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Special Issue "Steroids"

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Metabolites".

Deadline for manuscript submissions: closed (31 August 2013)

Special Issue Editor

Guest Editor
Prof. Dr. Erkki Kolehmainen (Website)

Department of Chemistry, University of Jyväskylä, P. O. Box 35, FI-40014, Jyväskylä, Finland
Phone: +358 40 805 3695
Fax: +358 14 260 2501
Interests: structural chemistry; bile acid chemistry

Special Issue Information

Dear Colleagues,

Steroid research has a long and brilliant history. It has helped us to understand vital and fatal processes in our bodies, to develop efficient drugs and pharmaceutical preparations, to manage age dependent athropies etc. In spite of that, steroid research is continuing its triumph. As examples can be mentioned recent genomic studies of primitive animals which has provided important data for understanding the origins of enzymes that synthesize adrenal and sex steroids and the receptors that mediate physiological response to these vertebrate steroids. Another new discovery is the hormonal activity of bile acids which means that their physiological role is much larger than as fat solubilizing agents alone. Further, steroidal conjugates of drug molecules can act as proper prodrugs via enterohepatic circulation or various types of steroid receptors. Steroidal supramolecular gels and micellar systems can be very valuable in developing pharmaceutical preparations as well. Taking into account the increased morbidity connected with obesity (diabetes, vascular disease, cancer etc.) in developed countries, functional food supplies based on phytosterols can be of great value. A basic aim of this "Steroids" special issue is to collect papers on the above mentioned new trends in steroid research but also other steroidal studies are welcome.

Prof. Dr. Erkki Kolehmainen
Guest Editor

Submission

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Keywords

  • vitamin D
  • steroid hormone synthesis
  • bile acid
  • phytosterols and their conjugates
  • steroids

Published Papers (21 papers)

