6 research outputs found

    Synthesis, molecular Docking and biological evaluation of new 1-Aryl-3-[3-(thieno[3,2-b]pyridin-7-ylthio)phenylureas as Potent Type II VEGFR-2 Tyrosine Kinase inhibitors

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    The vascular endothelial growth factor receptor 2 (VEGFR-2) is a tyrosine kinase receptor, expressed primarily in endothelial cells, and is activated by the specific binding of VEGF to the VEGFR-2 extracellular regulatory domain. Once activated, VEGFR-2 undergoes autophosphorylation, triggering signaling pathways leading to endothelial cell proliferation and subsequent angiogenesisY1 Small molecules may act as inhibitors by competing for the ATP-binding s'1te of the VEGFR-2 intracellular tyrosine kinase domain, thereby preventing the intracellular signa ling that leads to angiogenesis. [ZJ Here, we present the synthesis of new 1-aryl-3-[3-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas la-c, as potent type 11 VEGFR-2 inhibitors based on molecular docking (Figure A) and biological evaluation including enzymatic assays using the VEGFR-2 tyrosine kinase domain (ICso=l0-28 nM) and studies in human umbilical vein endothelial cells (HUVECs). The latter included cell viability (MTS), proliferation (BrdU) and Western blot for total and phosphorylated VEGFR-2 (Figure B). The predicted docked poses were analyzed in detail and a plausible explanation for compounds 1 potency was obtained base9 on the simultaneous presence of a S-linker and the arylurea moiety in the meta position as a new substitution pattern for the type 11 VEGFR-2 inhibitors. These chemical features place the thieno[3,2-b]pyridine and the terminal aryl ring in close superimposition to a pyrrolo[3,2-d]pyrimidine derivative. The presence of hydrofobic substituents (F and Me) in the terminal aryl ring is also important. For these compounds a significant inhibition in HUVECs proliferation upon VEGF stimulation was observed at low concentrations (0.5-1.0 IJ.M) without affecting cell viability. Westernblot analysis demonstrated that compounds 1 significantly the inhibited VEGFR-2 phosphorylation at 1.0 jlM, thus confirming their anti-angiogenic potential

    New di(heteroaryl)thioethers 1,3-diarylureas in the thieno[3,2-b]pyridine series as VEGFR2 tyrosine kinase inhibitors: docking, synthesis, enzymatic and cellular assays

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    Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) is a tyrosine kinase receptor, expressed primarily in endothelial cells, and is activated by the specific binding of VEGF, produced and released by the tumor, to the VEGFR2 extracellular regulatory domain, undergoing autophosphorylation, triggering signaling pathways leading to endothelial cell proliferation towards the tumor [!].Small molecules may act as inhibitors by competing for the ATP-binding site of the VEGFR2 intracellular tyrosine kinase domain, thereby preventing the intracellular signaling that leads to angiogenesis [2]. Herein, we report the synthesis using rational design of new 1-aryl-3-[3-thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas (la-c) as VEGFR2 tyrosine kinase inhibitors. The compounds presented, with the arylurea in the meta position to the thioether and with F or a Me group, showed very low !Cso values (11-28 nM) in enzymatic assays as predicted by molecular docking. To examine the activity of compounds 1 in endothelial cells, VEGF-stimulated (60 ng/mL) Human Umbilical Vein Endothelial Cells (HUVECs) were cultured in M199 medium in the absence (C) or presence of each compound at different concentrations. A remarkable reduction in the proliferation of HUVECs using the BrdU incorporation assay was observed for all compounds at I !JM, for compound la being observed a higher antiproliferative effect. Further studies are ongoing to examine whether these molecules affect the expression and activity of VEGFR2 and the signaling pathways, using western blotting assays. Given the established role of VEGFR2 in proliferation and migration of endothelial cells, these molecules are promising anti-angiogenic agents that can be used for therapeutic purposes in pathological conditions where angiogenesis is exacerbated, such as cancer

