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Two series of novel steroidal[17,16-d]pyrimidines derived from natural epiandrosterone and androsterone were designed and synthesized, and these compounds were screened for their potential anticancer activities. The preliminary bioassay indicated that some of these prepared compounds exhibited significantly good cytotoxic activities against human gastric cancer (SGC-7901), lung cancer (A549), and hepatocellular liver carcinoma (HepG2) cell lines compared with 5-fluorouracil (5-FU), epiandrosterone, and androsterone. Especially the respective pairs from epiandrosterone and androsterone showed significantly different inhibitory activities, and the possible configuration-activity relationships have also been summarized and discussed based on kinase assay and molecular docking, which indicated that the inhibition activities of these steroidal[17,16-d]pyrimidines might obviously be affected by the configuration of the hydroxyl group in the part of the steroidal scaffold. [ABSTRACT FROM AUTHOR]

Porcine carbonyl reductases (pCBR1 and pCBR-N1) and aldo-keto reductases (pAKR1C1 and pAKR1C4) exhibit hydroxysteroid dehydrogenase (HSD) activity. However, their roles in the metabolism of porcine-specific androgens (19-nortestosterone and epiandrosterone), 11-oxygenated androgens, neurosteroids, and corticosteroids remain unclear. Here, we compared the steroid specificity of the four recombinant enzymes by kinetic and product analyses. In C 18 /C 19 -steroids,11-keto- and 11β-hydroxy-5α-androstane-3,17-diones were reduced by all the enzymes, whereas 5α-dihydronandrolone (19-nortestosterone metabolite) and 11-ketodihydrotestosterone were reduced by pCBR1, pCBR-N1, and pAKR1C1, of which pCBR1 exhibited the lowest (submicromolar) K m values. Product analysis showed that pCBR1 and pCBR-N1 function as 3α/β-HSDs, in contrast to pAKR1C1 and pAKR1C4 (acting as 3β-HSD and 3α-HSD, respectively). Additionally, 17β-HSD activity was observed in pCBR1 and pCBR-N1 (toward epiandrosterone and its 11-oxygenated derivatives) and in pAKR1C1 (toward androsterone, 4-androstene-3,17-dione and their 11-oxygenated derivatives). The four enzymes also showed different substrate specificity for 3-keto-5α/β-dihydro-C 21 -steroids, including GABAergic neurosteroid precursors and corticosteroid metabolites. 5β-Dihydroprogesterone was reduced by all the enzymes, whereas 5α-dihydroprogesterone was reduced only by pCBR1, and 5α/β-dihydrodeoxycorticosterones by pCBR1 and pCBR-N1. The two pCBRs also reduced the 5α/β-dihydro-metabolites of cortisol, 11-deoxycortisol, cortisone, and corticosterone. pCBR1 exhibited lower K m values (0.3–2.9 μM) for the 3-keto-C 21 -steroids than pCBR-N1 (K m =10–36 μM). The reduced products of the 3-keto-C 21 -steroids by pCBR1 and pCBR-N1 were their 3α-hydroxy-metabolites. Finally, we found that human CBR1 has similar substrate specificity for the C 18 /C 19 /C 21 -steroids to pCBR-N1. Based on these results, it was concluded that porcine and human CBRs can be involved in the metabolism of the aforementioned steroids as 3α/β,17β-HSDs. [Display omitted] • Porcine CBR1 and CBR-N1 exhibit 3α/3β/17β-hydroxysteroid dehydrogenase activity. • They are involved in the metabolism of epiandrosterone and 5α-dihydronandrolone. • The metabolism of 11-keto/11β-hydroxy-C 19 -steroids is also mediated by the enzymes. • They additionally function in corticosteroid catabolism and neurosteroid synthesis. • Human CBR1 has similar steroid specificity to porcine CBR-N1. [ABSTRACT FROM AUTHOR]