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Research

Jump to: Review

Open AccessArticle Vascular Aldosterone Production at the Pre-Diabetic Stage of Young Otsuka Long-Evans Tokushima Fatty (OLETF) Rats, Compared with Long-Evans Tokushima Otsuka (LETO) Rats
Molecules 2013, 18(12), 15636-15647; doi:10.3390/molecules181215636
Received: 13 September 2013 / Revised: 10 December 2013 / Accepted: 10 December 2013 / Published: 13 December 2013
Cited by 1 | PDF Full-text (1039 KB) | HTML Full-text | XML Full-text
Abstract
We examined the ability of aortic smooth muscle cells (AoSMC) prepared from spontaneously diabetic rats to produce aldosterone (Aldo) and the regulatory mechanism that controls their Aldo production. AoSMC of 6 week-old Long-Evans Tokushima Otsuka (LETO: the control group) and 6 week-old [...] Read more.
We examined the ability of aortic smooth muscle cells (AoSMC) prepared from spontaneously diabetic rats to produce aldosterone (Aldo) and the regulatory mechanism that controls their Aldo production. AoSMC of 6 week-old Long-Evans Tokushima Otsuka (LETO: the control group) and 6 week-old Otsuka Long-Evans Tokushima Fatty (OLETF: the type 2 diabetes group) rats were used in the present experiments. CYP11B2 (Aldo synthetase) mRNA expression was detected in both the LETO and OLETF AoSMC. Basal Aldo production was significantly greater (4–5 fold higher) in the OLETF AoSMC culture medium than in the LETO AoSMC culture medium. When AoSMC were co-incubated with high-density lipoproteins (HDL), supplying cholesterol as a substrate for steroidogenesis in rats, angiotensin II (AII) significantly increased greater Aldo production in the OLETF AoSMC than in the LETO AoSMC. The present data suggested that future onset of diabetic vascular dysfunction is partly caused by excess Aldo production by AoSMC in young OLETF rats. Concomitant stimulation by HDL and AII resulted in elevated Aldo production in the OLETF and the LETO AoSMC, and also demonstrated that AII-induced Aldo production is greatly enhanced by HDL in OLETF, rather than in LETO. In conclusion, our data clearly demonstrated that Aldo production in the OLETF AoSMC was significantly higher than in the LETO AoSMC, suggesting possible future onset of vascular dysfunction in diabetes, induced by local Aldo production in the AoSMC. Full article
(This article belongs to the Special Issue Steroids)
Open AccessArticle Optimization of a Pre-MEKC Separation SPE Procedure for Steroid Molecules in Human Urine Samples
Molecules 2013, 18(11), 14013-14032; doi:10.3390/molecules181114013
Received: 30 August 2013 / Revised: 5 October 2013 / Accepted: 6 October 2013 / Published: 13 November 2013
Cited by 2 | PDF Full-text (867 KB) | HTML Full-text | XML Full-text
Abstract
Many steroid hormones can be considered as potential biomarkers and their determination in body fluids can create opportunities for the rapid diagnosis of many diseases and disorders of the human body. Most existing methods for the determination of steroids are usually time- [...] Read more.
Many steroid hormones can be considered as potential biomarkers and their determination in body fluids can create opportunities for the rapid diagnosis of many diseases and disorders of the human body. Most existing methods for the determination of steroids are usually time- and labor-consuming and quite costly. Therefore, the aim of analytical laboratories is to develop a new, relatively low-cost and rapid implementation methodology for their determination in biological samples. Due to the fact that there is little literature data on concentrations of steroid hormones in urine samples, we have made attempts at the electrophoretic determination of these compounds. For this purpose, an extraction procedure for the optimized separation and simultaneous determination of seven steroid hormones in urine samples has been investigated. The isolation of analytes from biological samples was performed by liquid-liquid extraction (LLE) with dichloromethane and compared to solid phase extraction (SPE) with C18 and hydrophilic-lipophilic balance (HLB) columns. To separate all the analytes a micellar electrokinetic capillary chromatography (MECK) technique was employed. For full separation of all the analytes a running buffer (pH 9.2), composed of 10 mM sodium tetraborate decahydrate (borax), 50 mM sodium dodecyl sulfate (SDS), and 10% methanol was selected. The methodology developed in this work for the determination of steroid hormones meets all the requirements of analytical methods. The applicability of the method has been confirmed for the analysis of urine samples collected from volunteers—both men and women (students, amateur bodybuilders, using and not applying steroid doping). The data obtained during this work can be successfully used for further research on the determination of steroid hormones in urine samples. Full article
(This article belongs to the Special Issue Steroids)
Open AccessArticle Synthesis and Structure-Activity Relationships of Amino Acid Conjugates of Cholanic Acid as Antagonists of the EphA2 Receptor
Molecules 2013, 18(10), 13043-13060; doi:10.3390/molecules181013043
Received: 29 August 2013 / Revised: 11 October 2013 / Accepted: 12 October 2013 / Published: 21 October 2013
Cited by 7 | PDF Full-text (4285 KB) | HTML Full-text | XML Full-text
Abstract
