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Steroid hormones are essential for the biological processes of eukaryotic organisms. The steroid endocrine system of C. elegans, which includes dafachronic acids (DA) and the nuclear receptor ceDAF-12, provides a simple model for exploring the role of steroid hormone signaling pathways in animals. In this study, we show for the first time the feasibility of designing synthetic steroids that can modulate different physiological processes, such as development, reproduction and ageing, in relation to ceDAF-12. Our results not only confirm the conclusions derived from genetic studies linking these processes but also provide new chemical tools to selectively manipulate them, as we found that different compounds produce different phenotypic results. The structures of these compounds are much more diverse than those of endogenous hormones and analogues previously described by other researchers, allowing further development of the chemical modulation of the steroid endocrine system in C. elegans and related nematodes.

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A protocol involving the irradiation of some 3-(2-alkenyl)estrone and 3-(2-alkenyl)-17-norestrone derivatives under a nitrogen atmosphere in organic solvents (both hexane and MeOH) followed by base-mediated intramolecular oxa-Michael cyclization reaction was investigated under steady-state conditions. The solvent effect and nature of the acyl group on the preparative photoreaction were studied and the multiplicity of the excited state was also demonstrated. The ortho-regioisomers were obtained in modest to good yields. Intramolecular based-mediate cyclization reaction of these synthons led to the formation of a set of novel substituted 4-chromanone moieties fused to estrone (and 17-norestrone) in good yields. This two-step sequential procedure involving a photochemical/intramolecular thermal cyclization strategy will be useful for the preparation of wide heterocyclic-fused-steroid compounds.

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Computer-aided drug discovery methods play a major role in the development of therapeutically important small molecules, but their performance needs to be improved. Molecular dynamics simulations in mixed solvents are useful in understanding protein-ligand recognition and improving molecular docking predictions. In this work, we used ethanol as a cosolvent to find relevant interactions for ligands toward protein kinase G, an essential protein of Mycobacterium tuberculosis (Mtb). We validated the hot spots by screening a database of fragment-like compounds and another one of known kinase inhibitors. Next, we performed a pharmacophore-guided docking simulation and found three low micromolar inhibitors, including one with a novel chemical scaffold that we expanded to four derivative compounds. Binding affinities were characterized by intrinsic fluorescence quenching assays, isothermal titration calorimetry, and the analysis of melting curves. The predicted binding mode was confirmed by X-ray crystallography. Finally, the compounds significantly inhibited the viability of Mtb in infected THP-1 macrophages.

Assuntos

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In this study, we carried out preparative and mechanistic studies on the photochemical reaction of a series of 3-acylestrone derivatives in confined and sustainable micellar environment under steady-state conditions and the results were compared with those obtained in cyclohexane solution. The aim of this work is mainly focused to show whether the nature of the surfactant (cationic, neutral and anionic) leads to noticeable selectivity in the photoproduct formation. The 3-acylestrone derivatives underwent the photo-Fries rearrangement, with concomitant homolytic fragmentation of the ester group and [1;3]-acyl migration. This pathway afforded the ortho-acyl estrone derivatives, the main photoproducts together with estrone. However, epimerization of the ortho regioisomer 2-acetylestrone and estrone through Norrish Type I photoreaction occurred involving the fragmentation of the C-α at the carbonyl group (C-17) of the steroid. UV-visible and 2D-NMR (NOESY) spectroscopies have been employed to measure the binding constant Kb and the location of the steroids within the hydrophobic core of the micelle.

Assuntos

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The delta-amino acid 5-aminolevulinic acid (ALA), is the precursor of the endogenous photosensitiser Protoporphyrin IX (PpIX), and is currently approved for Photodynamic Therapy (PDT) of certain superficial cancers. However, ALA-PDT is not very effective in diseases in which T-cells play a significant role. Cutaneous T-cell lymphomas (CTCL) is a group of non-Hodgkin malignant diseases, which includes mycosis fungoides (MF) and Sézary syndrome (SS). In previous work, we have designed new ALA esters synthesised by three-component Passerini reactions, and some of them showed higher performance as compared to ALA. This work aimed to determine the efficacy as pro-photosensitisers of five new ALA esters of 2-hydroxy-N-arylacetamides (1f, 1 g, 1 h, 1i and 1 k) of higher lipophilicity than ALA in Myla cells of MF and HuT-78 cells of SS. We have also tested its effectiveness against ALA and the already marketed ALA methyl ester (Me-ALA) and ALA hexyl ester (He-ALA). Both cell Myla and SS cells were effectively and equally photoinactivated by ALA-PDT. Besides, the concentration of ALA required to induce half the maximal porphyrin synthesis was 209 µM for Myla and 169 µM for HuT-78 cells. As a criterion of efficacy, we calculated the concentration of the ALA derivatives necessary to induce half the plateau porphyrin values obtained from ALA. These values were achieved at concentrations 4 and 12 times lower compared to ALA, according to the derivative used. For He-ALA, concentrations were 24 to 25 times lower than required for ALA for inducing comparable porphyrin synthesis in both CTCL cells. The light doses for inducing 50% of cell death (LD50) for He-ALA, 1f, 1 g, 1 h and 1i were around 18 and 25 J/cm2 for Myla and HuT-78 cells respectively, after exposure to 0.05 mM concentrations of the compounds. On the other hand, the LD50s for the compound 1 k were 40 and 57 J/cm2 for Myla and HuT-78, respectively. In contrast, 0.05 mM of ALA and Me-ALA did not provoke photokilling since the concentration employed was far below the porphyrin saturation point for these compounds. Our results suggest the potential use of ALA derivatives for topical application in PDT treatment of MF and extracorporeal PDT for the depletion of activated T-cells in SS.

