1-[2-(4-methyl-7-coumarinyloxy)ethyl]-4-(5-{1-[2-(4-methyl-7-coumarinyloxy)ethyl]-1h-1, 2, 3-triazol-4-yl}pentyl)-1h-1, 2, 3-triazole

Nature often produces compounds with a high degree of symmetry to reduce structural information and complexity. Synthesis of identical twin drugs, through the linkage of two identical pharmacophoric entities, is a classical strategy to produce more potent and/or selective drugs. Herein, two units of the privileged core of the coumarin hymecromone were linked together using “click chemistry”. Synthesis of 1-[2-(4-Methyl-7-coumarinyloxy)ethyl]-4-(5-{1-[2-(4-methyl- 7-coumarinyloxy)ethyl]-1H-1, 2, 3-triazol-4-yl}pentyl)-1H-1, 2, 3-triazole was achieved by coupling of two identical units of an azido coumarin with a symmetrical alkine using copper(I)-catalyzed alkyne-azide cycloaddition reaction, in good yields and with complete regioselectivity. © 2016 by the authors; licensee MDPI, Basel, Switzerland.2016

Novel coumarins active against Trypanosoma cruzi and toxicity assessment using the animal model Caenorhabditis elegans

From 2nd Latin American Congress of Clinical and Laboratorial Toxicology Porto Alegre, Brazil. 3-6 June 2018Background: Chagas disease (CD) is a tropical parasitic disease. Although the number of people infected is very high, the only drugs available to treat CD, nifurtimox (Nfx) and benznidazole, are highly toxic, particularly in the chronic stage of the disease. Coumarins are a large class of compounds that display a wide range of interesting biological properties, such as antiparasitic. Hence, the aim of this work is to find a good antitrypanosomal drug with less toxicity. The use of simple organism models has become increasingly attractive for planning and simplifying efficient drug discovery. Within these models, Caenorhabditis elegans has emerged as a convenient and versatile tool with significant advantages for the toxicological potential identification for new compounds. Methods: Trypanocidal activity: Forty-two 4-methylamino-coumarins were assayed against the epimastigote form of Trypanosoma cruzi (Tulahuen 2 strain) by inhibitory concentration 50% (IC50). Toxicity assays: Lethal dose 50% (LD50) and Body Area were determined by Caenorhabditis elegans N2 strain (wild type) after acute exposure. Structure-activity relationship: A classificatory model was built using 3D descriptors. Results: Two of these coumarins demonstrated near equipotency to Nifurtimox (IC50 = 5.0 ± 1 μM), with values of: 11 h (LaSOM 266), (IC50 = 6.4 ± 1 μM) and 11 g (LaSOM 231), (IC50 = 8.2 ± 2.3 μM). In C. elegans it was possible to observe that Nfx showed greater toxicity in both the LD50 assay and the evaluation of the development of worms. It is possible to observe that the efficacy between Nfx and the synthesized compounds (11 h and 11 g) are similar. On the other hand, the toxicity of Nfx is approximately three times higher than that of the compounds. Results from the QSAR-3D study indicate that the volume and hydrophobicity of the substituents have a significant impact on the trypanocidal activities for derivatives that cause more than 50% of inhibition. These results show that the C. elegans model is efficient for screening potentially toxic compounds. Conclusion: Two coumarins (11 h and 11 g) showed activity against T. cruzi epimastigote similar to Nifurtimox, however with lower toxicity in both LD50 and development of C. elegans assays. These two compounds may be a feasible starting point for the development of new trypanocidal drugs

Fenologia e produção de cultivares de amoreira-preta em sistema agroecológico.

A amoreira-preta é uma espécie de exploração recente no Brasil. Nos últimos ano, s tem sido dada especial atenção ao cultivo orgânico ou agroecológico dessa espécie. O objetivo deste trabalho foi verificar o comportamento fenológico e produtivo das cultivares de amora-preta ‘Tupy’, ‘Guarani’, ‘Caingangue’, ‘Cherokee’ e ‘Brazos’, e das seleções denominadas ‘seleção 97’ e ‘seleção 787’ na região de Pelotas, Rio Grande do Sul(RS), em sistema agroecológico. O trabalho foi realizado na Estação Experimental de Cascata (EEC), Embrapa Clima Temperado. As plantas foram dispostas no pomar, em blocos varietais aleatórios, com 10 plantas por genótipo, perfazendo quatro linhas com duas cultivares por linha. Foram observadas as datas de início da floração e fim da floração, início e final de colheita, massa (gramas) e número de frutos por planta, teor de sólidos solúveis totais (ºBrix), produção média por planta (g pl-1) e produtividade estimada por hectare (kg ha-1). Para análise das características dos frutos, a média de cada ano de avaliação (três) foi considerada como uma repetição. Na região de Pelotas-RS, é viável o cultivo agroecológico de amoreira-preta. Não há diferenças de produção, produtividade, número de frutos e teores de sólidos solúveis totais entre os genótipos estudados