The Eph–ephrin system plays a critical role in tumor growth and vascular functions during carcinogenesis. We had previously identified cholanic acid as a competitive and reversible EphA2 antagonist able to disrupt EphA2-ephrinA1 interaction and to inhibit EphA2 activation in prostate cancer cells. [...] Read more.
The Eph–ephrin system plays a critical role in tumor growth and vascular functions during carcinogenesis. We had previously identified cholanic acid as a competitive and reversible EphA2 antagonist able to disrupt EphA2-ephrinA1 interaction and to inhibit EphA2 activation in prostate cancer cells. Herein, we report the synthesis and biological evaluation of a set of cholanic acid derivatives obtained by conjugation of its carboxyl group with a panel of naturally occurring amino acids with the aim to improve EphA2 receptor inhibition. Structure-activity relationships indicate that conjugation of cholanic acid with linear amino acids of small size leads to effective EphA2 antagonists whereas the introduction of aromatic amino acids reduces the potency in displacement studies. The b-alanine derivative 4 was able to disrupt EphA2-ephrinA1 interaction in the micromolar range and to dose-dependently inhibit EphA2 activation on PC3 cells. These findings may help the design of novel EphA2 antagonists active on cancer cell lines. Full article
(This article belongs to the Special Issue Steroids)
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Open AccessArticle Chemometric Evaluation of Urinary Steroid Hormone Levels as Potential Biomarkers of Neuroendocrine Tumors
Molecules 2013, 18(10), 12857-12876; doi:10.3390/molecules181012857
Received: 7 August 2013 / Revised: 25 September 2013 / Accepted: 10 October 2013 / Published: 16 October 2013
PDF Full-text (674 KB) | HTML Full-text | XML Full-text
Abstract
Neuroendocrine tumors (NETs) are uncommon tumors which can secrete specific hormone products such as peptides, biogenic amines and hormones. So far, the diagnosis of NETs has been difficult because most NET markers are not specific for a given tumor and none of [...] Read more.
Neuroendocrine tumors (NETs) are uncommon tumors which can secrete specific hormone products such as peptides, biogenic amines and hormones. So far, the diagnosis of NETs has been difficult because most NET markers are not specific for a given tumor and none of the NET markers can be used to fulfil the criteria of high specificity and high sensitivity for the screening procedure. However, by combining the measurements of different NET markers, they become highly sensitive and specific diagnostic tests. The aim of the work was to identify whether urinary steroid hormones can be identified as potential new biomarkers of NETs, which could be used as prognostic and clinical course monitoring factors. Thus, a rapid and sensitive reversed-phase high-performance liquid chromatographic method (RP-HPLC) with UV detection has been developed for the determination of cortisol, cortisone, corticosterone, testosterone, epitestosterone and progesterone in human urine. The method has been validated for accuracy, precision, selectivity, linearity, recovery and stability. The limits of detection and quantification were 0.5 and 1 ng mL−1 for each steroid hormone, respectively. Linearity was confirmed within a range of 1–300 ng mL−1 with a correlation coefficient greater than 0.9995 for all analytes. The described method was successfully applied for the quantification of six endogenous steroid levels in human urine. Studies were performed on 20 healthy volunteers and 19 patients with NETs. Next, for better understanding of tumor biology in NETs and for checking whether steroid hormones can be used as potential biomarkers of NETs, a chemometric analysis of urinary steroid hormone levels in both data sets was performed. Full article
(This article belongs to the Special Issue Steroids)
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Open AccessArticle Sex Differences in the Hepatic Cholesterol Sensing Mechanisms in Mice
Molecules 2013, 18(9), 11067-11085; doi:10.3390/molecules180911067
Received: 25 July 2013 / Revised: 2 September 2013 / Accepted: 5 September 2013 / Published: 10 September 2013
Cited by 6 | PDF Full-text (1171 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Cholesterol is linked to many multifactorial disorders, including different forms of liver disease where development and severity depend on the sex. We performed a detailed analysis of cholesterol and bile acid synthesis pathways at the level of genes and metabolites combined with [...] Read more.
Cholesterol is linked to many multifactorial disorders, including different forms of liver disease where development and severity depend on the sex. We performed a detailed analysis of cholesterol and bile acid synthesis pathways at the level of genes and metabolites combined with the expression studies of hepatic cholesterol uptake and transport in female and male mice fed with a high-fat diet with or without cholesterol. Lack of dietary cholesterol led to a stronger response of the sterol sensing mechanism in females, resulting in higher expression of cholesterogenic genes compared to males. With cholesterol in the diet, the genes were down-regulated in both sexes; however, males maintained a more efficient hepatic metabolic flux through the pathway. Females had higher content of hepatic cholesterol but this was likely not due to diminished excretion but rather due to increased synthesis and absorption. Dietary cholesterol and sex were not important for gallbladder bile acids composition. Neither sex up-regulated Cyp7a1 upon cholesterol loading and there was no compensatory up-regulation of Abcg5 or Abcg8 transporters. On the other hand, females had higher expression of the Ldlr and Cd36 genes. These findings explain sexual dimorphism of cholesterol metabolism in response to dietary cholesterol in a high-fat diet in mice, which contributes to understanding the sex-basis of cholesterol-associated liver diseases. Full article