Two series of heterocyclic steroidal pyrazolo[1,5-a]pyrimidines derived from dehydroepiandrosterone (DHEA) and epiandrosterone (EPIA) were designed and synthesized, and these compounds were screened for their potential antiproliferation activities. The preliminary bioassay indicated that some of target compounds exhibited significantly good antiproliferation activities against human melanoma cell line (A875) and human hepatocellular carcinoma (Huh-7) cell lines compared with 5-fluorouracil (5-FU), and some of which present good antiproliferative activities as potential ALK inhibitors. The detailed analysis of structure-activity relationships (SARs) based on the inhibition activities, kinase assay, and molecular docking demonstrated that the antiproliferation activities of these steroidal pyrazolo[1,5-a]pyrimidine might be affected by the β-hydroxyl group of steroidal scaffold and the N atom of pyridine heterocycle. Especially, compound 4c has certain inhibitory effects on the tyrosine protein kinases ALK, CDK2/CyclinE1, FAK, CDK5/P35, CDK9/CyclinT1, CDK5/P25, PIM2, CDK2/CyclinA2, CDK1/CyclinB1, etc., and which displayed highest inhibitory effect on the kinases of ALK with inhibition rate 40.63 % at the concentration of 10 μM, which induced cell death in A875 cells at least partly (initially), by apoptosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Résumé Contexte L’insuffisance en androgènes affecte les hommes à l’âge adulte, causant plusieurs effets nocifs aux niveaux reproductif et comportemental. Puisque l’aromatase est. une enzyme qui catalyse la conversion des androgènes en œstrogènes, et qu’elle est. responsable d’un équilibre adéquat des hormones sexuelles chez les hommes et les femmes, l’administration de molécules agissant comme freinateurs peut contribuer à restaurer une activité enzymatique anormale. Une étude prospective pilote a été menée pour étudier l’effet du D-chiro-inositol, un potentiel freinateur de l’aromatase, sur les taux sériques de testostérone, estradiol, estrone, déhydroépiandrostérone et d’épiandrostérone d’un groupe d’hommes adultes volontaires. Le glucose, l’insuline, l’hormone folliculostimulante, l’hormone lutéinisante, l’inhibine B, le D-chiro-inositol et les taux sériques de myo-inositol ont également été mesurés. Résultats Les hommes volontaires ont été sélectionnés selon l’âge et l’indice de masse corporelle. Les hommes qui présentaient une glycémie et/ou un statut hormonal altérés en raison d’un âge avancé ou d’un poids anormal, ont été inclus dans l’étude. Chacun des 10 volontaires enrôlés a pris du D-chiro-inositol (1 g/jour) par voie orale pendant un mois. Des dosages sériques des marqueurs sélectionnés ont été réalisés avant (témoin) et après le traitement. L’administration de D-chiro-inositol a été associée à une réduction des taux sériques de l’estrone (− 85.0%) et de l’estradiol (− 14,4%), et a une augmentation des taux sériques de testostérone (+ 23,4%) et de déhydroépiandrostérone (+ 13,8%). En outre, les taux d’épiandrostérone étaient plus élevés (39%) après le traitement. D’autre part, les taux d’hormone folliculostimulante, d’hormone lutéinisante et d’inhibine B n’ont pas été modifiés. Une tendance à la diminution de la glycémie, de l’insulinémie et de l’indice d’évaluation du modèle homéostatique a été observée après traitement par D-chiro-inositol, bien que les différences n’aient pas atteint une signification statistique. Le traitement par D-chiro-inositol n’a causé aucun effet indésirable notable. Conclusions L’augmentation des androgènes et la diminution des œstrogènes semblent confirmer que le D-chiro-inositol agit comme un freinateur de l’aromatase, mais avec un mécanisme d’action encore inconnu. Cette étude pilote ouvre de nouvelles perspectives de recherche et d’applications thérapeutiques pour le D-chiro-inositol à différents dosages et durées de traitement.

Two series of novel steroidal[17,16-d]pyrimidines derived from natural epiandrosterone and androsterone were designed and synthesized, and these compounds were screened for their potential anticancer activities. The preliminary bioassay indicated that some of these prepared compounds exhibited significantly good cytotoxic activities against human gastric cancer (SGC-7901), lung cancer (A549), and hepatocellular liver carcinoma (HepG2) cell lines compared with 5-fluorouracil (5-FU), epiandrosterone, and androsterone. Especially the respective pairs from epiandrosterone and androsterone showed significantly different inhibitory activities, and the possible configuration-activity relationships have also been summarized and discussed based on kinase assay and molecular docking, which indicated that the inhibition activities of these steroidal[17,16-d]pyrimidines might obviously be affected by the configuration of the hydroxyl group in the part of the steroidal scaffold.

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Steroids are classes of natural products widely distributed in nature, which have been demonstrated to exhibit broad biological functions, and have also attracted increasing interest from bioorganic and pharmaceutical researches. In order to develop novel chemical entities as potential cytotoxic agents, a series of steroidal isatin conjugations derived from epiandrosterone and androsterone were efficiently prepared and characterized, and all these obtained compounds were screened for their potential cytotoxic activities. The preliminary bioassay indicated that most of the newly synthesized compounds exhibited good cytotoxic activities against human gastric cancer (SGC-7901), melanoma (A875), and hepatocellular liver carcinoma (HepG2) cell lines compared with 5-fluorouracil (5-FU), which might be considered as promising scaffold for further development of potential anticancer agents.

