The structure design of biotransformed unsymmetrical nitro-contained 1,5-diaryl-3-oxo-1,4-pentadienyls for the anti-parasitic activities

AbstractTwo 1,5-diaryl-3-oxo-1,4-pentadienyls (1 and 2) having nitro group attached exhibited potent anti-parasitic activity when evaluated against Trypanosoma cruzi and Leishmania amazonensis. In the present work, metabolomic analysis revealed that enzymatic action of T. cruzi reduces the CC bonds and let the nitro groups intact. Further, these two reduced compounds along with six other congeners were produced by chemical or microbiological methods and evaluated against T. cruzi. All reduced compounds showed less potency than compounds 1 and 2, proving the importance of unsaturated moieties for activity. This investigation provides insight into the mechanism of action of nitro unsaturated diarylpentadienones reinforcing previous studies showing their interference in the redox metabolism of T. cruzi. In the result increase in reactive oxygen and nitrogen species occurs, altering mitochondrial function and depleting the whole antioxidant system, which ultimately causes parasite death. Docking studies using trypanothione oxy-reductase as target helped understanding the activities. The present investigation confirms that enzymes play a pivotal role in drug activation

Copper and manganese cations alter secondary metabolism in the fungus Penicillium brasilianum

FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPCONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESThe fungus Penicillium brasilianum LaBioMMi 136 was isolated as an endophyte from Melia azedarach and has shown to be a prominent producer of great diversity of secondary metabolites, although it does not express some biosynthetic routes to other natural27814441451FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPCONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPCONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPES2014/03510-22010/52312-8SEM INFORMAÇÃOSEM INFORMAÇÃOThe authors are grateful to the Brazilian institutions (Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, Process No. 2014/03510-2 and 2010/52312-8), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfei

Eupomatenoid-5 Isolated from Leaves of Piper regnellii Induces Apoptosis in Leishmania amazonensis

Leishmania spp. are protozoa responsible for leishmaniasis, a neglected disease that kills up to 50,000 people every year. Current therapies mainly rely on antimonial drugs that are inadequate because of their poor efficacy and safety and increased drug resistance. An urgent need exists to find new and more affordable drugs. Our previous study demonstrated the antileishmanial activity of eupomatenoid-5, a neolignan obtained from leaves of Piper regnellii var. pallescens. The aim of the present study was to clarify the mode of action of eupomatenoid-5 against L. amazonensis. We used biochemical and morphological techniques and demonstrated that eupomatenoid-5 induced cell death in L. amazonensis promastigotes, sharing some phenotypic features observed in metazoan apoptosis, including increased reactive oxygen species production, hypopolarization of mitochondrial potential, phosphatidylserine exposure, decreased cell volume, and G0/G1 phase cell cycle arrest

Dibenzylideneacetone Induces Apoptosis in Cervical Cancer Cells through Ros-Mediated Mitochondrial Damage

Cervical cancer is a health problem among women worldwide. Considering the limitations of prevention and antineoplastic chemotherapy against cervical cancer, research is needed to discover new, more effective, and safe antitumor agents. In the present study, we investigated the in vitro cytotoxicity of a new synthetic dibenzylideneacetone derived from 1,5-diaryl-3-oxo-1,4-pentadienyl (A3K2A3) against cervical cancer cells immortalized by HPV 16 (SiHa), and 18 (HeLa) by MTT assay. Furthermore, we performed spectrofluorimetry, flow cytometry, and Western blot analyzes to explore the inhibitory mechanism of A3K2A3 in cervical cancer cells. A3K2A3 showed cytotoxic activity against both cell lines. Mitochondrial depolarization and reduction in intracellular ATP levels were observed, which may be dependent on the redox imbalance between increased ROS and reduced levels of the antioxidant defense. In addition, damage to the cell membrane and DNA, and effective blocking of cell division in the G2/M phase were detected, which possibly led to the induction of apoptosis. This result was further confirmed by the upregulation of apoptosis-related proteins Bax, cytochrome C, and caspases 9 and 3. Our results provided the first evidence that A3K2A3 contributes to the suppression of cervical cancer in vitro, showing promise as a possible alternative for the treatment of this cancer

Copper and Manganese Cations Alter Secondary Metabolism in the Fungus Penicillium brasilianum

The fungus Penicillium brasilianum LaBioMMi 136 was isolated as an endophyte from Melia azedarach and has shown to be a prominent producer of great diversity of secondary metabolites, although it does not express some biosynthetic routes to other natural compounds found in Penicillium genera. The present study aimed at the diversification of P. brasilianum secondary metabolism by varying the chemical composition used for its growth. Medium composition supplemented with CuSO4 and MnSO4 locked verruculogen biosynthesis and addressed proline to the production of a series of cyclodepsipeptides identified as JBIR 113, JBIR 114 and JBIR 115, never described for this species so far. The induced cyclodepsipeptide JBIR 113 was isolated by the use of combined chromatographic procedures and identified by spectroscopic methods. The unique structure with three neighboring cyclic amino acids proline and twice pipecolinic acid is rare as natural products and has been described for the first time in terrestrial organism. Verruculogen and JBIR 113 exhibited weak antiparasitary activity against Leishmania amazonensis

