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The strategy of antiangiogenic drugs is based on inhibiting formation of new blood vessels as alternative to limit cancer progression. In this work, we investigated the antitumor and antiangiogenic potential of eight thalidomide derivatives. Most of the molecules was not cytotoxic but 2a, 2d and 3d revealed weak antiproliferative activity on HL-60, Sarcoma 180 (S180) and normal peripheral blood mononuclear cells. Thalidomide, 2a and 2b were able to inhibit tumor growth (53.5%, 67.9% and 67.4%, respectively) in S180-bearing mice and presented moderate and reversible toxicity on liver, kidneys and spleens. Both analogs (2a and 2b) inhibited cell migration of endothelial (HUVEC) and melanoma cells (MDA/MB-435) at 50μg/mL. Immunohistochemistry labeling assays with CD-31 (PECAM-1) antibody showed microvascular density (MVD) was significantly reduced in thalidomide, 2a and 2b groups (30±4.9, 64.6±1.8 and 46.5±19.5%, respectively) (p

Fluorescent naphthoxazoles and their boron derivatives have been synthesized and applied as superior and selective probes for endocytic pathway tracking in live cancer cells. The best fluorophores were compared with the commercially available acridine orange (co-staining experiments), showing far better selectivity.

Natural α,β-amyrins were isolated from endemic Brazilian Esenbeckia grandiflora Mart., and eight synthetic derivatives were obtained by esterification reactions with bromo acetate, followed by amine treatment. The structures of the all compounds were confirmed by 1H and 13C nuclear magnetic resonance (NMR), Fourier transform infrared (FTIR) and high-resolution mass spectrometry (HRMS) data analysis. The derivatives were screened for cytotoxic activity against human tumor cell-lines PC3 (prostate carcinoma), HCT-116 (colon carcinoma) and HL60 (leukemia). HCT-116 and PC3 cell-lines showed weak tumor growth inhibition (range of 13.9-25.4 and 10.3-28.8%, respectively), but the derivatives presented moderate activity against HL60 (range of 13.6-59.0%). Diethyl, aniline, morpholine and imidazole moieties presented higher activities (range of 45.9-59.0%).

For the first time, a fluorescent lapachone-based BODIPY was synthesised and characterised by NMR and mass spectrometry. Computational and electrochemical aspects, as well as cytotoxic activity and subcellular localisation, were studied. Confocal microscopy experiments indicated that the probe was a specific mitochondria-staining agent. These in-detail analyses were useful in understanding the cytotoxic effects and mechanism of action of this novel hybrid compound. This molecule constitutes a promising prototype owing to its potential biological activities and the new strategies aimed at mechanistic investigations in cells and in vivo, and opens up an interesting avenue of research.

Introduction: e xperimental animal models represent a key tool used to elucidate the mechanisms of action and toxicity of anticancer drugs. Objective: t he purpose was to establish a correlation of neoplastic growth with the combinatorial therapeutic application of sodium alendronate (ALD) and methotrexate (MTX), and to evaluate the gastrointestinal toxicity of these drugs, in the rat Walker 256 carcinosarcoma inoculation model. Methods: female rats were selected and randomly distributed into 5 groups (n=10): negative control (NC), positive control (PC), MTX-treated group, ALD-treated group, and MTX-ALD-treated group (MTX/ALD). Tumor cells were inoculated as a suspension of 1x10 6 cells/mL into the alveolar cavities produced by exodontia procedures. The following parameters were evaluated: body weight, tumor volume and percentage of tumor inhibition, and gastrointestinal toxicity. Results: the body weight variation was statistically significant between NC animals and PC animals, and between NC animals and ALD-treated group (p

Molecules : a journal of synthetic chemistry and natural product chemistry 21(7), 873 (2016). doi:10.3390/molecules21070873, Published by MDPI, Basel