Identification and evaluation of long‐term markers is crucial in prolonging the detection window for anabolic steroid abuse in sport. Recently, sulfoconjugated epiandrosterone was identified as a potential long‐term marker for the abuse of certain endogenous anabolic agents, including testosterone, which continues to be widely used as a performance enhancing agent in sport. To evaluate the applicability of epiandrosterone sulfate as a marker for testosterone use, administration studies were conducted with multiple modes of testosterone administration – transdermal, intramuscular, and subcutaneous. A modified sample preparation method was used to collect both glucuronidated and sulfoconjugated analytes of interest. Carbon isotope ratio measurements from the administration studies are presented here. Epiandrosterone was less effective than the conventionally used target compounds for detection of the low dose application (transdermal gel). With intramuscular administration, epiandrosterone was more diagnostic than with transdermal administration, but it did not prolong the detection window more than the conventional target compounds. With subcutaneous administration, the doses administered to the subjects were varied and the effect on the epiandrosterone values was dependent on the magnitude of the dose administered. Epiandrosterone does not appear to be a useful marker in the detection of low dose testosterone administration. It is responsive to higher dose administration, but it does not provide an extension of the detection window relative to conventional target compounds. [ABSTRACT FROM AUTHOR]

Two series of hydrazones were synthesized from 3β-hydroxy- and 3β-(1-adamantoate)-5α-androstan-17- one, respectively, to study the structure–activity relationship. Cytotoxicity studies showed that 5α-androstan- 3β-ol-17-one m-nitrobenzoylhydrazone exhibited pronounced specific activity in a Hoechst experiment against lung carcinoma (A-549) and colorectal adenocarcinoma cell lines (DLD-1). [ABSTRACT FROM AUTHOR]

Steroids are classes of natural products widely distributed in nature, which have been demonstrated to exhibit broad biological functions, and have also attracted increasing interest from bioorganic and pharmaceutical researches. In order to develop novel chemical entities as potential cytotoxic agents, a series of steroidal isatin conjugations derived from epiandrosterone and androsterone were efficiently prepared and characterized, and all these obtained compounds were screened for their potential cytotoxic activities. The preliminary bioassay indicated that most of the newly synthesized compounds exhibited good cytotoxic activities against human gastric cancer (SGC-7901), melanoma (A875), and hepatocellular liver carcinoma (HepG2) cell lines compared with 5-fluorouracil (5-FU), which might be considered as promising scaffold for further development of potential anticancer agents. [ABSTRACT FROM AUTHOR]

Several new N-containing epiandrosterone derivatives modified by phenylacetic acid chloride were synthesized for biological activity studies. Compounds with antiviral activity were discovered among them and 3β-hydroxy-1′-aryl-3′-methyl-5′-androstano[17,16-d]pyrazolines prepared by us earlier. [ABSTRACT FROM AUTHOR]

In the course of investigations into the metabolism of testosterone (T) by means of deuterated T and hydrogen isotope ratio mass spectrometry, a pronounced influence of the oral administration of T on sulfoconjugated steroid metabolites was observed. Especially in case of epiandrosterone sulfate (EPIA_S), the contribution of exogenous T to the urinary metabolite was traceable up to 8 days after a single oral dose of 40 mg of T. These findings initiated follow-up studies on the capability of EPIA_S to extend the detection of T and T analogue misuse by carbon isotope ratio (CIR) mass spectrometry in sports drug testing. Excretion study urine samples obtained after transdermal application of T and after oral administration of 4-androstenedione, dihydrotestosterone, and EPIA were investigated regarding urinary concentrations and CIR. With each administered steroid, EPIA_S was significantly depleted and prolonged the detectability when compared to routinely used steroidal target compounds by a factor of 2 to 5. In order to simplify the sample preparation procedure for sulfoconjugated compounds, enzymatic cleavage by Pseudomonas aeruginosa arylsulfatase was tested and implemented into CIR measurements for the first time. Further simplification was achieved by employing multidimensional gas chromatography to ensure the required peak purity for CIR determinations, instead of sample purification strategies using liquid chromatographic fractionation. Taking into account these results that demonstrate the unique and broad applicability of EPIA_S for the detection of illicit administrations of T or T-related steroids, careful consideration of how this steroid can be implemented into routine doping control analysis appears warranted. Copyright © 2017 John Wiley & Sons, Ltd. [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]

In this work,Aspergillus candidusMRC 22634 converted epiandosterone1into 10 hydroxylated metabolites.A.candidushas been shown to hydroxylate1predominantly at C-11α, C-1α, and C-15β with minor hydroxylations occurring at C-14α and C-7α. Oxidation at C-3, reduction at C-17, and C-3 epimerization of some of the remaining substrate have also been shown. 15β-Hydroxylation and C-3 epimerization of1by a fungus were reported for the first time. Two of the metabolites, 1α,3α-dihydroxy-5α-androstan-17-one4and 15β,17β-dihydroxy-5α-androstan-3-one7, were identified as new compounds. [ABSTRACT FROM AUTHOR]