A versatile method for the selective core-crosslinking of hyaluronic acid nanogels via ketone-hydrazide chemistry : from chemical characterization to in vivo biodistribution

International audienceThe development of biopolymer-based nanogels has gained particular interest to achieve successful delivery of therapeutics for the treatment of various diseases, such as cancer, infection and diabetes. Herein, we report a new and simple methodology for the covalent stabilization of self-assembled gel nanoparticles based on hyaluronic acid (HA) modified with a thermoresponsive ketone-functional copolymer. This relies on the selective formation of hydrazone crosslinks with bishydrazides within the globular domains of the copolymer chains formed above the cloud point temperature. This approach allows tuning the crosslinking density by varying the dihydrazide crosslinker to ketone molar ratio. The size distributions and morphology of the nanogels were assessed using dynamic light scattering (DLS), cryo-transmission and scannning electron microscopy. In vitro cellular uptake in several cancer cells and in vivo biodistribution of the nanogels in different mouse tumor models were then explored to assess the effectiveness of this crosslinking strategy. The data from these experiments show prolonged blood circulation, longer than 24 hours, for the crosslinked nanogels and high tumor accumulation

β-Carboline-α-aminophosphonate Derivative: A Promising Antitumor Agent for Breast Cancer Treatment

Breast cancer is the most common type of cancer and the leading cause of cancer mortality among women worldwide. Considering the limitations of the current treatments available, we analyzed the in vitro cytotoxic potential of ((4-Fluoro-phenyl)-{2-[(1-phenyl-9H-β-carboline-3-carbonyl)-amino]-ethylamino}-methyl)-phosphonic acid dibutyl ester (BCP-1) in breast cancer cells (MCF-7 and MDA-MB-231) and in a non-tumor breast cell line (MCF-10A). BCP-1 has an α-aminophosphonate unit linked to the β-carboline nucleus, and the literature indicates that compounds of these classes have high biological potential. In the present study, the mechanism of action of BCP-1 was investigated through methods of spectrofluorimetry, flow cytometry, and protein expression analysis. It was found that BCP-1 inhibited the proliferation of both cancer cell lines. Furthermore, it induced oxidative stress and cell cycle arrest in G2/M. Upregulation of apoptosis-related proteins such as Bax, cytochrome C, and caspases, as well as a decrease in the anti-apoptotic protein Bcl-2, indicated potential induction of apoptosis in the MDA-MB-231 cells. While in MCF-7 cells, BCP-1 activated the autophagic death pathway, which was demonstrated by an increase in autophagic vacuoles and acidic organelles, in addition to increased expression of LC3I/LC3II and reduced SQSTM1/p62 expression. Further, BCP-1 demonstrated antimetastatic potential by reducing MMP-9 expression and cell migration in both breast cancer cell lines. In conclusion, BCP-1 is a promising candidate for breast cancer chemotherapy

X-ray structure of O-methyl-acrocol and anti-cancer, anti-parasitic, anti-bacterial and anti-Zika virus evaluations of the Brazilian palm tree Acrocomia totai

Acrocomia totai Mart ("macauba") is a palm tree native from Brazil, whose potential for biodiesel production has been widely explored. In spite of the industrial interest in the oil from the nuts, little is known about the potential applications of other parts of the plant, especially in the pharmacological area. A phytochemical study of the plant thorns led to the identification of a new compound 3-(R)-methoxy-21-(R)-H-hop-22(29)-en-30-ol 1, two known triterpenes 2-3, four steroids 4-7 and a stilbene, piceatannol 8. The structures were elucidated by spectroscopic analyses, including 1D and 2D NMR and low and high resolution mass spectrometry. Compound 1 was purified as crystals, which allowed the determination of the absolute configuration of the asymmetric carbons by analysis of the X-ray diffraction spectrum. Biological tests were performed with crude extract (CE), fractions and isolated compound. The assays showed activity for CE against lung carcinoma (GI(50) 59.2 mu g mL(-1)). The ethyl acetate fraction (EAF) showed efficacy against many tumor cell lines, and the tests showed the most prominent activity for breast cancer (GI(50) 10.4 mu g mL(-1)), glioma (GI(50) 77.3 mu g mL(-1)), uterine cervix (SiHa) HPV 16 (IC50 39.8 mu g mL(-1)), (HeLa) HPV 18 (IC50 12.0 pg mL(-1)) and Caco-2 (IC50 40.0 mu g mL(-1)) and showed bacteriostatic action against Staphylococcus aureus (MIC 50 mu g mL(-1)). Piceatannol 8 isolated from EAF showed activity against the protozoan which causes leishmaniosis (IC50 58.4 mu g mL(-1)). For Ttypanosorna cruzi, the methanol fraction (EC50 15.5 mu g mL(-1)), CE (20.5 mu g(-1)), and HEF (43.8 mu g mL(-1)) were the most active, being highly selective for the protozoan and less toxic against Vero cells. The compound 8 was further tested against Zika virus MR 766 strain on MOI 2, however the assays showed no inhibition against virus infection109483492CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO ARAUCÁRIA DE APOIO AO DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO DO ESTADO DO PARANÁ - FAFUNDAÇÃO DE AMPARO À PESQUISA E INOVAÇÃO DO ESTADO DE SANTA CATARINA - FAPESCsem informaçãosem informaçãosem informaçãosem informaçã