(This article belongs to the Special Issue Steroids)
Open AccessArticle Synthesis and Quantitative Structure-Property Relationships of Side Chain-Modified Hyodeoxycholic Acid Derivatives
Molecules 2013, 18(9), 10497-10513; doi:10.3390/molecules180910497
Received: 9 July 2013 / Revised: 21 August 2013 / Accepted: 27 August 2013 / Published: 30 August 2013
Cited by 3 | PDF Full-text (759 KB) | HTML Full-text | XML Full-text
Abstract
Bile acids have emerged as versatile signalling compounds of a complex network of nuclear and membrane receptors regulating various endocrine and paracrine functions. The elucidation of the interconnection between the biological pathways under the bile acid control and manifestations of hepatic and [...] Read more.
Bile acids have emerged as versatile signalling compounds of a complex network of nuclear and membrane receptors regulating various endocrine and paracrine functions. The elucidation of the interconnection between the biological pathways under the bile acid control and manifestations of hepatic and metabolic diseases have extended the scope of this class of steroids for in vivo investigations. In this framework, the design and synthesis of novel biliary derivatives able to modulate a specific receptor requires a deep understanding of both structure-activity and structure-property relationships of bile acids. In this paper, we report the preparation and the critical micellization concentration evaluation of a series of hyodeoxycholic acid derivatives characterized by a diverse side chain length and by the presence of a methyl group at the alpha position with respect to the terminal carboxylic acid moiety. The data collected are instrumental to extend on a quantitative basis, the knowledge of the current structure-property relationships of bile acids and will be fruitful, in combination with models of receptor activity, to design and prioritize the synthesis of novel pharmacokinetically suitable ligands useful in the validation of bile acid-responsive receptors as therapeutic targets. Full article
(This article belongs to the Special Issue Steroids)
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Open AccessArticle In Situ Formation of Steroidal Supramolecular Gels Designed for Drug Release
Molecules 2013, 18(4), 3745-3759; doi:10.3390/molecules18043745
Received: 25 February 2013 / Revised: 19 March 2013 / Accepted: 21 March 2013 / Published: 25 March 2013
Cited by 7 | PDF Full-text (452 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
In this work, a steroidal gelator containing an imine bond was synthesized, and its gelation behavior as well as a sensitivity of its gels towards acids was investigated. It was shown that the gels were acid-responsive, and that the gelator molecules could [...] Read more.
In this work, a steroidal gelator containing an imine bond was synthesized, and its gelation behavior as well as a sensitivity of its gels towards acids was investigated. It was shown that the gels were acid-responsive, and that the gelator molecules could be prepared either by a conventional synthesis or directly in situ during the gel forming process. The gels prepared by both methods were studied and it was found that they had very similar macro- and microscopic properties. Furthermore, the possibility to use the gels as carriers for aromatic drugs such as 5-chloro-8-hydroxyquinoline, pyrazinecarboxamide, and antipyrine was investigated and the prepared two-component gels were studied with regard to their potential applications in drug delivery, particularly in a pH-controlled drug release. Full article
(This article belongs to the Special Issue Steroids)
Open AccessArticle Synthesis and 5α-Reductase Inhibitory Activity of C21 Steroids Having 1,4-diene or 4,6-diene 20-ones and 4-Azasteroid 20-Oximes
Molecules 2012, 17(1), 355-368; doi:10.3390/molecules17010355
Received: 1 November 2011 / Revised: 14 December 2011 / Accepted: 16 December 2011 / Published: 30 December 2011
Cited by 15 | PDF Full-text (355 KB)
Abstract
The synthesis and evaluation of 5α-reductase inhibitory activity of some 4-azasteroid-20-ones and 20-oximes and 3β-hydroxy-, 3β-acetoxy-, or epoxy-substituted C21 steroidal 20-ones and 20-oximes having double bonds in the A and/or B ring are described. Inhibitory activity of synthesized compounds was assessed [...] Read more.
The synthesis and evaluation of 5α-reductase inhibitory activity of some 4-azasteroid-20-ones and 20-oximes and 3β-hydroxy-, 3β-acetoxy-, or epoxy-substituted C21 steroidal 20-ones and 20-oximes having double bonds in the A and/or B ring are described. Inhibitory activity of synthesized compounds was assessed using 5α-reductase enzyme and [1,2,6,7-3H]testosterone as substrate. All synthesized compounds were less active than finasteride (IC50: 1.2 nM). Three 4-azasteroid-2-oximes (compounds 4, 6 and 8) showed good inhibitory activity (IC50: 26, 10 and 11 nM) and were more active than corresponding 4-azasteroid 20-ones (compounds 3, 5 and 7). 3β-Hydroxy-, 3β-acetoxy- and 1α,2α-, 5α,6α- or 6α,7α-epoxysteroid-20-one and -20-oxime derivatives having double bonds in the A and/or B ring showed no inhibition of 5α-reductase enzyme. Full article