Incubation of epiandrosterone with Aspergillus sydowii MRC 200653 afforded ten metabolites. The fungal dehydrogenation of epiandrosterone is reported for the first time. The formation of the major metabolite, 6β-hydroxyandrost-4-ene-3,17-dione, involved first dehydrogenation to give a 4-ene and then hydroxylation at C-6β. Small amounts of the substrate were hydroxylated at C-1α, C-7α, C-7β and C-11α. [ABSTRACT FROM AUTHOR]

The biotransformation of androsterone (1), epiandrosterone (2), androstanedione (3) and DHEA (dehydroepiandrosterone) (4) by Penicillium lanosocoeruleum—a fungal species not used in biotransformations so far—were described. All the substrates were converted in high yield (70%–99%) into D ring δ-lactones. The oxidation of 1 produced 3α-hydroxy-17a-oxa-D-homo-5α-androstan-17-one (5). The oxidation of 2 led to 3β-hydroxy-17a-oxa-D-homo-5α-androstan-17-one (6). The biotransformation of 3 resulted in the formation of 3α-hydroxy-17a-oxa-D-homo-5α-androstan-17-one (5) and 17a-oxa-D-homo-5α-androstan-3,17-dione (7). An analysis of the transformation progress of the studied substrates as a function of time indicates that the Baeyer-Villiger monooxygenase of this fungus does not accept the 3β-hydroxy-5-ene functionality of steroids. In this microorganism steroidal 3β-hydroxy-dehydrogenase (3β-HSD) was active, and as a result DHEA (4) was transformed exclusively to testololactone (8). Apart from the observed oxidative transformations, a reductive pathway was revealed with the C-3 ketone being reduced to a C-3α-alcohol. It is demonstrated for the first time that the reduction of the 3-keto group of the steroid nucleus can occur in the presence of a ring-D lactone functionality.

Glucose-6-phosphate dehydrogenase (G6PDH) plays a housekeeping role in cell metabolism by generating reducing power (NADPH) and fueling the production of nucleotide precursors (ribose-5-phosphate). Based on its indispensability for pathogenic parasites from the genus Trypanosoma, G6PDH is considered a drug target candidate. Several steroid-like scaffolds were previously reported to target the activity of G6PDH. Epiandrosterone (EA) is an uncompetitive inhibitor of trypanosomal G6PDH for which its binding site to the enzyme remains unknown. Molecular simulation studies with the structure of Trypanosoma cruzi G6PDH revealed that EA binds in a pocket close to the G6P binding-site and protrudes into the active site blocking the interaction between substrates and hence catalysis. Site directed mutagenesis revealed the important steroid-stabilizing effect of residues (L80, K83 and K84) located on helix α -1 of T. cruzi G6PDH. The higher affinity and potency of 16 -Br EA by T. cruzi G6PDH is explained by the formation of a halogen bond with the hydrogen from the terminal amide of the NADP+-nicotinamide. At variance with the human enzyme, the inclusion of a 21-hydroxypregnane-20-one moiety to a 3β -substituted steroid is detrimental for T. cruzi G6PDH inhibition. The species-specificity of certain steroid derivatives towards the parasite G6PDH and the corresponding biochemically validated binding models disclosed in this work may prove valuable for the development of selective inhibitors against the pathogen’s enzyme. [ABSTRACT FROM AUTHOR]

Glucose-6-phosphate dehydrogenase (G6PDH) plays a housekeeping role in cell metabolism by generating reducing power (NADPH) and fueling the production of nucleotide precursors (ribose-5-phosphate). Based on its indispensability for pathogenic parasites from the genus Trypanosoma, G6PDH is considered a drug target candidate. Several steroid-like scaffolds were previously reported to target the activity of G6PDH. Epiandrosterone (EA) is an uncompetitive inhibitor of trypanosomal G6PDH for which its binding site to the enzyme remains unknown. Molecular simulation studies with the structure of Trypanosoma cruzi G6PDH revealed that EA binds in a pocket close to the G6P binding-site and protrudes into the active site blocking the interaction between substrates and hence catalysis. Site directed mutagenesis revealed the important steroid-stabilizing effect of residues (L80, K83 and K84) located on helix α-1 of T. cruzi G6PDH. The higher affinity and potency of 16α-Br EA by T. cruzi G6PDH is explained by the formation of a halogen bond with the hydrogen from the terminal amide of the NADP+-nicotinamide. At variance with the human enzyme, the inclusion of a 21-hydroxypregnane-20-one moiety to a 3β-substituted steroid is detrimental for T. cruzi G6PDH inhibition. The species-specificity of certain steroid derivatives towards the parasite G6PDH and the corresponding biochemically validated binding models disclosed in this work may prove valuable for the development of selective inhibitors against the pathogen’s enzyme.

