5-Hydroxy-3-(4-hydroxyphenyl)-8,8-dimethyl-6- (3-methylbut-2-enyl)pyrano[2,3-h]chromen-4-one

Natural and semi-synthetic compounds are being studied as novel phosphodiesterase 5 (PDE5) inhibitors for the treatment of erectile dysfunction, pulmonary hypertension, and lower urinary symptoms. Maclura pomifera is a source of flavonoids, one of the main classes of molecules investigated for these purposes. The extraction of the natural isoflavone osajin and its modification to obtain a semi-synthetic derivative are described in this short note. 1H and 13C-nuclear magnetic resonance spectroscopy (NMR), mass spectrometry, high-performance liquid chromatography (HPLC) and spectroscopic characterization of the title compound are also hereby provided. Two-dimensional (2D) nuclear Overhauser effect spectroscopy (NOESY) NMR, supported by in silico conformational studies, was used to achieve a complete assignment of the proton signals, assessing the correct chemical structure of the compound. Heteronuclear single quantum coherence spectroscopy (HSQC) and heteronuclear multiple bond correlation (HMBC) NMR experiments were performed to assign 13C chemical shifts. Calculated chemical properties and preliminary in silico docking suggest that this molecule might be a promising candidate as PDE5 inhibitor

Fatores que influenciam a sucessão nas unidades de produção familiar : elementos encontrados no município de Liberato Salzano/RS

A sucessão familiar, nas unidades de produção agrícola (UPAs) é um tema muito discuto atualmente. Este estudo tem como objetivo geral identificar os fatores que influenciam a sucessão nas unidades de produção familiar no município de Liberato Salzano/RS. Já os objetivos específicos foram (i) caracterizar as famílias e suas unidades de produção familiar estudadas no município de Liberato Salzano/RS; (ii) identificar a participação dos (as) filhos (as) na gestão e nas decisões da propriedade bem como nas atividades agrícolas nela desenvolvidas e (iii) identificar as principais dificuldades e facilidades no processo de sucessão familiar, na perspectiva dos pais e filhos. Para tanto, foram realizadas entrevistas com agricultores familiares do município. Foi possível caracterizar os fatores que contribuem para a sucessão familiar em Liberato Salzano/RS. Os resultados demonstram que nas propriedades mais desenvolvidas, com acesso a tecnologias de produção, onde o jovem possui autonomia e renda, participação nas decisões da família, disponibilidade de terras e estrutura viável à sucessão, os índices de permanência são mais elevados.The family succession, in agricultural production units (UPAs) is a very much discussed topic today. This study aims to identify factors that contribute to the succession of future expectations.Its main objective is to identify the factors that influence succession in family production units in the municipality of Liberato Salzano / RS. As a specific objective, to (i) characterize the families and their family production units studied in the municipality of Liberato Salzano / RS, (ii) to identify the participation of the children in the management and decisions of the property, as well as in the agricultural activities developed therein, (iii) to identify the main difficulties and facilities in the process of family succession, from the perspective of parents and children.For both questionnaires, interviews with family farmers were applied. It was possible to characterize the factors that contribute to the family succession in Liberato Salzano / RS. The results show that in the more developed properties with access to production technologies, where the youth has autonomy and income, participation in family decisions, availability of land, viable structure to succession, indices of permanence are higher

Aminoacyl-analogues of Mitoxantrone as novel DNA-damaging cytotoxic agents

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Sequence-specific interactions of drugs interfering with the topoisomerase–DNA cleavage complex

AbstractDNA-processing enzymes, such as the topoisomerases (tops), represent major targets for potent anticancer (and antibacterial) agents. The drugs kill cells by poisoning the enzymes' catalytic cycle. Understanding the molecular details of top poisoning is a fundamental requisite for the rational development of novel, more effective antineoplastic drugs. In this connection, sequence-specific recognition of the top–DNA complex is a key step to preferentially direct the action of the drugs onto selected genomic sequences. In fact, the (reversible) interference of drugs with the top–DNA complex exhibits well-defined preferences for DNA bases in the proximity of the cleavage site, each drug showing peculiarities connected to its structural features. A second level of selectivity can be observed when chemically reactive groups are present in the structure of the top-directed drug. In this case, the enzyme recognizes or generates a unique site for covalent drug–DNA binding. This will further subtly modulate the drug's efficiency in stimulating DNA damage at selected sites. Finally, drugs can discriminate not only among different types of tops, but also among different isoenzymes, providing an additional level of specific selection. Once the molecular basis for DNA sequence-dependent recognition has been established, the above-mentioned modes to generate selectivity in drug poisoning can be rationally exploited, alone or in combination, to develop tailor-made drugs targeted at defined loci in cancer cells

