Improvement of in vivo anticancer and antiangiogenic potential of thalidomide derivatives

AbstractThe 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<0.05). Neovascularization evaluated by Chorioallantoic Membrane Assay (CAM) with compounds 2a and 2b showed reduction of vessels’ number (12. 9±2.3 and 14.8±3.3%), neovascularization area (13.1±1.7 and 14.3±1.7%) and total length of vessels (9.2±1.5 and 9.9±1.9%). On the other hand, thalidomide did not alter vascularization parameters. Consequently, addition of thiosemicarbazone pharmacophore group into the phthalimidic ring improved the in vivo antitumor and antiangiogenic potential of the analogs 2a and 2b

A Importância das Medidas de Mitigação e Adaptação Frente às Mudanças Climáticas na Agropecuária Brasileira / The Importance of Mitigation and Adaptation Measures to Climate Change in Brazilian Agriculture

As mudanças climáticas apresentam-se como um iminente perigo que põe em risco os ecossistemas, a biodiversidade, as comunidades culturais, entre muitos outros aspectos, afetando o bem-estar humano e ambiental. A Agropecuária é um setor muito sensível a essas variações do clima com consequências imediatas perceptíveis como, por exemplo, o aumento da suscetibilidade de erosão em terras acarretando a perda de fertilidade de solos, o que coloca em questão a segurança alimentar global. No Brasil, a degradação de terras ocasionada por desmatamentos é uma das causas de maiores emissões de gases de efeito estufa (GEE) e é motivada principalmente pela expansão da fronteira agrícola e da pecuária. Portanto a premissa é de que tal setor contribua negativamente na emissão de GEE. Assim o objetivo deste estudo é verificar quais são as medidas de mitigação e adaptação frente às mudanças climáticas no setor Agropecuário. Foi realizado um estudo bibliográfico a fim de contextualizar a problemática, bem como evidenciar quais são as medidas indicadas pelo plano de Agricultura de Baixo Carbono (ABC) e pelo Painel Brasileiro de Mudanças Climáticas (PBMC). Tal discussão é importante porquanto se preza por um desenvolvimento sustentável em prol do bem-estar de todos. Desse modo há necessidade de respostas e ações urgentes para essas iminentes eventualidades. Tais ações visam primordialmente a manutenção de um meio ambiente equilibrado e o enfrentamento das consequências já antecipadas. 

2-Pyridyl thiazoles as novel anti-Trypanosoma cruzi agents: structural design, synthesis and pharmacological evaluation

The present work reports on the synthesis, anti-Trypanosoma cruzi activities and docking studies of a novel series of 2-(pyridin-2-yl)-1,3- thiazoles derived from 2-pyridine thiosemicarbazone. The majority of these compounds are potent cruzain inhibitors and showed excellent inhibition on the trypomastigote form of the parasite, and the resulting structure-activity relationships are discussed. Together, these data present a novel series of thiazolyl hydrazones with potential effects against Chagas disease and they could be important leads in continuing development against Chagas disease

Structural Insights Into Bioactive Thiazolidin-4-one: Experimental and Theoretical Data

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2016-04-14T17:53:03Z No. of bitstreams: 1 Cardoso MVO Structural insights....pdf: 373887 bytes, checksum: 3cbea7d50108fd1d0362e6ddbb01c83e (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2016-04-14T18:02:35Z (GMT) No. of bitstreams: 1 Cardoso MVO Structural insights....pdf: 373887 bytes, checksum: 3cbea7d50108fd1d0362e6ddbb01c83e (MD5)Made available in DSpace on 2016-04-14T18:02:35Z (GMT). No. of bitstreams: 1 Cardoso MVO Structural insights....pdf: 373887 bytes, checksum: 3cbea7d50108fd1d0362e6ddbb01c83e (MD5) Previous issue date: 2015Universidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilUniversidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilUniversidade Federal de Pernambuco. Centro de Ciências Exatas e da Natureza. Departamento de Química Fundamental. Recife, PE, BrasilUniversidade de São Paulo. Instituto de Física. Departamento de Física e Informática. São Carlos, SP, BrasilUniversidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilAlthough viewed as promising drug candidates, few efforts have been addressed towards the structural chemistry of 2-hydrazonothiazolidin-4-ones. Therefore, 2-[(3-phenylsulfanylpropylidene)- hydrazono]thiazolidin-4-one (ATZ3) was synthesized and its crystal and molecular structure was studied by NMR and X-ray single crystal diffraction. The 1H NMR spectral data indicated that the hydrazone group assumes the Econfiguration, which was further confirmed by bi-dimensional NMR and crystallographic data. Despite agreement between most bond lengths and angleswith their expected values, the crystalline packing provided important information with regard to the double bond position involving the C-4 carbon. Quantum chemical calculations at Semiempirical, Density Functional Theory (DFT) and Ab Initio levels provided a good agreement between calculated and structural results provided by X-ray analysis. The system’s dimerization energies were also estimated. Statistical and Hierarchic Cluster Analysis (HCA) revealed interesting aspects of the calculations and pointed to the B3LYP as the most accurate in the determination of structure among the methods considered, in spite of some good results achieved by semiempirical schemes

Phthalimido-thiazoles as building blocks and their effects on the growth and morphology of Trypanosoma cruzi.

