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

Cytotoxic and toxicological effects of phthalimide derivatives on tumor and normal murine cells

Moreira, Diogo Rodrigo de Magalhães “Documento produzido em parceria ou por autor vinculado à Fiocruz, mas não consta à informação no documento”.Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2017-07-31T18:21:31Z No. of bitstreams: 1 Ferreira PMP Cytotoxic and toxicological....pdf: 4094868 bytes, checksum: d5e028316d2b5ededa8fc20b950342e6 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2017-07-31T18:37:20Z (GMT) No. of bitstreams: 1 Ferreira PMP Cytotoxic and toxicological....pdf: 4094868 bytes, checksum: d5e028316d2b5ededa8fc20b950342e6 (MD5)Made available in DSpace on 2017-07-31T18:37:20Z (GMT). No. of bitstreams: 1 Ferreira PMP Cytotoxic and toxicological....pdf: 4094868 bytes, checksum: d5e028316d2b5ededa8fc20b950342e6 (MD5) Previous issue date: 2015Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico (FUNCAP) and Fundação de Amparo à Pesquisa do Estado do Piauí (FAPEPI)Universidade Federal do Piauí. Departamento de Biofísica e Fisiologia. Teresina, PI, Brasil / Universidade Federal do Piauí. Programa de Pós-Graduação em Ciências Farmacêuticas. Teresina, PI, BrasilUniversidade Federal do Ceará. Departamento de Fisiologia e Farmacologia. Fortaleza, CE, BrasilUniversidade Federal do Ceará. Departamento de Fisiologia e Farmacologia. Fortaleza, CE, BrasilUniversidade Federal do Ceará. Departamento de Fisiologia e Farmacologia. Fortaleza, CE, BrasilUniversidade Federal do Piauí. Programa de Pós-Graduação em Ciências Farmacêuticas. Teresina, PI, BrasilUniversidade Federal do Piauí. Programa de Pós-Graduação em Ciências Farmacêuticas. Teresina, PI, BrasilUniversidade Federal do Pernambuco. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilUniversidade Federal do Pernambuco. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilUniversidade Federal do Ceará. Departamento de Análises Clínicas e Toxicológicas. Fortaleza, CE, BrasilUniversidade Federal do Ceará. Departamento de Análises Clínicas e Toxicológicas. Fortaleza, CE, BrasilUniversidade Federal do Pernambuco. Departamento de Ciências Farmacêuticas. Recife, PE, BrasilUniversidade Federal do Ceará. Departamento de Fisiologia e Farmacologia. Fortaleza, CE, Brasil / Fundação Oswaldo Cruz. Fortaleza, CE, BrasilOnze 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.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 vivo tumor 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

Evaluation of the anti-Schistosoma mansoni activity of thiosemicarbazones and thiazoles

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2018-04-03T13:26:17Z No. of bitstreams: 1 Santiago EF Evaluation of the anti-Schistosoma ....pdf: 4333306 bytes, checksum: 0a4eafc14622c78b28659cb69c2c2996 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2018-04-03T14:24:14Z (GMT) No. of bitstreams: 1 Santiago EF Evaluation of the anti-Schistosoma ....pdf: 4333306 bytes, checksum: 0a4eafc14622c78b28659cb69c2c2996 (MD5)Made available in DSpace on 2018-04-03T14:24:14Z (GMT). No. of bitstreams: 1 Santiago EF Evaluation of the anti-Schistosoma ....pdf: 4333306 bytes, checksum: 0a4eafc14622c78b28659cb69c2c2996 (MD5) Previous issue date: 2014Conselho Nacional de Desenvolvimento Científico e Tecnológico (CPNq) and Fundação Oswaldo Cruz (FIOCRUZ). FAPESB postdoctoral scholarship.Federal University of Pernambuco. Department of Pharmacy. Recife, PE, Brazil / Federal University of Pernambuco. Laboratory of Immunopathology. Recife, PE, BrazilFederal University of Pernambuco. Laboratory of Immunopathology. Recife, PE, BrazilFederal University of Pernambuco. Department of Pharmacy. Recife, PE, BrazilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilFederal University of Pernambuco. Department of Pharmacy. Recife, PE, BrazilFederal University of Pernambuco. Laboratory of Immunopathology. Recife, PE, BrazilFederal University of Pernambuco. Laboratory of Immunopathology. Recife, PE, BrazilFederal University of Pernambuco. Laboratory of Immunogenetics. Recife, PE, BrazilFederal University of Pernambuco. Laboratory of Immunogenetics. Recife, PE, BrazilFederal University of Pernambuco. Laboratory of Immunogenetics. Recife, PE, BrazilFundação 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, BrasilFederal University of Pernambuco. Department of Physiology and Pharmacology. Recife, PE, BrazilFederal University of Pernambuco. Department of Pharmacy. Recife, PE, BrazilSchistosomiasis is a chronic and debilitating disease caused by a trematode of the genus Schistosoma and affects over 207 million people. Chemotherapy is the only immediate recourse for minimizing the prevalence of this disease and involves predominately the administration of a single drug, praziquantel (PZQ). Although PZQ has proven efficacy, there is a recognized need to develop new drugs as schistosomicides since studies have shown that repeated use of this drug in areas of endemicity may cause a temporary reduction in susceptibility in isolates of Schistosoma mansoni. Hydrazones, thiosemicarbazones, phthalimides, and thiazoles are thus regarded as privileged structures used for a broad spectrum of activities and are potential candidates for sources of new drug prototypes. The present study determined the in vitro schistosomicidal activity of 10 molecules containing these structures. During the assays, parameters such motility and mortality, oviposition, morphological changes in the tegument, cytotoxicity, and immunomodulatory activity caused by these compounds were evaluated. The results showed that compounds formed of thiazole and phthalimide led to higher mortality of worms, with a significant decline in motility, inhibition of pairing and oviposition, and a mortality rate of 100% starting from 144 h of exposure. These compounds also stimulated the production of nitric oxide and tumor necrosis factor alpha (TNF-α), thereby demonstrating the presence of immunomodulatory activity. The phthalyl thiazole LpQM-45 caused significant ultrastructural alterations, with destruction of the tegument in both male and female worms. According to the present study, phthalyl thiazole compounds possess antischistosomal activities and should form the basis for future experimental and clinical trials