Mechanisms of HIV-1 Nucleocapsid Protein Inhibition by Lysyl-Peptidyl-Anthraquinone Conjugates

The Nucleocapsid protein NCp7 (NC) is a nucleic acid chaperone responsible for essential steps of the HIV-1 life cycle and an attractive candidate for drug development. NC destabilizes nucleic acid structures and promotes the formation of annealed substrates for HIV-1 reverse transcription elongation. Short helical nucleic acid segments bordered by bulges and loops, such as the Trans-Activation Response element (TAR) of HIV-1 and its complementary sequence (cTAR), are nucleation elements for helix destabilization by NC and also preferred recognition sites for threading intercalators. Inspired by these observations, we have recently demonstrated that 2,6-disubstituted peptidylanthraquinone-conjugates inhibit the chaperone activities of recombinant NC in vitro, and that inhibition correlates with the stabilization of TAR and cTAR stem-loop structures. We describe here enhanced NC inhibitory activity by novel conjugates that exhibit longer peptidyl chains ending with a conserved Nterminal lysine. Their efficient inhibition of TAR/cTAR annealing mediated by NC originates from the combination of at least three different mechanisms, namely, their stabilizing effects on nucleic acids dynamics by threading intercalation, their ability to target TAR RNA substrate leading to a direct competition with the protein for the same binding sites on TAR, and, finally, their effective binding to the NC protein. Our results suggest that these molecules may represent the stepping-stone for the future development of NC-inhibitors capable of targeting the protein itself and its recognition site in RNA

Major depressive disorder and oxidative stress: In silico investigation of fluoxetine activity against ROS

Major depressive disorder is a psychiatric disease having approximately a 20% lifetime prevalence in adults in the United States (U.S.), as reported by Hasin et al. in JAMA Psichiatry 2018 75, 336\u2013346. Symptoms include low mood, anhedonia, decreased energy, alteration in appetite and weight, irritability, sleep disturbances, and cognitive deficits. Comorbidity is frequent, and patients show decreased social functioning and a high mortality rate. Environmental and genetic factors favor the development of depression, but the mechanisms by which stress negatively impacts on the brain are still not fully understood. Several recent works, mainly published during the last five years, aim at investigating the correlation between treatment with fluoxetine, a non-tricyclic antidepressant drug, and the amelioration of oxidative stress. In this work, the antioxidant activity of fluoxetine was investigated using a computational protocol based on the density functional theory approach. Particularly, the scavenging of five radicals (HO\u2022, HOO\u2022, CH3OO\u2022, CH2=CHOO\u2022, and CH3O\u2022) was considered, focusing on hydrogen atom transfer (HAT) and radical adduct formation (RAF) mechanisms. Thermodynamic as well as kinetic aspects are discussed, and, for completeness, two metabolites of fluoxetine and serotonin, whose extracellular concentration is enhanced by fluoxetine, are included in our analysis. Indeed, fluoxetine may act as a radical scavenger, and exhibits selectivity for HO\u2022 and CH3O\u2022, but is inefficient toward peroxyl radicals. In contrast, the radical scavenging efficiency of serotonin, which has been demonstrated in vitro, is significant, and this supports the idea of an indirect antioxidant efficiency of fluoxetine

Psychiatric Disorders and Oxidative Injury: Antioxidant Effects of Zolpidem Therapy disclosed In Silico

Zolpidem (N,N-Dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]acetamide) is a well-known drug for the treatment of sleeping disorders. Recent literature reports on positive effects of zolpidem therapy on improving renal damage after cisplatin and on reducing akinesia without sleep induction. This has been ascribed to the antioxidant and neuroprotective capacity of this molecule, and tentatively explained according to a generic structural similarity between zolpidem and melatonin. In this work, we investigate in silico the antioxidant potential of zolpidem as scavenger of five ROSs, acting via hydrogen atom transfer (HAT) mechanism; computational methodologies based on density functional theory are employed. For completeness, the analysis is extended to six metabolites. Thermodynamic and kinetic results disclose that indeed zolpidem is an efficient radical scavenger, similarly to melatonin and Trolox, supporting the biomedical evidence that the antioxidant potential of zolpidem therapy may have a beneficial effect against oxidative injury, which is emerging as an important etiopathogenesis in numerous severe diseases, including psychiatric disorders