Made available in DSpace on 2018-11-27T16:55:43Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-06-20 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Ethnopharmacological relevance: Casearia sylvestris (Salicaceae) is found in South America and presents antiulcerogenic, cytotoxic, antimicrobial, anti-inflammatory and antihypertensive activities. Aim of the study: To assess the in vivo and ex vivo antitumor action of a fraction with casearins (FC) and its main component- Casearin X-isolated from C sylvestris leaves. Materials and methods: Firstly, Sarcoma 180 bearing Swiss mice were treated with FC and Cas X for 7 days. Secondly, BALB/c nude animals received hollow fibers with colon carcinoma (HCT-116) or glioblastoma (SF-295) cells and were treated with FC for 4 days. On 5th day, proliferation was determined by MIT assay. Results: FC 10 and 25 mg/kg/day i.p. and 50 mg/kg/day oral and Cas X 25 mg/kg/day i.p. and 50 mg/kg/ day oral revealed tumor growth inhibition rates of 35.8, 86.2, 53.7, 90.0 and 65.5% and such tumors demonstrated rare mitoses and coagulation necrosis areas. Similarly, FC reduced multiplying of HCT-116 and SF-295 cells when evaluated by the Hollow Fiber Assay (2.5 and 5 mg/kg/day i.p. and 25 and 50 mg/ kg/day oral), with cell growth inhibition rates ranging from 33.3 to 67.4% (p < 0.05). Flow cytometry experiments revealed that FC reduced membrane integrity and induced DNA fragmentation and mitochondrial depolarization (p < 0.05). Conclusions: FC and Cas X were efficient antitumor substances against murine and human cancer cells and caused reversible morphological changes in liver, kidneys and spleens, emphasizing clerodane diterpenes as an emerging class of anticancer molecules. (C) 2016 Elsevier Ireland Ltd. All rights reserved. Univ Fed Piaui, Dept Physiol & Biophys, Expt Cancerol Lab, Teresina, Brazil Univ Fed Piaui, Postgrad Program Pharmaceut Sci, Teresina, Brazil Univ Fed Piaui, Postgrad Program Biotechnol, Teresina, Brazil Fundacao Oswaldo Cruz, Salvador, BA, Brazil Univ Fed Piaui, Dept Pharm, Teresina, Brazil Univ Fed Ceara, Fac Med, Dept Physiol & Pharmacol, Fortaleza, Ceara, Brazil State Univ Sao Paulo, Inst Chem, Araraquara, Brazil State Univ Sao Paulo, Ctr Med Nucl, Radioisotopes Res Lab, Sao Paulo, Brazil State Univ Sao Paulo, Fac Med, Dept Radiol, Sao Paulo, Brazil Univ Fed Ceara, Dept Clin Odontol, Fortaleza, Ceara, Brazil Fundacao Oswaldo Cruz, Fortaleza, Ceara, Brazil State Univ Sao Paulo, Inst Chem, Araraquara, Brazil State Univ Sao Paulo, Ctr Med Nucl, Radioisotopes Res Lab, Sao Paulo, Brazil State Univ Sao Paulo, Fac Med, Dept Radiol, Sao Paulo, Brazil CNPq: 473167/2012-3 CNPq: 301976/2013-9

A series of 2-hydroxy-3-arylnaphthalene-1,4-diones (3-aryllawsones) were synthesized by Suzuki-Miyaura cross coupling reaction of 3-iodolawsone with arylboronic acids/esters. The hydroxylated resulting products were transformed into their corresponding N,N-diethyl carbamates. The antineoplastic and antileishmanial activities of the compounds were evaluated and compared with lapachol and its carbamate, providing promising results.