The biotransformation of androsterone (1), epiandrosterone (2), androstanedione (3) and DHEA (dehydroepiandrosterone) (4) by Penicillium lanosocoeruleum-a fungal species not used in biotransformations so far-were described. All the substrates were converted in high yield (70%-99%) into D ring δ-lactones. The oxidation of 1 produced 3α-hydroxy-17a-oxa-D-homo-5α-androstan-17-one (5). The oxidation of 2 led to 3β-hydroxy-17a-oxa-D-homo-5α-androstan-17-one (6). The biotransformation of 3 resulted in the formation of 3α-hydroxy-17a-oxa-D-homo-5α-androstan-17-one (5) and 17a-oxa-Dhomo- 5α-androstan-3,17-dione (7). An analysis of the transformation progress of the studied substrates as a function of time indicates that the Baeyer-Villiger monooxygenase of this fungus does not accept the 3β-hydroxy-5-ene functionality of steroids. In this microorganism steroidal 3β-hydroxy-dehydrogenase (3β-HSD) was active, and as a result DHEA (4) was transformed exclusively to testololactone (8). Apart from the observed oxidative transformations, a reductive pathway was revealed with the C-3 ketone being reduced to a C-3α-alcohol. It is demonstrated for the first time that the reduction of the 3-keto group of the steroid nucleus can occur in the presence of a ring-D lactone functionality. [ABSTRACT FROM AUTHOR]

Abstract: Dehydroepiandrosterone (DHEA) is a multifunctional steroid with a broad range of biological effects in humans and animals. DHEA can be converted to multiple oxygenated metabolites in the brain and peripheral tissues. The mechanisms by which DHEA exerts its effects are not well understood. However, evidence that the effects of DHEA are mediated by its oxygenated metabolites has accumulated. This paper will review the panel of oxygenated DHEA metabolites (7, 16 and 17-hydroxylated derivatives) including a number of 5α-androstane derivatives, such as epiandrosterone (EpiA) metabolites. The most important aspects of the oxidative metabolism of DHEA in the liver, intestine and brain are described. Then, this article reviews the reported biological effects of oxygenated DHEA metabolites from recent findings with a specific focus on cancer, inflammatory and immune processes, osteoporosis, thermogenesis, adipogenesis, the cardiovascular system, the brain and the estrogen and androgen receptors. [Copyright &y& Elsevier]

Abstract: The efficient synthesis of some 17E-(2-aryl-2-oxo-1-ethylidene)-5α-androstan-3β-ols was investigated. 17-Alkynyl-3,17-androstanediols were prepared through the nucleophilic addition of epiandrosterone using the corresponding 1-alkynes in the presence of a strong base n-BuLi firstly. The Meyer–Schuster rearrangement of 17-alkynyl-3,17-androstanediols was carried out efficiently catalyzed by 10% H2SO4 and HgSO4 in THF. This strategy offered a very straightforward and efficient method for access to conjugated α,β-unsaturated ketone 17E,5α-androstan-3β-ols from the 17-alkynyl-3,17-androstanediols in good overall yields, which are key intermediates for the preparation of some biologically important modified 17-side chain steroids. Evaluation of the synthesized compounds for cytotoxicity against A549, SKOV3, MKN-45 and MDA-MB-435 cell lines showed that 17E-(2-aryl-2-oxo-1-ethylidene)-5α-androstanes possessing a hydroxyl groups at C-3 and fluoro-substituted group of aromatic ring in the side chain have significant inhibition activity. [Copyright &y& Elsevier]

Abstract: Steroids such as dehydroepiandrosterone (DHEA) and epiandrosterone (EA) exert multiple effects in mammals including the inhibition of glucose-6-phosphate dehydrogenase (G6PDH). Initially, the inhibition was considered specific for the mammalian enzyme. The beneficial effect of these steroids on infections by protists and nematodes was attributed to stimulation of the immune system. However, we showed previously that DHEA and EA also inhibit Trypanosoma brucei and T. cruzi G6PDH, with low micromolar K i’ values, but not the enzyme from Leishmania species, and kill in vitro cultured trypanosomes. We report here that, contrary to wild-type trypanosomes, mutant bloodstream-form T. brucei cells expressing L. mexicana G6PDH are not susceptible to the steroids, proving that G6PDH is the in situ target. Moreover, bromo-derivatives of the steroids show 50–100 fold lower K i’ values for the enzyme and display an increased potency to kill the parasites. Therefore, the compounds offer promise for use in development of parasite-selective drugs. [Copyright &y& Elsevier]