Assuntos

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Direct irradiation of estrone aryl and methyl sulfonates in different organic solvents under nitrogen atmosphere was investigated under steady-state conditions. The estrone derivatives reacted efficiently through the photo-Fries rearrangement reaction involving [1;3]-sulfonyl migration providing the ortho-sulfonyl estrone derivatives and estrone as the photoproducts. In addition, estrone and 2-arylsulfonyl estrone derivatives were epimerized involving a Norrish Type-I reaction. Chemical quenching and photosensitization experiments on the photoreaction have been also carried out to establish the photoreactive excited state. Likewise, the solvent effect and the nature of the sulfonyl group on the photoreactions have been also studied.

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Irradiation of a series of 3-acylestrones under a nitrogen atmosphere in cyclohexane, acetonitrile (MeCN), and methanol (MeOH) was investigated under steady-state conditions. The molecules underwent the photo-Fries rearrangement, with concomitant homolytic fragmentation of the ester group and [1;3]-acyl migration. This pathway afforded the ortho-acyl estrone derivatives, the main photoproducts, together with estrone. During the irradiation of 3-benzoyl estrone, epimerization of estrone through the Norrish type I reaction occurred, providing lumiestrone as the photoproduct. This photoreaction involves the fragmentation of the C-α at the carbonyl group (C-17) of the steroid. On the other hand, epimerization of ortho-regioisomer 2-acetyl estrone occurred during the irradiation of 3-acetyl estrone. Photosensitization with acetone and chemical quenching with N, N, N, N-tetramethyldiazetinedioxide of the photo-Fries reaction confirmed that the photoreaction took place from the singlet excited state while the Norrish type I reaction proceeds efficiently from the triplet excited state. Solvent effects, as well as the nature of the acyl group on the photoreactions, were also studied.

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A pseudo-five-multicomponent reaction involving an isocyanide, a primary amine, two molecules of formaldehyde and water is reported, which gives N,N'-substituted 4-imidazolidinones when trifluoroethanol is used as the solvent. The reaction proceeds with good yields and with a wide variety of amines and isocyanides, providing an efficient new entry to these heterocycles. A preliminary study of the reaction mechanism suggests that trifluoroethanol, although acting as the solvent, is directly involved as a reagent in the reaction pathway.

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Over the last decades, much effort has been devoted to the design of the "ideal" library for screening, the most promising strategies being those which draw inspiration from biogenic compounds, as the aim is to add biological relevance to such libraries. On the other hand, there is a growing understanding of the role that molecular complexity plays in the discovery of new bioactive small molecules. Nevertheless, the introduction of molecular complexity must be balanced with synthetic accessibility. In this work, we show that both concepts can be efficiently merged-in a minimalist way-by using very simple guidelines during the design process along with the application of multicomponent reactions as key steps in the synthetic process. Natural phenanthrenoids, a class of plant aromatic metabolites, served as inspiration for the synthesis of a library in which complexity-enhancing features were introduced in few steps using multicomponent reactions. These resulting chemical entities were not only more complex than the parent natural products, but also interrogated an alternative region of the chemical space, which led to an outstanding hit rate in an antiproliferative assay: four out of twenty-six compounds showed in vitro activity, one of them being more potent than the clinically useful drug 5-fluorouracil.

Assuntos

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Glycosylation studies for the construction of 1,2-cis α-linkages with O-(2,3,5,6-tetra-O-benzyl-ß-D-galactofuranosyl) trichloroacetimidate (1) and several acceptors, including D-mannosyl and l-rhamnosyl derivatives were performed. The reactions were conducted at low temperatures using CH(2)Cl(2), Et(2)O, and acetonitrile as solvents. A non-participating solvent such as CH(2)Cl(2) at -78°C, favored the α-D-configuration. In contrast, acetonitrile strongly favored the ß-D-configuration, whereas no selectivities were observed with Et(2)O. The use of thiophene as an additive did not enhance the α-D-selectivity as in the pyranose counterpart. Although selectivities strongly depended on the acceptor, trichloroacetimidate 1 constitutes a valuable donor for the synthesis of α-D-Galf-(1→2)-l-Rha and α-D-Galf-(1→6)-D-Man. As these motifs are present in pathogenic microorganisms, these procedures described here are useful for the straightforward synthesis of natural oligosaccharides.

Assuntos