Nonsteroidal androgen receptor ligands: versatile syntheses and biological data.
Ontology highlight
ABSTRACT:
SUBMITTER: Varchi G
PROVIDER: S-EPMC4025740 | biostudies-literature | 2012 Jun
REPOSITORIES: biostudies-literature
Publications
Nonsteroidal androgen receptor ligands: versatile syntheses and biological data.
Varchi Greta G Guerrini Andrea A Tesei Anna A Brigliadori Giovanni G Bertucci Carlo C Di Donato Marzia M Castoria Gabriella G
ACS medicinal chemistry letters 20120410 6
We report herein a stereoselective and straightforward methodology for the synthesis of new androgen receptor ligands with (anti)-agonistic activities. Oxygen-nitrogen replacement in bicalutamide-like structures paves the way to the disclosure of a new class of analogues, including cyclized/nitrogen-substituted derivatives, with promising antiandrogen (or anabolic) activity. ...[more]
Similar Datasets
Project description:The mechanism by which the androgen receptor (AR) distinguishes between agonist and antagonist ligands is poorly understood. AR antagonists are currently used to treat prostate cancer. However, mutations commonly develop in patients that convert these compounds to agonists. Recently, our laboratory discovered selective androgen receptor modulators, which structurally resemble the nonsteroidal AR antagonists bicalutamide and hydroxyflutamide but act as agonists for the androgen receptor in a tissue-selective manner. To investigate why subtle structural changes to both the ligand and the receptor (i.e. mutations) result in drastic changes in activity, we studied structure-activity relationships for nonsteroidal AR ligands through crystallography and site-directed mutagenesis, comparing bound conformations of R-bicalutamide, hydroxyflutamide, and two previously reported nonsteroidal androgens, S-1 and R-3. These studies provide the first crystallographic evidence of the mechanism by which nonsteroidal ligands interact with the wild type AR. We have shown that changes induced to the positions of Trp-741, Thr-877, and Met-895 allow for ligand accommodation within the AR binding pocket and that a water-mediated hydrogen bond to the backbone oxygen of Leu-873 and the ketone of hydroxyflutamide is present when bound to the T877A AR variant. Additionally, we demonstrated that R-bicalutamide stimulates transcriptional activation in AR harboring the M895T point mutation. As a whole, these studies provide critical new insight for receptor-based drug design of nonsteroidal AR agonists and antagonists.
| S-EPMC2072880 | biostudies-literature
Project description:Sex hormone-binding globulin (SHBG) determines the equilibrium between free and protein-bound androgens and estrogens in the blood and regulates their access to target tissues. Using crystallographic approaches and radiolabeled competitive binding-capacity assays, we report here how two nonsteroidal compounds bind to human SHBG, and how they influence androgen activity in cell culture. We found that one of these compounds, (-)3,4-divanillyltetrahydrofuran (DVT), present in stinging nettle root extracts and used as a nutraceutical, binds SHBG with relatively low affinity. By contrast, a synthetic compound, 3-(1H-imidazol-1-ylmethyl)-2phenyl-1H-indole (IPI), bound SHBG with an affinity similar to that of testosterone and estradiol. Crystal structures of SHBG in complex with DVT or IPI at 1.71-1.80 Å resolutions revealed their unique orientations in the SHBG ligand-binding pocket and suggested opportunities for the design of other nonsteroidal ligands of SHBG. As observed for estradiol but not testosterone, IPI binding to SHBG was reduced by ∼20-fold in the presence of zinc, whereas DVT binding was almost completely lost. Estradiol-dependent fibulin-2 interactions with SHBG similarly occurred for IPI-bound SHBG, but not with DVT-bound SHBG. Both DVT and IPI increased the activity of testosterone in a cell culture androgen reporter system by competitively displacing testosterone from SHBG. These findings indicate how nonsteroidal ligands of SHBG maybe designed to modulate the bioavailability of sex steroids.
| S-EPMC6996888 | biostudies-literature
Project description:High regenerative capacity of adult skeletal muscle relies on a self-renewing depot of adult stem cells, termed muscle satellite cells (MSCs). A novel MSC line was isolated from the rat levator ani muscle and termed Levator Ani Satellite Cells (LASCs). Androgen, a known mediator of overall body composition and specifically skeletal muscle mass, has been shown to regulate MSCs. The use of non-steroidal androgen receptor agonists (NARA) aims to retain the beneficial influence of androgen on skeletal muscle, while circumventing undesirable cardiovascular and prostate-related side-effects. Primary objectives: 1) Identify biomarkers of satellite cell growth and differentiation, 2) Characterize a novel muscle satellite cell line, 3) Understand the effects of androgen (NARA) on rat satellite cell activation and recruitment.