Numerous studies investigated the effects of pharmacological doses of DHEA in animals. Among protective effects, antiglucocorticoid potencies, triggering and modulation of immunity and anticancerous effects were reported. Because DHEA levels decrease in aging humans, this steroid has been assayed as replacement therapy in elderly volunteers without striking evidence for beneficial effects. Examination of the investigations carried out in animals lead to suspect that, rather than DHEA, its metabolites produced in tissues could be responsible for some of the observed effects. Known as the 'mother steroid', DHEA is a precursor for androgenic and estrogenic steroid hormones. In addition, DHEA is hydroxylated at the 7α position by the cytochrome P450 7B1 (CYP7B1), and the 7α-hydroxy-DHEA produced is a substrate for the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which converts it into 7β-hydroxy-DHEA. Both 7-hydroxylated metabolites were shown to favor the onset of immunity in mice and the activation of memory T cells in humans. Other DHEA and testosterone-derived metabolites, namely epiandrosterone and 5α-androstane-3β,17β-diol, are also substrates for the CYP7B1 and their 7α-hydroxylated products were also converted into the 7β epimer by the 11β-HSD1. When assayed at doses 104 lower than DHEA, 7β-hydroxy-epiandrosterone was shown to shift the prostaglandin metabolism patterns from prostaglandin E2 (PGE2) to PGD2 production, thus triggering the resolution of inflammation. In addition, 7β-hydroxy-epiandrosterone (1 nM) exerted the same effects as tamoxifen (1 μM) on the proliferation of MCF-7 and MDA-231 human breast cancer cells. These findings suggest that the observed effects of 7β-hydroxy-epiandrosterone could be mediated by estrogen receptors. This overview of recent research implies that DHEA does not act directly and that its effects are due to its metabolites when produced in tissues. Treatments with DHEA should take into account the target tissue abilities to produce the desired metabolites through the two key enzymes, CYP7B1 and 11β-HSD1. [ABSTRACT FROM AUTHOR]

Numerous studies investigated the effects of pharmacological doses of DHEA in animals. Among protective effects, antiglucocorticoid potencies, triggering and modulation of immunity and anticancerous effects were reported. Because DHEA levels decrease in aging humans, this steroid has been assayed as replacement therapy in elderly volunteers without striking evidence for beneficial effects. Examination of the investigations carried out in animals lead to suspect that, rather than DHEA, its metabolites produced in tissues could be responsible for some of the observed effects. Known as the 'mother steroid', DHEA is a precursor for androgenic and estrogenic steroid hormones. In addition, DHEA is hydroxylated at the 7α position by the cytochrome P450 7B1 (CYP7B1), and the 7α-hydroxy-DHEA produced is a substrate for the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which converts it into 7β-hydroxy-DHEA. Both 7-hydroxylated metabolites were shown to favor the onset of immunity in mice and the activation of memory T cells in humans. Other DHEA and testosterone-derived metabolites, namely epiandrosterone and 5α-androstane-3β,17β-diol, are also substrates for the CYP7B1 and their 7α-hydroxylated products were also converted into the 7β epimer by the 11β-HSD1. When assayed at doses 104 lower than DHEA, 7β-hydroxy-epiandrosterone was shown to shift the prostaglandin metabolism patterns from prostaglandin E2 (PGE2) to PGD2 production, thus triggering the resolution of inflammation. In addition, 7β-hydroxy-epiandrosterone (1 nM) exerted the same effects as tamoxifen (1 μM) on the proliferation of MCF-7 and MDA-231 human breast cancer cells. These findings suggest that the observed effects of 7β-hydroxy-epiandrosterone could be mediated by estrogen receptors. This overview of recent research implies that DHEA does not act directly and that its effects are due to its metabolites when produced in tissues. Treatments with DHEA should take into account the target tissue abilities to produce the desired metabolites through the two key enzymes, CYP7B1 and 11β-HSD1. [ABSTRACT FROM AUTHOR]

Abstract: Glucose 6-phosphate dehydrogenase (G6PDH) catalyzes the first step of the pentose-phosphate pathway which supplies cells with ribose 5-phosphate (R5P) and NADPH. R5P is the precursor for the biosynthesis of nucleotides while NADPH is the cofactor of several dehydrogenases acting in a broad range of biosynthetic processes and in the maintenance of the cellular redox state. RNA interference-mediated reduction of G6PDH levels in bloodstream-form Trypanosoma brucei validated this enzyme as a drug target against Human African Trypanosomiasis. Dehydroepiandrosterone (DHEA), a human steroidal pro-hormone and its derivative 16α-bromoepiandrosterone (16BrEA) are uncompetitive inhibitors of mammalian G6PDH. Such steroids are also known to enhance the immune response in a broad range of animal infection models. It is noteworthy that the administration of DHEA to rats infected by Trypanosoma cruzi, the causative agent of Human American Trypanosomiasis (also known as Chagas’ disease), reduces blood parasite levels at both acute and chronic infection stages. In the present work, we investigated the in vitro effect of DHEA derivatives on the proliferation of T. cruzi epimastigotes and their inhibitory effect on a recombinant form of the parasite’s G6PDH (TcG6PDH). Our results show that DHEA and its derivative epiandrosterone (EA) are uncompetitive inhibitors of TcG6PDH, with K i values of 21.5±0.5 and 4.8±0.3μM, respectively. Results from quantitative inhibition assays indicate 16BrEA as a potent inhibitor of TcG6PDH with an IC50 of 86±8nM and those from in vitro cell viability assays confirm its toxicity for T. cruzi epimastigotes, with a LD50 of 12±8μM. In summary, we demonstrated that, in addition to host immune response enhancement, 16BrEA has a direct effect on parasite viability, most likely as a consequence of TcG6PDH inhibition. [Copyright &y& Elsevier]