Ten novel a -santonin derivatives have been synthesized as cytotoxic agents. The in vitro antitumor activity of these compounds has been evaluated against cancer cells lines. Structure-activity relationships indicate that a -methylene- g -lactone and endoperoxide functionalities play important roles in conferring cytotoxicity. The compounds 2e4, possessing the a -methylene- g -lactone group showed IC 50 values between 5.70 and 16.40 m M. Mixture of isomers 5 and 6, with the a -methylene- g -lactone and endoperoxide functionalities, displayed the greatest activity, with IC 50 values between 1.45 and 4.35 m M. The biological assays conducted with normal cells revealed that the compounds 2, 5 and 6 are selective against cancer cells lines tested. Bioactive lactones described herein and in our previous report did not cause disruption of the cell membrane in mouse erythrocytes.

Two new diterpenes, 1 and 2, together with the known ent-15-oxo-kaur-16-en-18-oic acid (3), were isolated from the bark of Croton argyrophylloides. The structural characterization of 1 and 2 was determined on the basis of spectroscopic data interpretation. The cytotoxicity of each compound was evaluated against HL-60 (leukemia), MDAMB-435 (melanoma), SF-295 (glioblastoma), and HCT-8 (colon carcinoma) human tumor cell lines and against human peripheral blood mononuclear cells. The hemolytic potential in mouse erythrocytes was also tested for 1-3.

Physalis angulata L (Solanaceae) is a medicinal plant from North of Brazil, whose different extracts and infusions are commonly used in the popular medicine for the treatment of malaria, asthma, hepatitis, dermatitis and rheumatism. However, the genotoxic effects of P. angulata on human cells is not well known. The main purpose of the present study was to evaluate the in vitro genotoxic effects of aqueous extract of P. angulata using the comet assay and the micronucleus assay in human lymphocytes provided from 6 healthy donors. Treatments with P. angulata extracts were performed in vitro in order to access the extent of DNA damage. The comet assay has shown that treatments with P. angulata at 0.5, 1.0, 2.0, 3.0 and 6.0 microg/mL in culture medium were genotoxic. Lymphocytes treated with P. angulata at the concentrations of 3.0 and 6.0 microg/mL in culture medium showed a statistically significant increase in the frequency of micronucleus (p

Chalcogen-containing β-lapachone derivatives were synthesized using a straightforward methodology and evaluated against several cancer cell lines (leukaemia, human colon carcinoma, prostate, human metastatic prostate, ovarian, central nervous system and breast), showing, in some cases, IC50 values below 1 μM. The cytotoxic potential of the lapachones evaluated was also assayed using non-tumor cells: human peripheral blood mononuclear cells, two murine fibroblast lines (L929 and V79 cells) and MDCK (canine kidney epithelial cells). These compounds could provide promising new lead derivatives for anticancer drug development. This manuscript reports important findings since few authors have described C-3 substituted β-lapachone with potent antitumor activity. The methodology employed allowed the preparation of the compounds from lapachol within a few minutes in a green approach.

Novel naphthoquinone-based chalcones were prepared from the reaction between 3-bromo-nor-beta-lapachone and amino-chalcones. Lapachone derivatives are also described here. All the substances were evaluated against cancer and normal cell lines and several compounds demonstrated potent antitumor activity.

