A selective alpha1D-adrenoreceptor antagonist inhibits human prostate cancer cell proliferation and motility "in vitro"

The progression of prostate cancer (PC) to a metastatic hormone refractory disease is the major contributor to the overall cancer mortality in men, mainly because the conventional therapies are generally ineffective at this stage. Thus, other therapeutic options are needed as alternatives or in addition to the classic approaches to prevent or delay tumor progression. Catecholamines participate to the control of prostate cell functions by the activation of alpha1-adrenoreceptors (alpha1-AR) and increased sympathetic activity has been linked to PC development and evolution. Molecular and pharmacological studies identified three alpha1-AR subtypes (A, B and D), which differ in tissue distribution, cell signaling, pharmacology and physiological role. Within the prostate, alpha1A-ARs mainly control stromal cell functions, while alpha1B- and alpha1D- subtypes seem to modulate glandular epithelial cell growth. The possible direct contribution of alpha1D-ARs in tumor biology is supported by their overexpression in PC. The studies here presented investigate the "in vitro" antitumor action of A175, a selective alpha1D-AR antagonist we have recently obtained by modifying the potent, but not subtype-selective alpha1-AR antagonist (S)-WB4101, in the hormone-refractory PC3 and DU145 PC cell lines. The results indicate that A175 has an alpha1D-AR-mediated significant and dose-dependent antiproliferative action that possibly involves the induction of G0/G1 cell cycle arrest, but not apoptosis. In addition, A175 reduces cell migration and adhesiveness to culture plates. In conclusion, our work clarified some cellular aspects promoted by alpha1D-AR activity modulation and supports a further pharmacological approach in the cure of hormone-refractory PC, by targeting specifically this AR subtype

Liver and intestinal protective effects of Castanea sativa Mill. bark extract in high-fat diet rats

The effects of Castanea sativa Mill. have been studied in high fat diet (HFD) overweight rats. Natural Extract of Chestnut bark (Castanea sativa Mill.) (ENC®), rich in ellagitannins, has been studied in 120 male Sprague-Dawley rats, divided in four groups. Two groups were controls: regular (RD) and HDF diet. Two groups received ENC®(20 mg/kg/day): RD + ENC®and HFD + ENC®. At baseline and at 7, 14 and 21 days, weight gain, serum lipids, plasma cytokines, liver histology, microsomial enzymes and oxidation, intestinal oxidative stress and contractility were studied. HFD increased body weight, increased pro-inflammatory cytokines, induced hepatocytes microvescicular steatosis, altered microsomial, increased liver and intestinal oxidative stress, deranged intestinal contractility. In HFD-fed rats, ENC®exerted antiadipose and antioxidative activities and normalized intestinal contractility, suggesting a potential approach to overweight management associated diseases

Small molecule ligands for α9 * and α7 nicotinic receptors: A survey and an update, respectively

The α9- and α7-containing nicotinic acetylcholine receptors (nAChRs) mediate numerous physiological and pathological processes by complex mechanisms that are currently the subject of intensive study and debate. In this regard, selective ligands serve as invaluable investigative tools and, in many cases, potential therapeutics for the treatment of various CNS disfunctions and diseases, neuropathic pain, inflammation, and cancer. However, the present scenario differs significantly between the two aforementioned nicotinic subtypes. Over the past few decades, a large number of selective α7-nAChR ligands, including full, partial and silent agonists, antagonists, and allosteric modulators, have been described and reviewed. Conversely, reports on selective α9-containing nAChR ligands are relatively scarce, also due to a more recent characterization of this receptor subtype, and hardly any focusing on small molecules. In this review, we focus on the latter, providing a comprehensive overview, while providing only an update over the last five years for α7-nAChR ligands

Determinants for α4β2 vs. α3β4 subtype selectivity of pyrrolidine-based nachrs ligands:A computational perspective with focus on recent cryo-em receptor structures