Abstract: Four kinds of large port zeolites BEA, FAU, LTL and MOR, were used as catalysts in the dehydration of a large molecule, epiandrosterone, to elucidate the effect of their pore structure on its conversion and the selectivity for 5α-androst-2-en-17-one (Δ2-olefin). Silane masking of the zeolite acid sites, measurement of their epiandrosterone uptake, and theoretical calculations to find the energy-minimized conformation in zeolite pores revealed the roles of pore structure and acid sites in the dehydration. LTL and MOR zeolites showed poor conversion and low selectivity for Δ2-olefin because of the close packing in their linear pores. BEA and FAU zeolites with three-dimensionally connected pores exhibited high conversion. Since the supercages of FAU zeolite provided enough space to allow tilted conformation of epiandrosterone with high preference for the formation of Δ2-olefin, FAU zeolites with a sufficient number of acid sites demonstrated both high conversion and selectivity in the dehydration of epiandrosterone. [Copyright &y& Elsevier]

Abstract: Cytochrome P4507B1 7α-hydroxylates dehydroepiandrosterone (DHEA), epiandrosterone (EpiA) and 5α-androstane-3β,17β-diol (Adiol). 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) interconverts 7α- and 7β-forms. Whether the interconversion proceeds through oxido-reductive steps or epimerase activity was investigated. Experiments using [3H]-labelled 7β-hydroxy-DHEA, 7β-hydroxy-EpiA and 7β-hydroxy-Adiol showed the 3H-label to accumulate in the 7-oxo-DHEA trap but not in 7-oxo-EpiA or 7-oxo-Adiol traps. Computed models of 7-oxygenated steroids docked in the active site of 11β-HSD1 either in a flipped or turned form relative to cortisone and cortisol. 7-Oxo-steroid reduction in 7α- or 7β-hydroxylated derivatives resulted from either turned or flipped forms. 11β-HSD1 incubation in H2 18O medium with each 7-hydroxysteroid did not incorporate 18O in 7-hydroxylated derivatives of EpiA and Adiol independently of the cofactor used. Thus oxido-reductive steps apply for the interconversion of 7α- and 7β-hydroxy-DHEA through 7-oxo-DHEA. Epimerization may proceed on the 7-hydroxylated derivatives of EpiA and Adiol through a mechanism involving the cofactor and Ser170. The physiopathological importance of this epimerization process is related to 7β-hydroxy-EpiA production and its effects in triggering the resolution of inflammation. [Copyright &y& Elsevier]

Abstract: Sulfonic acid-incorporated-MCM-41 mesoporous materials show exceptional yield and regioselectivity for Δ2-olefin in the dehydration of 3β-hydroxy-5α-androstan-17-one (epiandrosterone), due to its specific orientation on the sulfonic acid sites located on the surface of the large pores, allowing it to adopt a sufficiently tilted structure with small steric hindrance. The preferred orientation of epiandrosterone on the surface without any steric limitation was confirmed by theoretical calculation using a simplified surface model. [Copyright &y& Elsevier]

Abstract: We have previously shown that pentose phosphate pathway (PPP) inhibitors, 6-aminonicotimade (6-AN) and epiandrosterone (EPI), markedly reduce hypoxic pulmonary vasoconstriction (HPV). Although it has been suggested that changes in the NADPH/NADP+ ratio and redox status are involved in the mechanism of HPV, the role of PPP-derived NADPH in this phenomenon is not known. The aim of this study, therefore, was to investigate the role of PPP-derived NADPH in HPV using isolated rat pulmonary arteries (PA) and perfused rat lungs. The NADPH/NADP+ ratio and NADPH levels in PA and lungs exposed to hypoxia increased 2-fold and 7-fold, respectively, compared to time-matched normoxic controls. Both hypoxia-induced increases in lung NADPH levels and lung perfusion pressure were inhibited by 6-AN (500μM) or EPI (300μM). The chemical inhibitors of PPP and hypoxia similarly decreased lung tissue NOx levels by approximately 50%. In contrast, hypoxia increased the lung soluble guanylate cyclase (sGC) activity (from 22.9±6.3 to 57.1±7.6pmol/min/g), which was prevented by PPP inhibitors. ODQ, a sGC inhibitor, potentiated HPV. These results suggest that while PPP-derived NADPH may play a significant role in HPV, it may also moderate the magnitude of HPV through activation of the NO-sGC-cGMP vasodilation pathway. [Copyright &y& Elsevier]