(This article belongs to the Special Issue Steroids)
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Open AccessArticle Shortcut Access to Peptidosteroid Conjugates: Building Blocks for Solid-Phase Bile Acid Scaffold Decoration by Convergent Ligation
Molecules 2011, 16(12), 10168-10186; doi:10.3390/molecules161210168
Received: 10 November 2011 / Accepted: 30 November 2011 / Published: 7 December 2011
Cited by 9 | PDF Full-text (635 KB) | Supplementary Files
Abstract
We present three versatile solid-supported scaffold building blocks based on the (deoxy)cholic acid framework and decorated with handles for further derivatization by modern ligation techniques such as click chemistry, Staudinger ligation or native chemical ligation. Straightforward procedures are presented for the synthesis [...] Read more.
We present three versatile solid-supported scaffold building blocks based on the (deoxy)cholic acid framework and decorated with handles for further derivatization by modern ligation techniques such as click chemistry, Staudinger ligation or native chemical ligation. Straightforward procedures are presented for the synthesis and analysis of the steroid constructs. These building blocks offer a new, facile and shorter access route to bile acid-peptide conjugates on solid-phase with emphasis on heterodipodal conjugates with defined spatial arrangements. As such, we provide versatile new synthons to the toolbox for bile acid decoration. Full article
(This article belongs to the Special Issue Steroids)
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Open AccessArticle Succinobucol’s New Coat — Conjugation with Steroids to Alter Its Drug Effect and Bioavailability
Molecules 2011, 16(11), 9404-9420; doi:10.3390/molecules16119404
Received: 29 September 2011 / Revised: 2 November 2011 / Accepted: 7 November 2011 / Published: 10 November 2011
Cited by 5 | PDF Full-text (397 KB)
Abstract
Synthesis, detailed structural characterization (X-ray, NMR, MS, IR, elemental analysis), and studies of toxicity, antioxidant activity and bioavailability of unique potent anti-atherosclerotic succinobucol-steroid conjugates are reported. The conjugates consist of, on one side, the therapeutically important drug succinobucol ([4-{2,6-di-tert-butyl-4-[(1-{[3-tert [...] Read more.
Synthesis, detailed structural characterization (X-ray, NMR, MS, IR, elemental analysis), and studies of toxicity, antioxidant activity and bioavailability of unique potent anti-atherosclerotic succinobucol-steroid conjugates are reported. The conjugates consist of, on one side, the therapeutically important drug succinobucol ([4-{2,6-di-tert-butyl-4-[(1-{[3-tert-butyl-4-hydroxy-5-(propan-2-yl)phenyl]sulfanyl}ethyl)sulfanyl]phenoxy}-4-oxo-butanoic acid]) possessing an antioxidant and anti-inflammatory activity, and on the other side, plant stanol/sterols (stigmastanol, β-sitosterol and stigmasterol) possessing an ability to lower the blood cholesterol level. A cholesterol-succinobucol prodrug was also prepared in order to enhance the absorption of succinobucol through the intestinal membrane into the organism and to target the drug into the place of lipid metabolism—The enterohepatic circulation system. Their low toxicity towards mice fibroblasts at maximal concentrations, their antioxidant activity, comparable or even higher than that of ascorbic acid as determined by direct quenching of the DPPH radical, and their potential for significantly altering total and LDL cholesterol levels, suggest that these conjugates merit further studies in the treatment of cardiovascular or other related diseases. A brief discussion of succinobucol’s ability to quench the radicals, supported with a computational model of the electrostatic potential mapped on the electron density surface of the drug, is also presented. Full article
(This article belongs to the Special Issue Steroids)
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Open AccessArticle Stigmasterol-Based Novel Low Molecular Weight/Mass Organic Gelators
Molecules 2011, 16(11), 9357-9367; doi:10.3390/molecules16119357
Received: 25 October 2011 / Revised: 31 October 2011 / Accepted: 2 November 2011 / Published: 8 November 2011
Cited by 4 | PDF Full-text (318 KB) | Supplementary Files
Abstract
Conjugates consisting of stigmasterol and L-phenylalanine, interconnected through short-chained dicarboxylic acyls by ester and amide bonds, respectively, were synthesized as potential low molecular weight/mass organic gelators (LMWGs/LMMGs). Their physico-chemical properties were subjected to investigation, especially their ability to form gels reversibly based [...] Read more.
Conjugates consisting of stigmasterol and L-phenylalanine, interconnected through short-chained dicarboxylic acyls by ester and amide bonds, respectively, were synthesized as potential low molecular weight/mass organic gelators (LMWGs/LMMGs). Their physico-chemical properties were subjected to investigation, especially their ability to form gels reversibly based on changes of the environmental conditions. Other self-assembly properties detectable by UV-VIS traces were measured in systems consisting of two miscible solvents (water/acetonitrile) with varying solvent ratios and using constant concentrations of the studied compounds. Partition and diffusion coefficients and solubility in water were calculated for the target conjugates. The conjugate 3a was the only compound from this series capable of forming a gel in 1-octanol. All three conjugates 3a–3c displayed supramolecular characteristics in the UV-VIS spectra. Full article
