11-Oxa and 17alpha-hydroxymethyl analogues of steroid hormones and their derivatives.

The syntheses of 11-oxa and 17alpha-hydroxymethyl analogues of steroid hormones and their derivatives are reported and some of their biological activities are discussed. Generally, the replacement of the 11-methylene group by oxygen results in a diminution of the progestational, androgenic-anabolic, and estrogenic activities. This effect is least pronounced in the case of the progestational activity of 11-oxa-ethisterone and particularly strong in the case of the uterotropic activity of 11-oxa-estradiol. 17alpha-acetoxymethylprogesterone and 17alpha-hydroxymethylprogesterone were synthesized by 2 pathways, 1 of which can be advantageously applied also to the synthesis of 17alpha-acyloxymethyl and 17alpha-hydroxymethyl glucocorticoids. 17alpha-acetoxymethylprogesterone was inactive in the Clauberg test even at high doses.     

The expression of androgen receptors in human neck and limb muscles: effects of training and self-administration of androgenic-anabolic steroids

The purpose of this study was to investigate the immunohistochemical expression of androgen receptors (AR) in human vastus lateralis and trapezius muscles and to determine whether long-term strength training and self-administration of androgenic-anabolic steroids are accompanied by changes in AR content. Biopsy samples were taken from eight high-level power-lifters (P), nine high-level power-lifters who used anabolic steroids (PAS) and six untrained subjects (U). Myonuclei and AR were visualised in cross-sections stained with the monoclonal antibody against AR and 4’,6-diamidino-2-phenylindole. The proportion of AR-containing myonuclei per fibre cross-section was higher in the trapezius than in the vastus lateralis (P<0.05). In the trapezius, the proportion of AR-containing myonuclei was higher in P compared to U and in PAS compared to both P and U (P<0.05). On the contrary, in the vastus lateralis, there were no differences in AR content between the three groups. Myonuclear number in both muscles was higher in P compared to U and in PAS compared to both P and U (P<0.05). In conclusion, AR content differs greatly between human neck and limb muscles. Moreover, the regulation of AR-containing myonuclei following training and self-administration of androgenic-anabolic steroids is muscle dependent. Accepted: 15 October 1999     

Effect of Nandrolone decanoate induced-oxidative stress on rat testes,prostate, and seminal vesicle: Biochemical,morphometric and histopathological studies

Nandrolone decanoate (Nd) is a highly abused androgenic-anabolic steroid among body builders. Even though it has weak androgenic effects, its prolonged use may have harmful impact on male reproductive system which needs to be evaluated. This study aimed to reinvestigate its possible oxidative stress induced alteration on male rat reproductive system. Twenty-eight male rats were divided into two groups. Nd treated group (n = 18) injected intramuscular with 10 mg/kg body weight once a week for four weeks. While, the control group (n = 10) was injected with physiologic saline by the same route for four weeks. Body weight was recorded for all rats and after animal dissection weight of testes, prostate and seminal vesicles were also recorded. The results showed that the average testicular weight was decreased in treated group compared to the control. The average weights of the prostate and seminal vesicles were increased compared to the control. Morphometric study revealed that in Nd treated group, there was a decrease in the width of seminiferous tubules and the height of spermatogenic cell layer compared to the control. Testicular degeneration was expressed by presence of spermatid giant cells, vacuolation, and degenerated spermatozoa. Tunnel technique showed scattered positive reaction among the spermatogenic cell layers and interstitial cells. Severe alterations of the prostate were expressed by benign prostate hyperplasia and retained secretions. Lipid peroxidation products (malonaldehyde concentration as ng/g of testicular tissue) were increased in treated group compared to the control and suggested the occurrence of oxidative damage. Nd induced severe alterations in the male genital organs were resulted from oxidative stress. It is concluded that the male genital organs are highly sensitive to the anabolic steroids and there is a high extent of reproductive risk associated with the use of AASs.     