Abstract: We implemented both structure-based drug design and the concept of polyvalency to discover a series of potent and unsymmetrical Schistosoma japonicum glutathione S-transferase (SjGST) inhibitors 10–12. This strategy achieved not only an excellent enhancement (10- to 490-fold) in the inhibitory potency, compared to the monofunctional analogues 1–5, but was also an effective modification by selecting a hydrophobic moiety with a flexible linker. The designed compounds with a low micromolar hit demonstrate special values in refining the new generation of SjGST inhibitors. The stoichiometry of the binding is one inhibitor molecule per SjGST monomer via isothermal titration calorimetric measurement. [Copyright &y& Elsevier]

Purpose:Men with epilepsy often have sexual or reproductive abnormalities that are attributed to alterations in androgen levels, including subnormal free testosterone. Levels of the major metabolites of testosterone—androsterone (5α-androstan-3α-ol-17-one; 5α,3α-A), a neurosteroid that acts as a positive allosteric modulator of GABAA receptors, and its 5β-epimer etiocholanolone (5β-androstan-3α-ol-17-one; 5β,3α-A)—also may be reduced in epilepsy. 5α,3α-A has been found in adult brain, and both metabolites, which also can be derived from androstenedione, are present in substantial quantities in serum along with their glucuronide and sulfate conjugates. This study sought to determine whether these endogenous steroid metabolites can protect against seizures.Methods:The anticonvulsant activity of 5α,3α-A and 5β,3α-A was investigated in electrical and chemoconvulsant seizure models in mice. The steroids also were examined for activity against extracellularly recorded epileptiform discharges in the CA3 region of the rat hippocampal slice induced by perfusion with 55μ M4-aminopyridine (4-AP).Results:Intraperitoneal injection of 5α,3α-A–protected mice in a dose-dependent fashion from seizures in the following models (ED50, dose in mg/kg protecting 50% of animals): 6-Hz electrical stimulation (29.1), pentylenetetrazol (43.5), pilocarpine (105), 4-AP (215), and maximal electroshock (224). 5β,3α-A also was active in the 6-Hz and pentylenetetrazol models, but was less potent (ED50 values, 76.9 and 139 mg/kg, respectively), whereas epiandrosterone (5α,3β-A) was inactive (ED50,≤300 mg/kg). 5α,3α-A (10–100μ M) also inhibited epileptiform discharges in a concentration-dependent fashion in the in vitro slice model, whereas 5β,3α-A was active but of lower potency, and 5α,3β-A was inactive.Conclusions:5α,3α-A and 5β,3α-A have anticonvulsant properties. Although of low potency, the steroids are present in high abundance and could represent endogenous modulators of seizure susceptibility. [ABSTRACT FROM AUTHOR]

Abstract: Both dehydroepiandrosterone (DHEA) and epiandrosterone (EpiA) are substrate for cytochrome P450 species and enzymes that produce 7α- and 7β-hydroxylated metabolites in the brain and other organs. In contrast to DHEA and EpiA, the 7-hydroxylated derivatives were shown to mediate neuroprotection, and 7β-hydroxy-EpiA was the most potent. The suggested use of any of these steroids as drugs administered per os for neuroprotection requires the assessment of their metabolism in the human intestine and liver. To achieve this, we produced radio-labeled 7α-hydroxy-DHEA, 7β-hydroxy-DHEA, 7α-hydroxy-EpiA and 7β-hydroxy-EpiA that were used as substrates in incubations with human intestine microsomes supplemented with reduced or oxidized cofactors. Identity of the radio-labeled metabolites obtained was determined by gas chromatography/mass spectrometry after comparison with authentic steroid references. The proportions of metabolites produced resulted from their radioactivity contents. The only metabolite obtained with DHEA, EpiA, 7α-hydroxy-DHEA and 7β-hydroxy-DHEA substrates was its 17β-reduced derivative, thus inferring the presence of 17β-hydroxysteroid oxidoreductases in the human intestine microsomes. In addition to the 7α-hydroxy-EpiA and 7β-hydroxy-EpiA substrates, their 17β-reduced metabolites were obtained with 7β-hydroxy-EpiA and 7α-hydroxy-EpiA, respectively. The identity of the enzyme responsible for the 7α-hydroxy-EpiA/7β-hydroxy-EpiA inter-conversion is unknown. The incubation conditions used produced these metabolites in low but significant yields that suggest their presence in the portal blood before access to the liver. [Copyright &y& Elsevier]