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2016-05-13T16:12:59Z No. of bitstreams: 1 Gomes PATM Phthalimido....pdf: 1703584 bytes, checksum: 52e53fea525abd4a9ca1d384144f5738 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2016-05-13T17:31:23Z (GMT) No. of bitstreams: 1 Gomes PATM Phthalimido....pdf: 1703584 bytes, checksum: 52e53fea525abd4a9ca1d384144f5738 (MD5)Made available in DSpace on 2016-05-13T17:31:23Z (GMT). No. of bitstreams: 1 Gomes PATM Phthalimido....pdf: 1703584 bytes, checksum: 52e53fea525abd4a9ca1d384144f5738 (MD5) Previous issue date: 2016Universidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Centro de Ciências da Saúde. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Centro de Ciências da Saúde. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Centro de Ciências da Saúde. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Centro de Ciências da Saúde. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Centro de Ciências da Saúde. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Centro de Ciências da Saúde. Recife, PE, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilLaboratório de Imunologia Keizo Asami-LIKA/UFPE. Recife, PE, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhães. Recife, PE, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhães. Recife, PE, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhães. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Centro de Ciências da Saúde. Recife, PE, BrasilChagas disease is a parasitic infection caused by protozoan Trypanosoma cruzi that affects approximately 6e7 million people worldwide. Benznidazole is the only drug approved for treatment during the acute and asymptomatic chronic phases; however, its efficacy during the symptomatic chronic phase is controversial. The present work reports the synthesis and anti-T. cruzi activities of a novel series of phthalimido-thiazoles. Some of these compounds showed potent inhibition of the trypomastigote form of the parasite at low cytotoxicity concentrations in spleen cells, and the resulting structure-activity relationships are discussed. We also showed that phthalimido-thiazoles induced ultrastructural alterations on morphology, flagellum shortening, chromatin condensation, mitochondria swelling, reservosomes alterations and endoplasmic reticulum dilation. Together, these data revealed, for the first time, a novel series of phthalimido-thiazoles-structure-based compounds with potential effects against T. cruzi and lead-like characteristics against Chagas disease

Synthesis, Cruzain docking, and in vitro studies of aryl-4-oxothiazolylhydrazones against Trypanosoma cruzi.

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2015-04-16T17:31:27Z No. of bitstreams: 1 Leite A C L Synthesis, docking....pdf: 610757 bytes, checksum: 9534d4781408434b33184616f3a5f517 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2015-04-16T18:10:59Z (GMT) No. of bitstreams: 1 Leite A C L Synthesis, docking....pdf: 610757 bytes, checksum: 9534d4781408434b33184616f3a5f517 (MD5)Made available in DSpace on 2015-04-16T18:10:59Z (GMT). No. of bitstreams: 1 Leite A C L Synthesis, docking....pdf: 610757 bytes, checksum: 9534d4781408434b33184616f3a5f517 (MD5) Previous issue date: 2007Universidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Laboratório de Planejamento. Avaliação e Síntese de Fármacos. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Laboratório de Planejamento. Avaliação e Síntese de Fármacos. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Laboratório de Planejamento. Avaliação e Síntese de Fármacos. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Laboratório de Planejamento. Avaliação e Síntese de Fármacos. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Laboratório de Planejamento. Avaliação e Síntese de Fármacos. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Laboratório de Planejamento. Avaliação e Síntese de Fármacos. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Laboratório de Química Teórica Medicinal. Recife, PE, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilResearch in recent years has demonstrated that the Trypanosoma cruzi cysteine protease cruzain (TCC) is a valid chemotherapeutic target. Herein we describe a small library of aryl-4-oxothiazolylhydrazones that have been tested in assays against T. cruzi cell cultures. The docking studies carried out suggest that these compounds are potential ligands for the TCC enzyme. The most promising compound of this series, N-(4-oxo-5-ethyl-2'-thiazolin-2-yl)-N'-phenylthio-(Z)-ethylidenehydrazone (6 f), was shown to be very active at non-cytotoxic concentrations in in vitro assays with mammalian cells and has a potency comparable with reference drugs such as nifurtimox (Nfx) and benznidazole (Bdz)

Antitumor and immunomodulatory activities of thiosemicarbazones and 1,3-Thiazoles in Jurkat and HT-29 cells