Serum hormones during prolonged training of neuromuscular performance

The effects of a 24-weeks' progressive training of neuromuscular performance capacity on maximal strength and on hormone balance were investigated periodically in 21 male subjects during the course of the training and during a subsequent detraining period of 12 weeks. Great increases in maximal strength were noted during the first 20 weeks, followed by a plateau phase during the last 4 weeks of training. Testosterone/cortisol ratio increased during training. During the last 4 weeks of training changes in maximal strength correlated with the changes in testosterone/cortisol (P less than 0.01) and testosterone/SHBG (P less than 0.05) ratios. During detraining, correlative decreases were found between maximal strength and testosterone/cortisol ratio (P less than 0.05) as well as between the maximal strength and testosterone/SHBG ratio (P less than 0.05). No statistically significant changes were observed in the levels of serum estradiol, lutropin (LH), follitropin (FSH), prolactin, and somatotropin. The results suggest the importance of the balance between androgenic-anabolic activity and catabolizing effects of glucocorticoids during the course of vigorous strength training.     

Comparative in vitro metabolism of the ‘designer’ steroid estra-4,9-diene-3,17-dione between the equine, canine and human: Identification of target metabolites for use in sports doping control

Effective detection of the abuse of androgenic-anabolic steroids in human and animal sports often requires knowledge of the drug's metabolism in order to target appropriate urinary metabolites. ‘Designer’ steroids are problematic since it is difficult to obtain ethical approval for in vivo metabolism studies due to a lack of a toxicological profile.In this study, the in vitro metabolism of estra-4,9-diene-3,17-dione is reported for the first time. This is also the first study comparing the metabolism of a designer steroid in the three major species subject to sport's doping control; namely the equine, canine and human. In order to allow the retrospective analysis of sample testing data, the use of a high-resolution (HR) accurate-mass Thermo LTQ-Orbitrap LC-MS instrument was employed for metabolite identification of underivatised sample extracts. The full scan HR-LC-MS Orbitrap data was complimented by several further experiments targeted at elucidating more detailed structural information for the most abundant metabolites. These included; HR-LC-MS/MS of the underivatised metabolites, functional group selective chemical derivatisation followed by full scan HR-LC-MS, enzyme inhibition experiments and full scan electron ionization GC-MS analysis of methoxyamine-trimethylsilyl derivatives.The major metabolite detected in all species, and therefore the most suitable candidate for screening of estra-4,9-diene-3,17-dione abuse, was proposed to be an isomer of 17-hydroxy-estra-4,9-dien-3-one. Less significant metabolic pathways in all species included hydroxylation and reduction followed by hydroxylation. Reductive metabolism in the canine was less significant than in the other two species, while the equine was unique in producing a di-reduced metabolite (proposed to be an isomer of estra-4,9-diene-3,17-diol) and also relatively large quantities of d-ring hydroxy and hydroxy-reduced metabolites.     

Classes of Proteins Synthesized in Oocytes, Eggs, Embryos, and Differentiated Tissues of Xenopus Zaevis

Two-dimensional gel electrophoresis has been used to analyse protein synthesis in embryonic stages and in three differentiated tissues of Xenopus laevis. The patterns found in oocyte, unfertilized eggs, embryos shortly after fertilization and at progressively later stages of development have been characterized and compared with the patterns found in the brain, heart and liver of tadpoles. The results suggest that at least four classes of proteins can be recognized among the proteins synthesized, although other categories may exist. They also suggest that some proteins synthesized rapidly in the oocyte are likely to be synthesized in differentiated tissues as well, while proteins synthesized for the first time only after fertilization are much less likely to be synthesized in differentiated tissues.     

Design,Synthesis, Molecular Docking Studies,and Biological Evaluation of Pyrazoline Incorporated Isoxazole Derivatives

Russian Journal of Bioorganic Chemistry - A novel series of pyrazoline incorporated isoxazole derivatives were designed and synthesized. The synthesized compounds were characterized by 1H NMR, IR...     

