are examined with the aid of a theory that was developed recently to include effects of vibrational relaxations and dephasing. The electronic-interaction matrix element and other parameters needed for the theory are obtained by quantum-mechanical/molecular-mechanical simulations of the reactions in five solvents ranging from iso-octane to methyltetrahydrofuran. Intramolecular vibrational modes that are coupled to electron transfer are resolved in simulations in iso-octane and cyclohexane. The energies and coupling factors for these modes allow extension of the theory to incorporate transitions to and from excited vibrational levels. The calculated rates of electron transfer agree well with experimental measurements from the literature, except for reactions in which excited electronic states of the products become important. [ABSTRACT FROM AUTHOR]

Novel ring D- and A-fused pyrimidines in the androstane series were efficiently synthesized within 10–15 min in polar protic solvents under microwave irradiation via two kinds of multicomponent heterocyclization reactions followed by spontaneous or promoted oxidation. The rates of the one-pot catalyst-free transformations of steroidal β-ketoaldehydes, ammonium acetate and substituted benzaldehydes in EtOH were found to be affected slightly by the steric and electronic feature of the substituents on the aromatic ring of the arylaldehyde component and the different reactivities of rings D and A of the sterane core. At the same time, the acid-catalyzed Biginelli-type reaction of dihydrotestosterone acetate, urea and arylaldehydes, and subsequent Jones oxidation of the primarily formed dihydropyrimidinones led to the corresponding ring A-fused 1 H -pyrimidin-2-ones in moderate yields independently of the substituents on the aromatic moiety. The synthesized compounds were tested in vitro on human cancer cell lines as well as on non-cancerous fibroblast cells by the MTT assay in order to investigate their biological effects. As a result of the pharmacological screen, a remarkable structure-function relationship has been observed as the acetylated Biginelli products exhibited higher toxicity compared to the deacetylated version of each compound. Furthermore, in case of three 2′-arylpyrimidine derivatives a strong prostate cancer cell specific activity has been identified. [ABSTRACT FROM AUTHOR]

Elevated androgens and glucocorticoids displayed by males during the reproductive season have been proposed to mediate a possible trade-off between reproduction and immunocompetence. Anurans living in arid and semiarid environments display a strong seasonal reproduction, which could accentuate the variation in physiological, immunological, and behavioral parameters. We studied covariation between steroid plasma levels, morphometric variables associated with body condition and immunity, leukocyte profile, parasite load, and response to an immunological challenge across different phases of the annual life-history cycle of three anuran species from a Brazilian semiarid area. Our results showed a seasonal pattern of covariation among leukocyte parameters, kidney mass, and steroid plasma levels, with higher values measured during the reproductive season, particularly when males were sampled during calling activity. Moreover, these anurans showed a stronger response to an immunological challenge during the reproductive period. The immunosuppression during the dry period was particularly evident for the species that aestivate, indicating that the availability of energetic resources might be an important factor determining seasonal variation in inflammatory response. Intensity of the helminth infection was associated with eosinophil count but showed a more complex pattern with regard to androgens levels. These data emphasize that variations in the intensity of helminth infection might be more closely related to specific aspects of the immune response than to the general seasonal patterns of variation in steroid plasma levels, total circulating leukocytes, and inflammatory response. [ABSTRACT FROM AUTHOR]

The majority of breast cancer cases are estrogen receptor positive (ER + ). Although, third-generation aromatase inhibitors (AIs) are used as first-line treatment in post-menopausal women, they cause endocrine resistance and bone loss, which limits their success. Therefore, there is a demand to discover new potent molecules, with less toxicity that can circumvent these drawbacks. Our group has previously demonstrated that new 7α-substituted steroidal molecules, 7α-(2ξ,3ξ-epoxypropyl)androsta-1,4-diene-3,17-dione (3) , 7α-allylandrost-4-ene-3,17-dione (6) , 7α-allylandrost-4-en-17-one (9) , 7α-allyl-3-oxoandrosta-1,4-dien-17β-ol (10) and 7α-allylandrosta-1,4-diene-3,17-dione (12) are potent AIs in placental microsomes. In this work, it was investigated their anti-aromatase activity and in vitro effects in sensitive and resistant breast cancer cells. All the steroids efficiently inhibit aromatase in breast cancer cells, allowing to establish new structure-activity relationships for this class of compounds. Moreover, the new AIs can inhibit breast cancer cell growth, by causing cell cycle arrest and apoptosis. The effects of AIs 3 and 12 on sensitive cells were dependent on aromatase inhibition and androgen receptor (AR), while for AI 9 and AI 10 were AR- and ER-dependent, respectively. In addition, it was shown that all the AIs can sensitize resistant cancer cells being their behavior similar to the sensitive cells. In summary, this study contributes to the understanding of the structural modifications in steroidal scaffold that are translated into better aromatase inhibition and anti-tumor properties, providing important information for the rational design/synthesis of more effective AIs. In addition, allowed the discovery of new potent 7α-substituted androstane molecules to inhibit tumor growth and prevent endocrine resistance. [ABSTRACT FROM AUTHOR]

An efficient four-step method has been developed for the synthesis of 3β,14β-dihydroxy-5α-androst-15-en-17-one from a common androstane derivative. The X-ray crystal structures of the alkenes, the epoxide and the 14-hydroxy compound have been determined. [ABSTRACT FROM AUTHOR]

Starting from 3β-acetoxy-17a-homo-17-oxa-androst-5-en-16-one ( 1) and in the reaction with N-bromoacetamide (NBA) and perchloric acid, the 5α-bromo-6β-hydroxy ( 2), 5β,6β-epoxy ( 3) and 5α,6β-dibromo ( 4) derivatives were obtained. The structure of compounds 2- 4, particularly stereochemistry at C5 and C6, is established by detailed NMR and X-ray analysis. The in vitro antiproliferative activity of newly synthesized compounds 2-4 against six human tumor cell lines was evaluated. All three compounds showed a significant toxicity toward hormone-independent breast adenocarcinoma MDA-MB-231 and cervical carcinoma cells HeLa, while dibromo derivative 4 was active toward five human cancer cell lines. These new 5,6-disubstituted-D-homolactone steroidal compounds have also displayed selectivity toward cancerous cell lines against inactivity found for noncancerous control cell line. This selectivity was not found for control compound, well-known chemotherapy drug cisplatin. [ABSTRACT FROM AUTHOR]