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2016-12-29T13:13:53Z No. of bitstreams: 1 Santos TAR Antitumor and immunomodulatory....pdf: 770132 bytes, checksum: b6d055670f9e6f1821da4d2895ab7c0d (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2016-12-29T13:24:03Z (GMT) No. of bitstreams: 1 Santos TAR Antitumor and immunomodulatory....pdf: 770132 bytes, checksum: b6d055670f9e6f1821da4d2895ab7c0d (MD5)Made available in DSpace on 2016-12-29T13:24:03Z (GMT). No. of bitstreams: 1 Santos TAR Antitumor and immunomodulatory....pdf: 770132 bytes, checksum: b6d055670f9e6f1821da4d2895ab7c0d (MD5) Previous issue date: 2016Brazilian National Research Council (CNPq), Research Foundation of Pernambuco State (FACEPE) and FIOCRUZ.Fundação Oswaldo Cruz. Centro de Pesquisa Aggeu Magalhães. Laboratório de Imunogenética. Recife, PE, BrasilFundação Oswaldo Cruz. Centro de Pesquisa Aggeu Magalhães. Laboratório de Imunogenética. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilUniversidade Federal de Pernambuco. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilFundação Oswaldo Cruz. Centro de Pesquisa Aggeu Magalhães. Laboratório de Imunogenética. Recife, PE, BrasilCancer remains a high incidence and mortality disease, causing around 8.2 million of deaths in the last year. Current chemotherapy needs to be expanded, making research for new drugs a necessary task. Immune system modulation is an emerging concept in cancer cell proliferation control. In fact, there are a number of mechanisms underlying the role immune system plays in tumor cells. In this work, we describe the structural design, synthesis, antitumor and immunomodulatory potential of 31 new 1,3-thiazole and thiosemicarbazone compounds. Cisplatin was used as anticancer drug control. Cytotoxicity against J774A.1 macrophages and antitumor activity against HT-29 and Jurkat cells was determined. These 1,3-thiazole and thiosemicarbazone compounds not only exhibited cytotoxicity in cancer cells, but were able to cause irreversible cancer cell damage by inducing necrosis and apoptosis. In addition, these compounds, especially pyridyl-thiazoles compounds, regulated immune factors such as interleukin 10 and tumor necrosis factor, possible by directing immune system in favor of modulating cancer cell proliferation. By examining their pharmacological activity, we were able to identify new potent and selective anticancer compounds

Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2018-04-04T17:27:48Z No. of bitstreams: 1 Silva EB Desing and synthesis of potent....pdf: 1101357 bytes, checksum: 05dda8ac2e41eb232464eae9599dab02 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2018-04-04T17:42:18Z (GMT) No. of bitstreams: 1 Silva EB Desing and synthesis of potent....pdf: 1101357 bytes, checksum: 05dda8ac2e41eb232464eae9599dab02 (MD5)Made available in DSpace on 2018-04-04T17:42:18Z (GMT). No. of bitstreams: 1 Silva EB Desing and synthesis of potent....pdf: 1101357 bytes, checksum: 05dda8ac2e41eb232464eae9599dab02 (MD5) Previous issue date: 2017Conselho Nacional de Desenvolvimento Científico e Tecnol ogico, Fundaç~ao de Amparo a Ci^encia e Tecnologia de Pernambuco (FACEPE).Universidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. Recife, PE, Brasil / Universidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, BrasilUniversidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilUniversidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilUniversidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhães. Recife, PE, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhães. Recife, PE, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhães. Recife, PE, Brasil / Universidade Federal de Pernambuco. Centro Acadêmico de Vit oria. Laborat orio de Parasitologia. Vit oria de Santo Antão, PE, BrasilUniversidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilUniversidade de Pernambuco. Colegiado de Nutrição. Petrolina, PE, BrasilUniversidade de São Paulo. Instituto de Física. Departamento de Física e Inform atica. São Carlos, SP, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Aggeu Magalhães. Recife, PE, BrasilUniversidade Federal de Pernambuco. Centro de Ciências da Saúde. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilChagas disease, caused by the kinetoplastid protozoan parasite Trypanosoma cruzi, remains a relevant cause of illness and premature death and it is estimated that 6 million to 7 million people are infected worldwide. Although chemotherapy options are limited presenting serious problems, such as low efficacy and high toxicity. T. cruzi is susceptible to thiazoles, making this class of compounds appealing for drug development. Previously, thiazoles resulted in an increase in anti-T. cruzi activity in comparison to thiosemicarbazones. Here, we report the structural planning, synthesis and anti-T. cruzi evaluation of new thiazoles derivatives (3a-m and 4a-m), designed from molecular hybridization associated with non-classical bioisosterism. By varying substituents attached to the phenyl and thiazole rings, substituents were observed to retain, enhance or greatly increase their anti-T. cruzi activity, in comparison to the corresponding thiosemicarbazones. In most cases, electron-withdrawing substituents, such as bromine, 3,4-dichloro and nitro groups, greatly increased antiparasitic activity. Specifically, new thiazoles were identified that inhibit the epimastigote proliferation and were toxic for trypomastigotes without affecting macrophages viability. These compounds were also evaluated against cruzain. However, inhibition of this enzyme was not observed, suggesting that the compounds work through another mechanism. In addition, examination of T. cruzi cell death showed that these molecules induce apoptosis. In conclusion, except for compounds 3h and 3k, all thiazoles derivatives evaluated exhibited higher cytotoxic activity against the trypomastigote forms than the reference medicament benznidazole, without affecting macrophages viability. Compounds 4d and 4k were highlights, CC50 = 1.2 e 1.6 μM, respectively. Mechanistically, these compounds do not inhibit the cruzain, but induce T. cruzi cell death by an apoptotic process, being considered a good starting point for the development of new anti-Chagas drug candidates