Eleven phthalimide derivatives were evaluated with regards to their antiproliferative activity on tumor and normal cells and possible toxic effects. Cytotoxic analyses were performed against murine tumors (Sarcoma 180 and B-16/F-10 cells) and peripheral blood mononuclear cells (PBMC) using MTT and Alamar Blue assays. Following, the investigation of cytotoxicity was executed by flow cytometry analysis and antitumoral and toxicological potential by in vivo techniques. The molecules 3b, 3c, 4 and 5 revealed in vitro cytotoxicity against Sarcoma 180, B-16/F-10 and PBMC. Since compound 4 was the most effective derivative, it was chosen to detail the mechanism of action after 24, 48 and 72 h exposure (22.5 and 45 µM). Sarcoma 180 cells treated with compound 4 showed membrane disruption, DNA fragmentation and mitochondrial depolarization in a time- and dose-dependent way. Compounds 3c, 4 and 5 (50 mg/kg/day) did not inhibit in vivotumor growth. Compound 4-treated animals exhibited an increase in total leukocytes, lymphocytes and spleen relative weight, a decreasing in neutrophils and hyperplasia of spleen white pulp. Treated animals presented reversible histological changes. Molecule 4 had in vitro antiproliferative action possibly triggered by apoptosis, reversible toxic effects on kidneys, spleen and livers and exhibited immunostimulant properties that can be explored to attack neoplasic cells. Onze derivados da ftalimida foram avaliados quanto a sua atividade antiproliferativa em células tumorais e normais e possíveis efeitos tóxicos. Avaliou-se a citotoxicidade contra tumores murinos (células de Sarcoma 180 e B-16/F-10) e células mononucleares do sangue perférico (CMSP) usando os ensaios de MTT e Alamar Blue. Em seguida, a investigação de citotoxicidade foi executada por citometria de fluxo e potencial antitumoral e toxicológico por meio de métodos in vivo. As moléculas 3b, 3c, 4 e 5 revelaram citotoxicidade in vitro contra Sarcoma 180, B-16/F-10 e PBMC. Uma vez que o composto 4 foi o derivado mais efetivo, ele foi escolhido para detalhar o mecanismo de ação após 24, 48 e 72h de exposição (22.5 e 45 µM). Células de Sarcoma 180 tratadas com o composto 4 mostraram desintegração de membrana, fragmentação de DNA e despolarização mitocondrial de maneira tempo e concentracão dependente. Os compostos 3c, 4 e 5 (50 mg/kg/dia) não inibiu o crescimento tumoral in vivo. Os animals tratados com o composto 4 exibiram aumento do total de leucócitos, linfócitos e no peso relativo do baço, diminuição de neutrófilos e hiperplasia da polpa branca esplênica. Os animais tratados apresentaram alterações histológicas reversíveis. A molécula 4 tem ação antiproliferativa in vitro provavelmente por ativação de apoptose, efeitos tóxicos reversíveis e exibiu propriedades imunoestimulantes que podem ser exploradas para atacar células neoplásicas.

Specimens of Leonotis nepetiflolia were obtained from cultivated and wild environments to verify their influences in chemical composition. Phytochemical analyses were conducted for the ethyl acetate phase obtained by partitioning the crude ethanol extract from the cultivated leaves of L. nepetifolia. In doing so, flavonoid 3',4',5-trimethoxy-6,7-dihidroxyflavone (cirsiliol), a chemotaxonomic marker of the family Lamiaceae, was isolated. The results reveal that all phases and extracts tested exhibited weak to moderate antimicrobial activity against the strains of bacteria tested. The evaluation of in vitrocytotoxic and antitumor activity showed that the ethyl acetate phases obtained from both wild and cultivated leaves exhibit high potential cytotoxic and antitumor (> 78.0% of inhibition) activity. The major component of these phases was identified by high-performance liquid chromatography-diode array detector and nuclear magnetic resonance analyses using both 1D and 2D methods. The results further indicate that the flavonoid cirsiliol is the agent responsible for the activity observed in these phases.

Piper tuberculatum, popularly known in Brazil as “jaborandi falso” and “pimenta darta”, is widely used in folk medicine for the treatment of several diseases. In this study, the in vivo hollow fiber assay was used to investigate the antitumour efficacy of the crude extract and piplartine obtained from P. tuberculatum roots. Human glioblastoma (SF-295) and colon carcinoma (HCT-8) cell lines were used. In vitro cytotoxicity was assayed by the MTT assay. In the hollow fiber assay, nude mice implantedwith tumour cells in hollow fibers were treated for four consecutive days via the intraperitoneal route, and tumour cell populations were assessed by the MTT assay. Both the crude extract and piplartine displayed cytotoxicity. In the hollow fiber assay, tumour growth inhibition rates were 24.6–54.8% for the crude extract and 33.7–62.2% for piplartine. No signal of toxicity was noticed. In conclusion, the crude extract and piplartine obtained from P. tuberculatum roots displayed in vitro and in vivo anticancer efficacy.