The selectivity of α4β2 nAChR agonists over the α3β4 nicotinic receptor subtype, predominant in ganglia, primarily conditions their therapeutic range and it is still a complex and challenging issue for medicinal chemists and pharmacologists. Here, we investigate the determinants for such subtype selectivity in a series of more than forty α4β2 ligands we have previously reported, docking them into the structures of the two human subtypes, recently determined by cryo-electron microscopy. They are all pyrrolidine based analogues of the well-known α4β2 agonist N-methylprolinol pyridyl ether A-84543 and differ in the flexibility and pattern substitution of their aromatic portion. Indeed, the direct or water mediated interaction with hydrophilic residues of the relatively narrower β2 minus side through the elements decorating the aromatic ring and the stabilization of the latter by facing to the not conserved β2-Phe119 result as key distinctive features for the α4β2 affinity. Consistently, these compounds show, despite the structural similarity, very different α4β2 vs. α3β4 selectivities, from modest to very high, which relate to rigidity/extensibility degree of the portion containing the aromatic ring and to substitutions at the latter. Furthermore, the structural rationalization of the rat vs. human differences of α4β2 vs. α3β4 selectivity ratios is here proposed

Methyl 8- and 5-Bromo-1,4-Benzodioxane-2-carboxylate: Unambiguous Identification of the Two Regioisomers

A variety of biological active compounds can be classified as 2-substituted 1,4-benzodioxanes bearing one or more substituents at the benzene. The synthesis of these important templates can be approached by different strategies. The most straightforward ones generally lead to mixtures of positional isomers, whose identification can be more problematic than separation. Here, we unambiguously elucidate, by HSQC and HMBC NMR analyses, the structure of methyl 8- and 5-bromo-1,4-benzodioxane-2-carboxylate, two versatile synthetic intermediates that are one-step-obtainable from commercial products and easily separable. As conceived, the identification procedure is, in principle, generalizable to any pair of 2-substituted 1,4-benzodioxanes bearing an X substituent at C(8) or C(5)

Preparation and unequivocal identification of the regioisomers of nitrocatechol monobenzyl ether

<p>The four positional isomers of nitrocatechol monobenzyl ether were prepared as intermediates to nitrobenzodioxanes directly from 2-benzyloxyphenol or, through two-four steps, from catechol. These preparations addressed the issue of the certain identification of the nitration products prescinding from chemical correlation to the synthetic precursors because the positional isomers are very similar for some properties and analytical data available from the literature are largely incomplete and not conclusive. The here provided NMR, DSC, and acidity data unequivocally distinguish each nitrocatechol monobenzyl ether from its regioisomers.</p

Simple route to synthesize (<i>E</i>)-3-propyl-4-oxo-2-butenoic acid esters through the <i>Z</i> isomer

<p>Esters of 3-alkyl-4-oxo-2-butenoic acid, which are very important synthons, are not equally accessible in both <i>E</i> and <i>Z</i> configurations. The (<i>Z</i>)-isomers can be easily obtained from 3-alkyl-4-hydroxybutenolides, in turn prepared by aminoalkylation of aliphatic aldehydes with glyoxylic acid. The (<i>E</i>)-isomers, on the contrary, result from laborious procedures: the condensation of aldehydes with glyoxylic acid, followed by separation from γ-hydroxybutenolide by-product and esterification, or of aldehyde enamines with glyoxylic esters, followed by <i>Z</i> ester by-product conversion into γ-aminobutenolide and purification. Here, we describe a straightforward route to the title compounds, applied to methyl (<i>E</i>)-3-propyl-4-oxo-2-butenoate, avoiding any problematic by-product or isomer chromatographic separation: pentanal and glyoxylic acid are condensed to 3-propyl-4-hydroxybutenolide, which is converted to methyl (<i>Z</i>)-3-propyl-4-oxo-2-butenoate and then isomerized to <i>E</i> ester under acidic conditions.</p

Methyl 8- and 5-Nitro-1,4-Benzodioxane-2-Carboxylate

2-Substituted 1,4-benzodioxanes bearing one or more substituents at benzene are important templates in the design and synthesis of a large variety of biologically active compounds. One of the most straightforward synthetic strategies to prepare them in racemic form and with a 2-substituent susceptible to further synthetically useful conversions is the condensation of commercially available methyl 2,3-dibromopropionate with already suitably functionalized catechol. Here, we obtain methyl 8- and 5-nitro-1,4-benzodioxane-2-carboxylate by reaction of methyl 2,3-dibromopropionate with 3-nitrocatechol. After separation, the two positional isomers could be unequivocally identified by HMBC NMR analysis