Perceptions and attitudes toward androgenic-anabolic steroid use among two age categories: a qualitative inquiry

We attempted to qualitatively investigate why men of 2 age categories have chosen not to use androgenic-anabolic steroids (AASs). Twelve men (22.28 +/- 1.38 years [group I] and 53.00 +/- 13.28 years [group II]) were selected on the basis of specific inclusion criteria, including age and fitness levels (i.e., "do you weight train?"). Subjects were classified in 1 of 2 categories-younger or older precluders-and were asked to complete 2 survey instruments before their participation. The Drive for Muscularity Scale (reliability 0.85) and Body Image Questionnaire were used to gain a better understanding of perceptions and motivations regarding health, fitness, and body image. A series of semistructured questions were used to enhance focus group discussion regarding attitudes. Questions were validated by a panel of experts in qualitative methods. Member checks were conducted to enhance trustworthiness of the data. Data were transcribed verbatim and analyzed with thematic open-coding techniques. Various behaviors were reported regarding body image. Emerging themes showed a clear demarcation between age categories. Younger subjects cited power, control, body image, and narcissism, whereas older subjects viewed AAS use as more of an athletic-based phenomenon, such as with performance enhancement, when asked about steroids. Groups were in agreement that media trends and perceptions of the ideal male body are becoming "superhuman" and unattainable without chemical means. Understanding attitudinal perspectives might help complement national data on AAS trends. Future investigations could help coaches and allied health professionals collaborate with each other, as well as with national groups and foundations, to devise more appropriate strategies in addressing this growing athletic and public health concern.     

Molecular modeling, synthesis, and screening of new bacterial quorumsensing antagonists

Abstract A new series comprising 7 analogs of N-(sulfanyl ethanoyl)-L-HSL derivatives, 2 analogs of N-(fluoroalkanoyl)- L-HSL derivatives, N-(fluorosulfonyl)-L-HSL, and 2,2-dimethyl butanoyl HSL were synthesized using a solid-phase organic synthesis method. Each of the 11 synthesized compounds was analyzed using NMR and mass spectroscopies, and molecular modeling studies of the 11 ligands were performed using SYBYL packages. Thereafter, a bacterial test was designed to identify their quorum-sensing inhibition activity and antifouling efficacy. Most of the synthesized compounds were found to be effective as quorum-sensing antagonists, where antagonist screening revealed that 10 among the 11 synthesized ligands were able to antagonize the quorum sensing of A. tumefaciens.     

Simultaneous synthesis,translation, and storage of mRNA including histone mRNA in sea urchin eggs

The kinetics of accumulation of RNA labeled with uridine and the time course of change in the specific activity of the UTP pool were used to estimate the rate constants for synthesis and decay of RNA synthesized in unfertilized eggs of the sea urchin Lytechinus pictus. The rate of synthesis per haploid genome is similar to that in embryos. Most of the RNA is turning over with a half-life of about 5 hr, and an average of 11 pg of newly synthesized RNA accumulates at steady state. About 3.7% of the RNA in the polysomes of the egg is newly synthesized and this RNA has the heterogeneous size distribution expected for mRNA. Thus most, probably all, of the mRNA translated in the egg is also synthesized in the egg. Little, if any, of the RNA synthesized in the egg enters polysomes following fertilization. Thus the egg synthesizes a population of mRNA which is unstable and translated, but it also contains a more stable, untranslated population of previously synthesized, stored mRNA, which is translated only after fertilization. Since the two populations of mRNA code for the same abundant proteins (Brandhorst, B. P. (1976). Develop. Biol., 52, 310–317), there is a temporal separation in the metabolism and function of coexisting mRNA molecules of identical coding sequence. Among the mRNAs synthesized and translated in the egg are histone mRNAs having the same electrophoretic mobilities and rates of synthesis per genome as those synthesized in rapidly cleaving embryos. Thus the synthesis, entry into the cytoplasm, and translation of histone mRNA are not restricted to the S phase of the cell cycle or the period of cell division.     