Vanillin Analogues o-Vanillin and 2,4,6-Trihydroxybenzaldehyde Inhibit NF kappa B Activation and Suppress Growth of A375 Human Melanoma

Background/Aim: Constitutive activation of nuclear factor kappa-B (NF kappa B) is a hallmark of various cancer types, including melanoma. Chemotherapy may further increase tumour NF kappa B activity, a phenomenon that, in turn, exacerbates drug resistance. This study aimed at preliminary screening of a panel of aromatic aldehydes, including vanillin, for cytotoxicity and suppression of tumour cell NF kappa B activity. Materials and Methods: The cytotoxic and NF kappa B-inhibitory effects of 10 aromatic aldehydes, including vanillin, were investigated in cultured A375 human melanoma cells. Each compound was assayed alone and in combination with the model NF kappa B-activating drug doxorubicin. The most promising analogues were then tested alone and in combination with 4-hydroperoxycyclophosphamide in vitro, and with cyclophosphamide in mice bearing A375 xenografts. Results: The vanillin analogues o-vanillin and 2,4,6-trihydroxybenzaldehyde exhibited cytotoxicity against cultured A375 cells, and inhibited doxorubicin-and 4-hydroperoxycyclophosphamide-induced NF kappa B activation. They also suppressed A375 cell growth in mice. Conclusion: o-vanillin and 2,4,6-trihydroxybenzaldehyde deserve further evaluation as potential anticancer drugs

Mapping Drug Interactions at the Covalent Topoisomerase II-DNA Complex by Bisantrene/Amsacrine Congeners *

To identify structural determinants for the sequence-specific recognition of covalent topoisomerase II-DNA complexes by anti-cancer drugs, we investigated a number of bisantrene congeners, including a 10-azabioisoster, bearing one or two 4, 5-dihydro-1H-imidazol-2-yl hydrazone side chains at positions 1, 4, or 9 of the anthracene ring system. The studied bisantrene/amsacrine (m-AMSA) hybrid and bisantrene isomers were able to poison DNA topoisomerase II with an intermediate activity between those of bisantrene and m-AMSA. Moving the side chain from the central to a lateral ring (from C-9 to C-1/C-4) only slightly modified the drug DNA affinity, whereas it dramatically affected local base preferences of poison-stimulated DNA cleavage. In contrast, switching the planar aromatic systems of bisantrene and m-AMSA did not substantially alter the sequence specificity of drug action. A computer-assisted steric and electrostatic alignment analysis of the test compounds was in agreement with the experimental data, since a common pharmacophore was shared by bisantrene, m-AMSA, and 9-substituted analogs, whereas the 1-substituted isomer showed a radically changed pharmacophoric structure. Thus, the relative space occupancy and electron distribution of putative DNA binding (aromatic rings) and enzyme binding (side chains) moieties are fundamental in directing the specific action of topoisomerase II poisons and in determining the poison pharmacophore

Targeting the Major Groove of the Palindromic d(GGCGCC)2 Sequence by Oligopeptide Derivatives of Anthraquinone Intercalators

GC-rich sequences are recurring motifs in oncogenes and retroviruses, and could be targeted by non-covalent major-groove therapeutic ligands. We considered the palindromic sequence d(G1G2C3G4C5C6)2, and designed several oligopeptide derivatives of the anti-cancer intercalator mitoxantrone. The stability of their complexes with a 18-mer oligonucleotide encompassing this sequence in its center was validated using polarizable molecular dynamics. We report the most salient structural features of two novel compounds, having a dialkylammonium group as a side-chain on both arms. The anthraquinone ring is intercalated in the central d(CpG)2 sequence with its long axis perpendicular to that of the two base-pairs. On each strand, this enables each ammonium group to bind in-register to O6/N7 of the two facing G bases upstream. We subsequently designed tris-intercalating derivatives, each dialkylammonium substituted with a connector to an N9-aminoacridine intercalator extending our target range from six- to a ten-base pair palindromic sequence, d(C1G2G3G4C5G6C7C8C9G10)2. The structural features of the complex of the most promising derivative are reported. The present design strategy paves the way for designing intercalator-oligopeptide derivatives with an even higher selectivity, targeting an increased number of DNA bases, going beyond ten