Human spermatogenic failure purges deleterious mutation load from the autosomes and both sex chromosomes, including the gene DMRT1

Gonadal failure, along with early pregnancy loss and perinatal death, may be an important filter that limits the propagation of harmful mutations in the human population. We hypothesized that men with spermatogenic impairment, a disease with unknown genetic architecture and a common cause of male infertility, are enriched for rare deleterious mutations compared to men with normal spermatogenesis. After assaying genomewide SNPs and CNVs in 323 Caucasian men with idiopathic spermatogenic impairment and more than 1,100 controls, we estimate that each rare autosomal deletion detected in our study multiplicatively changes a man’s risk of disease by 10% (OR 1.10 [1.04–1.16], p,261023), rare X-linked CNVs by 29%, (OR 1.29 [1.11–1.50], p,161023), and rare Y-linked duplications by 88% (OR 1.88 [1.13–3.13], p,0.03). By contrasting the properties of our case-specific CNVs with those of CNV callsets from cases of autism, schizophrenia, bipolar disorder, and intellectual disability, we propose that the CNV burden in spermatogenic impairment is distinct from the burden of large, dominant mutations described for neurodevelopmental disorders. We identified two patients with deletions of DMRT1, a gene on chromosome 9p24.3 orthologous to the putative sex determination locus of the avian ZW chromosome system. In an independent sample of Han Chinese men, we identified 3 more DMRT1 deletions in 979 cases of idiopathic azoospermia and none in 1,734 controls, and found none in an additional 4,519 controls from public databases. The combined results indicate that DMRT1 loss-of-function mutations are a risk factor and potential genetic cause of human spermatogenic failure (frequency of 0.38% in 1306 cases and 0% in 7,754 controls, p = 6.261025). Our study identifies other recurrent CNVs as potential causes of idiopathic azoospermia and generates hypotheses for directing future studies on the genetic basis of male infertility and IVF outcomes.This work was partially funded by the Portuguese Foundation for Science and Technology FCT/MCTES (PIDDAC) and co-financed by European funds (FEDER) through the COMPETE program, research grant PTDC/SAU-GMG/101229/2008. IPATIMUP is an Associate Laboratory of the Portuguese Ministry of Science, Technology, and Higher Education and is partially supported by FCT. AML is the recipient of a postdoctoral fellowship from FCT (SFRH/BPD/73366/2010). CO is supported by a grant from the United States National Institutes of Health (R01 HD21244), JDS is supported by Damon Runyon Clinical Investigator Award, Alex's Lemonade Stand Foundation Epidemiology Award, and the Eunice Kennedy Shriver Children's Health Research Career Development Award NICHD 5K12HD001410. Support for humans studies and specimens were provided by the NIH/NIDDK George M. O'Brien Center for Kidney Disease Kidney Translational Research Core (P30DK079333) grant to Washington University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Poda drástica para a produção da amora-preta em regiões subtropicais

O objetivo deste trabalho foi avaliar podas diferenciadas como alternativa para a produção da amora-preta 'Tupy', em regiões subtropicais do Brasil. O experimento foi realizado no Município de Marechal Cândido Rondon, PR. Utilizou-se o delineamento experimental de blocos ao acaso, com oito blocos e três tratamentos: poda convencional, poda drástica de verão e poda drástica de inverno. Em cada parcela, constituída de 12 plantas úteis, foram coletados dados fenológicos e produtivos no ciclo de produção de 2010/2011 e 2011/2012, tendo-se realizado quantificação físico-química dos frutos no último ciclo de produção. A poda drástica de verão facilita a condução da amoreira-preta e possibilita aumento na produção de 4.375,6 kg ha-1, em comparação à poda convencional. A poda drástica de inverno causa elevada queda na produção das plantas