Two new isoflavonoids, 7-hydroxy-6,4'-dimethoxy-isoflavonequinone (1) and 2'-hydroxy-6,4',6' ',4' ''-tetramethoxy-[7-O-7' ']-bisisoflavone (2), and seven other known flavonoids, 3-hydroxy-9-methoxypterocarpan (medicarpin), 3,10-dihydroxy-9-methoxypterocarpan, 3,9-dimethoxypterocarpan (homopterocarpin) (3), 2,3,9-trimethoxypterocarpan (4), 3,4-dihydroxy-9-methoxypterocarpan (vesticarpan) (5), 2',4,4'-trihydroxychalcone (isoliquiritigenin), and 7,4'-dihydroxyflavanone (liquiritigenin) (6), were isolated from the heartwood of Platymiscium floribundum. The structures of compounds 1 and 2 were established by spectroscopic methods. Compounds 3-6 showed cytotoxic activity when evaluated against five human cancer cell lines in vitro.

The use of mesoporous silica in targeted cancer therapy is increasing daily. The combination of a rigid model of nanoparticles like mesoporous silica and biological compounds with an affinity for oncological diseases is the most promising drug-targeting system nowadays. In this study, we used the mesoporous silica SBA-15 combined with aptamer (functionalized for tumor with MUC1). The results obtained were of interest and showed the formation of the silica mesoporous structure. The impregnation methodology of mesoporous silica with the aptamer was also confirmed. Cytotoxicity results demonstrated that the particle associated with the aptamer has no cytotoxicity. We conclude that although further studies are required, the mesoporous silica nanoparticle model loaded with aptamer is very functional and can be used for other applications, especially in nuclear medicine.

A series of novel sesquiterpenes is prepared starting from the known α-santonin derived derivatives (I) and (VII).

Many compounds used in the treatment of cancer possess tubulin-interacting properties that lead to mitotic arrest. Withaphysalins are potent cytotoxic compounds that are commonly found in plants belonging to the Solanaceae family, such as Acnistus arborescens; however, the cytotoxic mechanisms or molecular targets of these compounds remain unknown. Thus, the aim of this study was to evaluate the effects of whitaphysalins on cancer cell cycle progression and tubulin interaction. In this report, we show the antiproliferative activity of withaphysalin F and its effect in arresting cells in the G(2)/M phase of the cell cycle. These two effects are the result of the interference of withaphysalin F in the polymerization of microtubules. Withaphysalin F also induced DNA fragmentation, which can be related to an increase in mitochondrial membrane depolarization. These results suggest that interference of withaphysalin F in microtubule polymerization may induce cell cycle arrest in the G(2)/M phase and therefore contribute to growth inhibition of tumor cells in vitro. Taken together, these studies indicate that withaphysalin F could potentially be used as an anticancer drug.

The present study evaluated the cytotoxic activity of nepetin and quercetin-3-O-glucoside, compounds isolated from the aerial parts of Eupatorium ballotaefolium. The antimitotic activity was determined as the ability to inhibit sea urchin eggs development and five tumor cells lines growth. Moreover, the activities of these compounds were compared to quercetin in the same models. Nepetin inhibited the proliferation of the five tumor cell lines, once quercetin-3-O-glucoside did not present any activity even at the highest tested concentration and quercetin only inhibited proliferation of the B16 cell line. On the sea urchin assay, nepetin and quercetin induced a dose-dependent inhibition on egg development, while quercetin-3-O-glucoside did not modify normalegg cleavage, even at the highest tested concentration (100 microg/ml).

This work reports for the first time the production a furanoheliangolide (goyazensolide) by plant cell culture. Monitoring of the goyazensolide metabolism revealed that the maximum production occurred during the lag phase of the Lychnophora ericoides callus culture. The antiproliferative activity of obtained goyazensolide was evaluated against seven cancer cell lines using MTT assay. The results revealed a potent cytotoxic activity for the furaheliangolide with IC50 values in the range of 0.06 microg/ml for CEM leukemia cells to 0.75 microg/ml for B16 melanome cells.