(This article belongs to the Special Issue Steroids)
Open AccessArticle Two New Epoxysteroids from Helianthus tuberosus
Molecules 2011, 16(10), 8646-8653; doi:10.3390/molecules16108646
Received: 5 September 2011 / Revised: 10 October 2011 / Accepted: 11 October 2011 / Published: 13 October 2011
Cited by 3 | PDF Full-text (424 KB)
Abstract
Two new epoxy steroids, 5α,8α-epidioxy-22β,23β-epoxyergosta-6-en-3β-ol (1) and 5α,8α-epidioxy-22α,23α-epoxyergosta-6-en-3β-ol (2), and ten known steroids including (24R)-5α [...] Read more.
Two new epoxy steroids, 5α,8α-epidioxy-22β,23β-epoxyergosta-6-en-3β-ol (1) and 5α,8α-epidioxy-22α,23α-epoxyergosta-6-en-3β-ol (2), and ten known steroids including (24R)-5α,8α-epidioxyergosta-6-en-3β-ol (3), (22E,24R)-5α,8α-epidioxyergosta-6,22-dien-3β-ol (4), (22E,24R)-5α,8α-epidioxyergosta-6,9(11),22-trien-3β-ol (5), β-sitosterol (6), sitost-5-en-3β-ol acetate (7), 7α-hydroxysitosterol (8), schleicheol 2 (9), (24R)-24-ethyl-5α-cholestane-3β,5α,6β-triol (10), 7α-hydroxystigmasterol (11), and stigmasterol (12) were isolated from Helianthus tuberosus grown in Laizhou salinized land of coastal zone of Bohai Sea, China. The structures of these compounds were unambiguously established by 1D, 2D NMR and mass spectroscopic techniques. The new compounds 1 and 2 exhibited weak antibacterial activity and no antifungal activity. Full article
(This article belongs to the Special Issue Steroids)
Open AccessArticle Quantitative Structure Inter-Activity Relationship (QSInAR). Cytotoxicity Study of Some Hemisynthetic and Isolated Natural Steroids and Precursors on Human Fibrosarcoma Cells HT1080
Molecules 2011, 16(8), 6603-6620; doi:10.3390/molecules16086603
Received: 30 June 2011 / Revised: 28 July 2011 / Accepted: 29 July 2011 / Published: 5 August 2011
Cited by 7 | PDF Full-text (493 KB)
Abstract
Combined experimental and quantitative structure inter-activity relationship (QSIAR) computation methods were advanced in order to establish the structural and mechanistic influences that steroids and triterpenes, either as newly synthesized or naturally isolated products, have on human HT1080 mammalian cancer cells. The main [...] Read more.
Combined experimental and quantitative structure inter-activity relationship (QSIAR) computation methods were advanced in order to establish the structural and mechanistic influences that steroids and triterpenes, either as newly synthesized or naturally isolated products, have on human HT1080 mammalian cancer cells. The main Hansch structural indicators such as hydrophobicity (LogP), polarizability (POL) and total energy (Etot) were considered and both the structure-projected as well as globally computed correlations were reported; while the inter-activity correlation of the global activity with those projected on structural information was revealed as equal to the direct structural-activity one for the trial sets of compounds, the prediction for the testing set of molecules reported even superior performances respecting those characteristic for the calibration set, validating therefore the present QSInAR models; accordingly, it follows that the LogP carries the most part of the cytotoxic signal, while POL has little influence on inhibiting tumor growth—A complementary behavior with their earlier known influence on genotoxic carcinogenesis. Regarding the newly hemisynthetic compounds it was found that stigmasta-4,22-dien-3-one is not adapted for cell membrane diffusion; it is recommended that aminocinnamyl chlorohydrate be further modified in order to acquire better steric influence, while aminocinnamyl-2,3,4,6-O-tétraacétyl-α-D-glucopyranoside was identified as being inhibited in the tumor cell by other molecular mechanisms–here not revealed–although it has a moderate-high anti-cancer structurally predicted activity. Full article
(This article belongs to the Special Issue Steroids)
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Open AccessArticle Synthesis of Both Ionic Species of Ammonium Dithiocarbamate Derived Cholic Acid Moieties
Molecules 2011, 16(8), 6306-6312; doi:10.3390/molecules16086306
Received: 1 July 2011 / Revised: 18 July 2011 / Accepted: 25 July 2011 / Published: 26 July 2011
Cited by 3 | PDF Full-text (417 KB)
Abstract
The reaction of 3-aminopropylamide of cholic acid with CS2 produced a bile acid derivative of dithiocarbamic acid which further formed an ammonium salt with another molecule of 3-aminopropylamide of cholic acid. The cationic 3-ammonium propylamide of cholic acid did not react [...] Read more.
The reaction of 3-aminopropylamide of cholic acid with CS2 produced a bile acid derivative of dithiocarbamic acid which further formed an ammonium salt with another molecule of 3-aminopropylamide of cholic acid. The cationic 3-ammonium propylamide of cholic acid did not react further with CS2 and the formed salt was stable in the reaction mixture, even when excess CS2 was used. When the reaction was carried out in the presence of aqueous sodium hydroxide, only the bile acid derivative of sodium dithiocarbamate was formed. The dithiocarbamate derivatives were characterized by 1H- and 13C-NMR spectroscopy and ESI-TOF mass spectrometry. Full article
(This article belongs to the Special Issue Steroids)
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Review