    Essential oil from leaves of Lantana camara : a potential source of medicine against leishmaniasis

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    Leishmaniasis is an infection of viscera or tegument caused by protozoa Leishmania sp. The extensive period required for the treatment, which involves the use of toxic medicines, leads patients to drop treatment increasing the development of resistant forms of Leishmania sp. Lantana camara L., Verbenaceae, is a tropical plant native from America. Folk uses have been described for treatment of tumors, tetanus, rheumatism and malaria. This study evaluates the leishmanicidal activity of the essential oil of leaves from L. camara on promastigote forms of Leishmania chagasi and L. amazonensis and its toxic effects on Artemia salina (brine shrimp test), macrophage cultures and BALB/c mice. The chemical composition was evaluated using the gas chromatography coupled with mass spectrometer (GC-MS). Thirty substances, mostly mono and sesquiterpenes were identifi ed. The most representative constituents were: germacrene D (24.90%), farnesene derivatives (22%) and (E)-cariophylene (14.31%). Bioassays revealed a signifi cant leishmanicidal activity of essential oil against L. amazonensis (IC50 0.25 μg/ mL) and a potential toxic effect on Brine shrimp (LC50 10 μg/mL) and macrophage assays (CC50 4 μg/mL), while there was no toxic manifestation on mice. The data show the relevant potential of L. camara as a source of medicine for leishmaniasis treatment

    Brazilian Flora 2020: Leveraging the power of a collaborative scientific network

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    International audienceThe shortage of reliable primary taxonomic data limits the description of biological taxa and the understanding of biodiversity patterns and processes, complicating biogeographical, ecological, and evolutionary studies. This deficit creates a significant taxonomic impediment to biodiversity research and conservation planning. The taxonomic impediment and the biodiversity crisis are widely recognized, highlighting the urgent need for reliable taxonomic data. Over the past decade, numerous countries worldwide have devoted considerable effort to Target 1 of the Global Strategy for Plant Conservation (GSPC), which called for the preparation of a working list of all known plant species by 2010 and an online world Flora by 2020. Brazil is a megadiverse country, home to more of the world's known plant species than any other country. Despite that, Flora Brasiliensis, concluded in 1906, was the last comprehensive treatment of the Brazilian flora. The lack of accurate estimates of the number of species of algae, fungi, and plants occurring in Brazil contributes to the prevailing taxonomic impediment and delays progress towards the GSPC targets. Over the past 12 years, a legion of taxonomists motivated to meet Target 1 of the GSPC, worked together to gather and integrate knowledge on the algal, plant, and fungal diversity of Brazil. Overall, a team of about 980 taxonomists joined efforts in a highly collaborative project that used cybertaxonomy to prepare an updated Flora of Brazil, showing the power of scientific collaboration to reach ambitious goals. This paper presents an overview of the Brazilian Flora 2020 and provides taxonomic and spatial updates on the algae, fungi, and plants found in one of the world's most biodiverse countries. We further identify collection gaps and summarize future goals that extend beyond 2020. Our results show that Brazil is home to 46,975 native species of algae, fungi, and plants, of which 19,669 are endemic to the country. The data compiled to date suggests that the Atlantic Rainforest might be the most diverse Brazilian domain for all plant groups except gymnosperms, which are most diverse in the Amazon. However, scientific knowledge of Brazilian diversity is still unequally distributed, with the Atlantic Rainforest and the Cerrado being the most intensively sampled and studied biomes in the country. In times of “scientific reductionism”, with botanical and mycological sciences suffering pervasive depreciation in recent decades, the first online Flora of Brazil 2020 significantly enhanced the quality and quantity of taxonomic data available for algae, fungi, and plants from Brazil. This project also made all the information freely available online, providing a firm foundation for future research and for the management, conservation, and sustainable use of the Brazilian funga and flora
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