Metal-based new sulfonamides: Design, synthesis, antibacterial, antifungal, and cytotoxic properties

Cobalt(II), copper(II), nickel(II) and zinc(II) metal complexes with 5-chlorosalicyladehyde derived Schiff base sulfonamides have been synthesized and characterized. Structure and bonding nature of all the synthesized compounds have been deduced from physical, analytical, and spectral (IR, (1)H NMR, (13)C NMR, Mass, electronic) data. An octahedral geometry has been proposed for all the metal complexes. The ligands and their metal complexes have been screened for their in vitro antibacterial, antifungal, and cytotoxic properties and results are reported.     

New homocamptothecins: synthesis, antitumor activity, and molecular modeling

Homocamptothecins (hCPTs) represent a class of new emerging antitumor agents, which contains a seven-membered beta-hydroxylactone in place of the conventional six-membered alpha-hydroxylactone ring (E ring) of camptothecins. Some novel 7-substituted hCPTs were designed and synthesized based on a newly developed synthetic route which couples ring A with ring C, E and D. Most of the synthesized compounds exhibit very high cytotoxic activity on tumor cell line A549. Some compounds, such as 9b, 9l, and 9y, show broad in vitro antitumor spectrum and are more potent than topotecan. Three-dimensional quantitative structure-activity relationship (3D-QSAR) methods, CoMFA and CoMSIA, were applied to explain the structure-activity relationship (SAR) of the synthesized compounds. Furthermore, molecular docking was used to clarify the binding mode of the synthesized compounds to human DNA topoisomerase I. The important hydrophobic, base-pair stacking, and hydrogen-bonding interactions were observed between the hCPT derivatives and their receptor. The results from molecular modeling will guide the design of novel hCPTs with higher antitumor activity.     

Synthesis, phosphorylation, and nuclear localization of human papillomavirus E7 protein in Schizosaccharomyces pombe

The complete E7 protein-encoding open reading frame of human papillomavirus type 16 (HPV-16) was expressed in the fission yeast Schizosaccharomyces pombe, under the control of a cloned yeast promoter. The HPV-16 E7 protein synthesized in S. pombe is a 17-kDa phosphoprotein which is recognized by anti-E7 antibodies (raised in rabbits against E7 fusion protein produced in Escherichia coli). The mobility during sodium dodecyl sulfate-polyacrylamide-gel electrophoresis of native E7 phosphoprotein synthesized in S. pombe is identical to that of the E7 phosphoprotein immunoprecipitated from human CaSki cells. Immunofluorescence staining showed that HPV-16 E7 phosphoprotein is localized in the nuclei of transformed S. pombe. These results indicate that E7 protein synthesized by S. pombe is apparently indistinguishable from HPV-16 E7 protein synthesized in higher eukaryotic cells expressing genes of HPV-16, and also that the phosphorylated, nuclear HPV-16 E7 protein is synthesized in S. pombe in a form compatible with its biological activity.     

Synthesis,Fungistatic, Protistocidal,and Antibacterial Activity of 1-(3-Amino-2-Hydroxypropyl)Indoles

A series of new indole derivatives containing the 3-amino-2-hydroxypropyl group at the nitrogen atom has been synthesized by the ring-opening of the oxirane cycle of 1-oxiranylmethylindoles. Their antibacterial, fungicidal, and protistocidal activities have been studied. Most of the synthesized compounds have been shown to exhibit a high protistocidal activity that several times exceeds that of the reference drug, baikoks (toltrazuril).     

Tetramethylthiuram disulfide or dimethyldithiocarbamate induces the synthesis of cadystins, heavy metal chelating peptides, in Schizosaccharomyces pombe.