2014-11-20 | GSE63489 | GEO
Project description:High regenerative capacity of adult skeletal muscle relies on a self-renewing depot of adult stem cells, termed muscle satellite cells (MSCs). A novel MSC line was isolated from the rat levator ani muscle and termed Levator Ani Satellite Cells (LASCs). Androgen, a known mediator of overall body composition and specifically skeletal muscle mass, has been shown to regulate MSCs. The use of non-steroidal androgen receptor agonists (NARA) aims to retain the beneficial influence of androgen on skeletal muscle, while circumventing undesirable cardiovascular and prostate-related side-effects. Primary objectives: 1) Identify biomarkers of satellite cell growth and differentiation, 2) Characterize a novel muscle satellite cell line, 3) Understand the effects of androgen (NARA) on rat satellite cell activation and recruitment. LASCs will be treated with one of the following conditions (N=4 for all groups): 1) 0.2% DMSO, 4 hours; 2) 10 nM NARA, 4 hours; 3) 0.2% DMSO, 48 hours; 4) 10nM NARA, 48 hours
2014-11-20 | E-GEOD-63489 | biostudies-arrayexpress
Project description:Opioid-induced constipation (OIC) is a common adverse effect of opioid analgesics. Peripherally acting μ opioid receptor antagonists (PAMORAs) can be applied in the treatment of OIC without compromising the analgesic effects. NAP, a 6β-N-4-pyridyl-substituted naltrexamine derivative, was previously identified as a potent and selective MOR antagonist mainly acting peripherally but with some CNS effects. Herein, we introduced a highly polar aromatic moiety, for example, a pyrazolyl or imidazolyl ring to decrease CNS MPO scores in order to reduce passive BBB permeability. Four compounds 2, 5, 17, and 19, when administered orally, were able to increase intestinal motility during morphine-induced constipation in the carmine red dye assays. Among them, compound 19 (p.o.) improved GI tract motility by 75% while orally administered NAP and methylnaltrexone showed no significant effects at the same dose. Thus, this compound seemed a promising agent to be further developed as an oral treatment for OIC.
| S-EPMC10546485 | biostudies-literature
Project description:The estrogen receptor (ER) is a hormone-regulated transcription factor that binds, as a dimer, to estrogens and to specific DNA sequences. To explore at a fundamental level the geometric and topological features of bivalent-ligand binding to the ER dimer, dimeric ER crystal structures were used to rationally design nonsteroidal bivalent estrogen ligands. Guided by this structure-based ligand design, we prepared two series of bivalent ligands (agonists and antagonists) tethered by flexible spacers of varying lengths (7-47 Å) and evaluated their ER-binding affinities for the two ER subtypes and their biological activities in cell lines. Bivalent ligands based on the agonist diethylstilbestrol (DES) proved to be poor candidates, but bivalent ligands based on the antagonist hydroxytamoxifen (OHT) were well suited for intensive study. Binding affinities of the OHT-based bivalent ligands were related to spacer length in a distinctive fashion, reaching two maximum values at 14 and 29 Å in both ER subtypes. These results demonstrate that the bivalent concept can operate in determining ER-ligand binding affinity and suggest that two distinct modes operate for the binding of bivalent estrogen ligands to the ER dimers, an intermolecular as well as an intramolecular mode. Our insights, particularly the possibility of intramolecular bivalent binding on a single ER monomer, may provide an alternative strategy for preparing more selective and active ER antagonists for endocrine therapy of breast cancer.