Eleven known compounds and a new prenylated naphthoquinone, lippsidoquinone (13), were isolated from ethanol extracts of Lippia sidoides. Their structures were established by a combination of 1D and 2D NMR, IR, and EIMS spectral data analysis. The cytotoxic properties of compounds 3--13 were evaluated against HL60, SW1573, and CEM cell lines. Only tectol (6) and lippsidoquinone (13) exhibited significant activity against human leukemia cell lines HL60 and CEM.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior As an attempt at promoting the approximation between the Universities and the social movements in order to qualify the processes of formation of technicians in Technical Assistance and Rural Extension (ATER), MDA/INCRA created the Agrarian Residence Program. The Agrarian Residence Program is a national coverage program; it is coordinated by MDA/INCRA Ministry of Agrarian Development/National Institute for Colonization and Agrarian Reform, and is developed in the North, Northeast, Mid-West and the South/Southeast regions of Brazil. The Federal University of Santa Maria (UFSM) joined the program as one of the program units in the South/Southeast region (with UFRJ, UNICAMP and UFPR). This work aimed at contributing to the identification of the challenges implied in the formation of professionals of higher education with a differentiated profile to work with family farmers and settlers, through a critical evaluation of the experience of the UFSM project. It attempts at explicitating the perception of the participants in the Agrarian Residence Program about their main difficulties in the formation of competences for the work of ATER in the Program scope. In order to reach the objectives, a qualitative research was done through a participant observation of the researcher in several activities of the course, and semi-structured interviews in the several stages of the course with the participant students in the Agrarian Residence Project of UFSM and the Program managers. It was observed that before the experiences and challenges placed in each stage, different reactions on the part of students are perceived, who basically decide for their permanence or not in the project, as well as face or not the challenges of learning. It is understood that such dynamics determines differences in the individual trajectories and in the progress in terms of formation of competences made in the project. Such interpretation reveals the importance and central role of the subjects decisions in the improvement of the learning processes and, as a consequence, it indicates that the progress was differentiated from individual to individual. Buscando favorecer a aproximação entre as Universidades e os movimentos sociais para qualificar os processos de formação de técnicos de ATER o MDA/INCRA criou o Programa Residência Agrária. O Programa Residência Agrária tem abrangência nacional, é coordenado pelo MDA/INCRA e desenvolvido nas regiões Norte, Nordeste, Centro-Oeste e Sul/Sudeste. A UFSM integrou-se como uma das unidades do programa na região Sul/Sudeste (com UFRJ, a UNICAMP e a UFPR). O presente trabalho teve como objetivo contribuir para a identificação dos desafios implicados na formação de profissionais de nível superior com perfil diferenciado para trabalho com agricultores familiares e assentados, mediante uma avaliação crítica da experiência do projeto da UFSM. Busca-se explicitar a percepção dos participantes do Programa Residência Agrária sobre suas principais dificuldades na formação de competências para o trabalho de ATER no âmbito do Programa. Para atingir os objetivos, realizou-se uma pesquisa qualitativa através de observação participante em diversas atividades do curso, e entrevistas semi-estruturadas em três etapas do Curso de Especialização com os alunos participantes do projeto Residência Agrária da UFSM e gestores do Programa. Observou-se que frente às experiências e desafios colocados em cada etapa percebem-se diferentes reações por parte dos alunos que basicamente decidem pela permanência, ou não, no projeto e enfrentar ou não os desafios de aprendizagem. Entende-se que tal dinâmica determina diferenças nas trajetórias individuais e no avanço em termos de formação de competências alcançado no projeto. Tal interpretação revela a importância e centralidade das decisões dos sujeitos no avanço dos processos de aprendizagem e, consequentemente, indica que os avanços foram diferenciados de indivíduo para indivíduo.