Tetramethylthiuram disulfide (TMTD) or dimethyldithiocarbamate (DMDTC) induces the synthesis of cadystins, a family of heavy metal chelating isopeptides with the formula (gamma-Glu-Cys)n-Gly (n = 2,3,4,...), in the fission yeast Schizosaccharomyces pombe. Amount of cadystins synthesized in TMTD or DMDTC treated cells is less than that synthesized in CdCl2 treated cells but much more than that synthesized in ZnCl2 or CuSO4 treated cells.     

Design, synthesis, and evaluation of novel ethambutol analogues

Ethambutol is one of the front-line agents recommended by the World Health Organization for the treatment of tuberculosis. In an effort to develop more potent therapies to treat tuberculosis, novel unsymmetrical ethambutol analogues were successfully synthesized by a new route utilizing novel building blocks synthesized using Ellman's sulfinyl chemistry. The resulting analogues were tested for anti-tuberculosis activity yielding compounds with comparable anti-tuberculosis activity to ethambutol and increased lipophilicity that may instill better tissue penetration and serum half-life.     

Design,synthesis, evaluation,and molecular docking of ursolic acid derivatives containing a nitrogen heterocycle as anti-inflammatory agents

Ursolic acid derivatives containing oxadiazole, triazolone, and piperazine moieties were synthesized in an attempt to develop potent anti-inflammatory agents. Structures of the synthesized compounds were elucidated by ¹H NMR, ¹³C NMR, and HRMS. Most of the synthesized compounds showed pronounced anti-inflammatory effects at 100?mg/kg. In particular, compound 11b, which displayed the most potent anti-inflammatory activity of all of the compounds prepared, with 69.76% inhibition after intraperitoneal administration, was more potent than the reference drugs indomethacin and ibuprofen. The cytotoxicity of the compounds was also assessed by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and no compounds showed any appreciable cytotoxic activity (IC₅₀ >100?μmol/L). Furthermore, molecular docking studies of the synthesized compounds were performed to rationalize the obtained biological results. Overall, the results indicate that compound 11b could be a therapeutic candidate for the treatment of inflammation.     

1,3,4-oxadiazole/chalcone hybrids: Design,synthesis, and inhibition of leukemia cell growth and EGFR,Src, IL-6 and STAT3 activities

A new series of 1,3,4-oxadiazole/chalcone hybrids was designed, synthesized, identified with different spectroscopic techniques and biologically evaluated as inhibitors of EGFR, Src, and IL-6. The synthesized compounds showed promising anticancer activity, particularly against leukemia, with 8v being the most potent. The synthesized compounds exhibited strong to moderate cytotoxic activities against K-562, KG-1a, and Jurkat leukemia cell lines in MTT assays. Compound 8v showed the strongest cytotoxic activity with IC₅₀ of 1.95 µM, 2.36 µM and 3.45 µM against K-562, Jurkat and KG-1a leukemia cell lines, respectively. Moreover; the synthesized compounds inhibited EGFR, Src, and IL-6. Compound 8v was most effective at inhibiting EGFR (IC₅₀ = 0.24 μM), Src (IC₅₀ = 0.96 μM), and IL-6 (% of control = 20%). Additionally, most of the compounds decreased STAT3 activation.     

Metal-based new sulfonamides: Design,synthesis, antibacterial,antifungal, and cytotoxic properties

Cobalt(II), copper(II), nickel(II) and zinc(II) metal complexes with 5-chlorosalicyladehyde derived Schiff base sulfonamides have been synthesized and characterized. Structure and bonding nature of all the synthesized compounds have been deduced from physical, analytical, and spectral (IR, ¹H NMR, ¹³C NMR, Mass, electronic) data. An octahedral geometry has been proposed for all the metal complexes. The ligands and their metal complexes have been screened for their in vitro antibacterial, antifungal, and cytotoxic properties and results are reported.