| S-EPMC3631453 | biostudies-literature
Project description:The androgen receptor (AR) is a ligand-regulated transcription factor that belongs to the family of nuclear receptors. In addition to regulation by steroid, the AR is also regulated by post-translational modifications generated by signal transduction pathways. Thus, the AR functions not only as a transcription factor but also as a node that integrates multiple extracellular signals. The AR plays an important role in many diseases, including complete androgen insensitivity syndrome, spinal bulbar muscular atrophy, prostate and breast cancer, etc. In the case of prostate cancer, dependence on AR signaling has been exploited for therapeutic intervention for decades. However, the effectiveness of these therapies is limited in advanced disease due to restoration of AR signaling. Greater understanding of the molecular mechanisms involved in AR action will enable the development of improved therapeutics to treat the wide range of AR-dependent diseases. The AR is subject to regulation by a number of kinases through post-translational modifications on serine, threonine, and tyrosine residues. In this paper, we review the AR phosphorylation sites, the kinases responsible for these phosphorylations, as well as the biological context and the functional consequences of these phosphorylations. Finally, what is known about the state of AR phosphorylation in clinical samples is discussed.
| S-EPMC4437516 | biostudies-literature
Project description:Amines are a class of compounds of essential importance in organic synthesis, pharmaceuticals and agrochemicals. Due to the importance of chirality in many practical applications of amines, enantioselective syntheses of amines are of high current interest. Here, we wish to report the development of (R,Ra)-N-Nap-Pyrinap and (R,Sa)-N-Nap-Pyrinap ligands working with CuBr to catalyze the enantioselective A3-coupling of terminal alkynes, aldehydes, and amines affording optically active propargylic amines, which are platform molecules for the effective derivatization to different chiral amines. With a catalyst loading as low as 0.1 mol% even in gram scale reactions, this protocol is applied to the late stage modification of some drug molecules with highly sensitive functionalities and the asymmetric synthesis of the tubulin polymerization inhibitor (S)-(-)-N-acetylcolchinol in four steps. Mechanistic studies reveal that, unlike reported catalysts, a monomeric copper(I) complex bearing a single chiral ligand is involved in the enantioselectivity-determining step.
| S-EPMC7782703 | biostudies-literature
Project description:The androgen receptor (AR) plays a critical role in prostate cancer development and progression. This study aimed to use a computerized docking approach to examine the interactions between the human AR and phyto-oestrogens (genistein, daidzein, and flavone) and xeno-oestrogens (bisphenol A, 4-nonylphenol, dichlorodiphenyl trichloroethane [DDT], diethylstilbestrol [DES]). The predicted three-dimensional structure of AR and androgens was established using X-ray diffraction. The binding of four xeno-oestrogens and three phyto-oestrogens to AR was analysed. The steroids estradiol and dihydrotestosterone (DHT) were used as positive controls and thyroxine as negative control. All the ligands shared the same binding site except for thyroxine. The endogenous hormones DHT and 17beta-oestradiol showed the strongest binding with the lowest affinity energy (< -10 kcal mol(-1)). All three phyto-oestrogens and two xeno-oestrogens (bisphenol A and DES) showed strong binding to AR. The affinities of flavone, genistein, and daidzein were between -8.8 and -8.5 kcal mol(-1), while that of bisphenol A was -8.1 kcal mol(-1) and DES -8.3 kcal mol(-1). Another two xeno-oestrogens, 4-nonylphenol and DDT, although they fit within the binding domain of AR, showed weak affinity (-6.4 and -6.7 kcal mol(-1), respectively). The phyto-oestrogens genistein, daidzein and flavone, and the xeno-oestrogens bisphenol A and DES can be regarded as androgenic effectors. The xeno-oestrogens DDT and 4-nonylphenol bind only weakly to AR.
| S-EPMC3739360 | biostudies-literature
Project description:Androgen receptor (AR) is an important therapeutic target for the treatment of diseases such as prostate cancer, hypogonadism, muscle wasting, etc. In this study, the complex structures of the AR ligand-binding domain (LBD) with fifteen ligands were analyzed by molecular dynamics simulations combined with the alanine-scanning-interaction-entropy method (ASIE). The quantitative free energy contributions of the pocket residues were obtained and hotspot residues are quantitatively identified. Our calculation shows that that these hotspot residues are predominantly hydrophobic and their interactions with binding ligands are mainly van der Waals interactions. The total binding free energies obtained by summing over binding contributions by individual residues are in good correlation with the experimental binding data. The current quantitative analysis of binding mechanism of AR to ligands provides important insight on the design of future inhibitors.
| S-EPMC7994597 | biostudies-literature