Jump to: Research

Open AccessReview OSBP-Related Proteins: Liganding by Glycerophospholipids Opens New Insight into Their Function
Molecules 2013, 18(11), 13666-13679; doi:10.3390/molecules181113666
Received: 11 September 2013 / Revised: 1 November 2013 / Accepted: 1 November 2013 / Published: 5 November 2013
Cited by 6 | PDF Full-text (666 KB) | HTML Full-text | XML Full-text
Abstract
Oxysterol-binding protein (OSBP) and its homologs designated OSBP-related (ORP) or OSBP-like (OSBPL) proteins constitute a conserved family of lipid binding/transfer proteins (LTP) in eukaryotes. The mechanisms of ORP function have remained incompletely understood, but they have been implicated as intracellular sterol sensors [...] Read more.
Oxysterol-binding protein (OSBP) and its homologs designated OSBP-related (ORP) or OSBP-like (OSBPL) proteins constitute a conserved family of lipid binding/transfer proteins (LTP) in eukaryotes. The mechanisms of ORP function have remained incompletely understood, but they have been implicated as intracellular sterol sensors or transporters. A number of studies have provided evidence for the roles of ORPs at membrane contact sites (MCS), where endoplasmic reticulum is closely apposed with other organelle limiting membranes. ORPs are postulated to either transport sterols over MCSs or control the activity of enzymatic effectors or assembly of protein complexes with functions in signaling and lipid metabolism. Studies of yeast Saccharomyces cerevisiae ORPs Osh4p, Osh3p, Osh6p and Osh7p have revealed that ORPs do not exclusively bind sterols within their OSBP-related ligand-binding domain (ORD): The Osh4p ORD accommodates either sterols or phosphatidylinositol-4-phosphate (PI4P), and the Osh3p ORD was shown to specifically bind PI4P, the binding cavity being too narrow for a sterol to fit in. Most recently, Osh6p and Osh7p were demonstrated to show specific affinity for phosphatidylserine (PS), and to play a role in the intracellular transport of this glycerophospholipid; Additionally, two mammalian ORPs were shown to bind PS. Thus, the term frequently used for ORPs/OSBPLs, oxysterol-binding proteins, is a misnomer. While a number of ORPs bind oxysterols or cholesterol, other family members appear to interact with phospholipid ligands to regulate lipid fluxes, organelle lipid compositions and cell signaling. As a conclusion, ORPs are LTPs with a wide ligand spectrum and marked functional heterogeneity. Full article
(This article belongs to the Special Issue Steroids)
Open AccessReview 11β-Hydroxyandrostenedione Returns to the Steroid Arena: Biosynthesis, Metabolism and Function
Molecules 2013, 18(11), 13228-13244; doi:10.3390/molecules181113228
Received: 11 September 2013 / Revised: 18 October 2013 / Accepted: 21 October 2013 / Published: 25 October 2013
Cited by 4 | PDF Full-text (469 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The biological significance of 11β-hydroxyandrostenedione (11OHA4) has eluded researchers for the past six decades. It is now known that 11OHA4 is biosynthesized in the androgen arm of the adrenal steroidogenesis pathway and subsequently metabolized by steroidogenic enzymes in vitro, serving as [...] Read more.
The biological significance of 11β-hydroxyandrostenedione (11OHA4) has eluded researchers for the past six decades. It is now known that 11OHA4 is biosynthesized in the androgen arm of the adrenal steroidogenesis pathway and subsequently metabolized by steroidogenic enzymes in vitro, serving as precursor to recognized and novel androgenic steroids. These in vitro findings extend beyond the adrenal, suggesting that 11OHA4 could be metabolized in steroid-responsive peripheral tissues, as is the case for androgen precursor metabolites of adrenal origin. The significance thereof becomes apparent when considering that the metabolism of 11OHA4 in LNCaP androgen dependent prostate cancer cells yields androgenic steroid metabolites. It is thus possible that 11OHA4 may be metabolized to yield ligands for steroid receptors in not only the prostate but also in other steroid-responsive tissues. Future investigations of 11OHA4 may therefore characterize it as a vital steroid with far-reaching physiological consequences. An overview of the research on 11OHA4 since its identification in 1953 will be presented, with specific focus on the most recent works that have advanced our understanding of its biological role, thereby underscoring its relevance in health and disease. Full article
(This article belongs to the Special Issue Steroids)
Open AccessReview Synthesis of 3,4-Dibenzyltetrahydrofuran Lignans (9,9′-Epoxylignanes)
Molecules 2013, 18(11), 13124-13138; doi:10.3390/molecules181113124
Received: 28 August 2013 / Revised: 23 September 2013 / Accepted: 25 September 2013 / Published: 24 October 2013
Cited by 3 | PDF Full-text (478 KB) | HTML Full-text | XML Full-text
Abstract
Different strategies for the racemic or enantiospecific total syntheses of plant and mammalian 3,4-dibenzyltetrahydrofuran lignans are reviewed and compared. The multi-step approaches have various key step strategies: Diels–Alder reactions, Stobbe condensations, Michael additions, alkylations, nitrile oxide cycloadditions, radical cyclisations, dianion and oxidative [...] Read more.
Different strategies for the racemic or enantiospecific total syntheses of plant and mammalian 3,4-dibenzyltetrahydrofuran lignans are reviewed and compared. The multi-step approaches have various key step strategies: Diels–Alder reactions, Stobbe condensations, Michael additions, alkylations, nitrile oxide cycloadditions, radical cyclisations, dianion and oxidative couplings. Full article
(This article belongs to the Special Issue Steroids)
Open AccessReview Pregnenolone Sulfate: From Steroid Metabolite to TRP Channel Ligand
Molecules 2013, 18(10), 12012-12028; doi:10.3390/molecules181012012
Received: 2 September 2013 / Revised: 20 September 2013 / Accepted: 21 September 2013 / Published: 27 September 2013
Cited by 9 | PDF Full-text (952 KB) | HTML Full-text | XML Full-text
Abstract
Pregnenolone sulfate is a steroid metabolite with a plethora of actions and functions. As a neurosteroid, pregnenolone sulfate modulates a variety of ion channels, transporters, and enzymes. Interestingly, as a sulfated steroid, pregnenolone sulfate is not the final- or waste-product of pregnenolone [...] Read more.
Pregnenolone sulfate is a steroid metabolite with a plethora of actions and functions. As a neurosteroid, pregnenolone sulfate modulates a variety of ion channels, transporters, and enzymes. Interestingly, as a sulfated steroid, pregnenolone sulfate is not the final- or waste-product of pregnenolone being sulfated via a phase II metabolism reaction and renally excreted, as one would presume from the pharmacology textbook knowledge. Pregnenolone sulfate is also the source and thereby the starting point for subsequent steroid synthesis pathways. Most recently, pregnenolone sulfate has been functionally “upgraded” from modulator of ion channels to an activating ion channel ligand. This review will focus on molecular aspects of the neurosteroid, pregnenolone sulfate, its metabolism, concentrations in serum and tissues and last not least will summarize the functional data. Full article
(This article belongs to the Special Issue Steroids)
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Open AccessReview Modulation of Xenobiotic Receptors by Steroids
Molecules 2013, 18(7), 7389-7406; doi:10.3390/molecules18077389
Received: 24 May 2013 / Revised: 13 June 2013 / Accepted: 19 June 2013 / Published: 24 June 2013
Cited by 8 | PDF Full-text (1081 KB) | HTML Full-text | XML Full-text
Abstract
Nuclear receptors (NRs) are ligand-activated transcription factors that regulate the expression of their target genes. NRs play important roles in many human diseases, including metabolic diseases and cancer, and are therefore a key class of therapeutic targets. Steroids play important roles in [...] Read more.
Nuclear receptors (NRs) are ligand-activated transcription factors that regulate the expression of their target genes. NRs play important roles in many human diseases, including metabolic diseases and cancer, and are therefore a key class of therapeutic targets. Steroids play important roles in regulating nuclear receptors; in addition to being ligands of steroid receptors, steroids (and their metabolites) also regulate other NRs, such as the pregnane X receptor and constitutive androstane receptor (termed xenobiotic receptors), which participate in steroid metabolism. Xenobiotic receptors have promiscuous ligand-binding properties, and their structurally diverse ligands include steroids and their metabolites. Therefore, steroids, their metabolism and metabolites, xenobiotic receptors, steroid receptors, and the respective signaling pathways they regulate have functional interactions. This review discusses these functional interactions and their implications for activities mediated by steroid receptors and xenobiotic receptors, focusing on steroids that modulate pathways involving the pregnane X receptor and constitutive androstane receptor. The emphasis of the review is on structure-function studies of xenobiotic receptors bound to steroid ligands. Full article
(This article belongs to the Special Issue Steroids)
Open AccessReview The Use of Stable and Radioactive Sterol Tracers as a Tool to Investigate Cholesterol Degradation to Bile Acids in Humans in Vivo
Molecules 2012, 17(2), 1939-1968; doi:10.3390/molecules17021939
Received: 13 January 2012 / Revised: 3 February 2012 / Accepted: 8 February 2012 / Published: 16 February 2012
Cited by 2 | PDF Full-text (328 KB)
Abstract
Alterations of cholesterol homeostasis represent important risk factors for atherosclerosis and cardiovascular disease. Different clinical-experimental approaches have been devised to study the metabolism of cholesterol and particularly the synthesis of bile acids, its main catabolic products. Most evidence in humans has derived [...] Read more.
Alterations of cholesterol homeostasis represent important risk factors for atherosclerosis and cardiovascular disease. Different clinical-experimental approaches have been devised to study the metabolism of cholesterol and particularly the synthesis of bile acids, its main catabolic products. Most evidence in humans has derived from studies utilizing the administration of labeled sterols; these have several advantages over in vitro assay of enzyme activity and expression, requiring an invasive procedure such as a liver biopsy, or the determination of fecal sterols, which is cumbersome and not commonly available. Pioneering evidence with administration of radioactive sterol derivatives has allowed to characterize the alterations of cholesterol metabolism and degradation in different situations, including spontaneous disease conditions, aging, and drug treatment. Along with the classical isotope dilution methodology, other approaches were proposed, among which isotope release following radioactive substrate administration. More recently, stable isotope studies have allowed to overcome radioactivity exposure. Isotope enrichment studies during tracer infusion has allowed to characterize changes in the degradation of cholesterol via the “classical” and the “alternative” pathways of bile acid synthesis. Evidence brought by tracer studies in vivo, summarized here, provides an exceptional tool for the investigation of sterol metabolism, and integrate the studies in vitro on human tissue. Full article
(This article belongs to the Special Issue Steroids)
Open AccessReview Inhibitors of Testosterone Biosynthetic and Metabolic Activation Enzymes
Molecules 2011, 16(12), 9983-10001; doi:10.3390/molecules16129983
Received: 2 November 2011 / Revised: 21 November 2011 / Accepted: 21 November 2011 / Published: 2 December 2011
Cited by 28 | PDF Full-text (254 KB)
Abstract
The Leydig cells of the testis have the capacity to biosynthesize testosterone from cholesterol. Testosterone and its metabolically activated product dihydrotestosterone are critical for the development of male reproductive system and spermatogenesis. At least four steroidogenic enzymes are involved in testosterone biosynthesis: [...] Read more.
The Leydig cells of the testis have the capacity to biosynthesize testosterone from cholesterol. Testosterone and its metabolically activated product dihydrotestosterone are critical for the development of male reproductive system and spermatogenesis. At least four steroidogenic enzymes are involved in testosterone biosynthesis: Cholesterol side chain cleavage enzyme (CYP11A1) for the conversion of cholesterol into pregnenolone within the mitochondria, 3β-hydroxysteroid dehydrogenase (HSD3B), for the conversion of pregnenolone into progesterone, 17α-hydroxylase/17,20-lyase (CYP17A1) for the conversion of progesterone into androstenedione and 17β-hydroxysteroid dehydrogenase (HSD17B3) for the formation of testosterone from androstenedione. Testosterone is also metabolically activated into more potent androgen dihydrotestosterone by two isoforms 5α-reductase 1 (SRD5A1) and 2 (SRD5A2) in Leydig cells and peripheral tissues. Many endocrine disruptors act as antiandrogens via directly inhibiting one or more enzymes for testosterone biosynthesis and metabolic activation. These chemicals include industrial materials (perfluoroalkyl compounds, phthalates, bisphenol A and benzophenone) and pesticides/biocides (methoxychlor, organotins, 1,2-dibromo-3-chloropropane and prochloraz) and plant constituents (genistein and gossypol). This paper reviews these endocrine disruptors targeting steroidogenic enzymes. Full article
(This article belongs to the Special Issue Steroids)

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