Navegando por Autor "Siqueira, Raoni Pais"
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Item Antimetastatic effect of the pharmacological inhibition of serine/arginine-rich protein kinases (SRPK) in murine melanoma(Toxicology and Applied Pharmacology, 2018-10-01) Moreira, Gabriela Alves; Lima, Graziela Domingues de Almeida; Siqueira, Raoni Pais; Barros, Marcus Vinícius de Andrade; Adjanohoun, Abraham Landry Mahuvi; Santos, Viviane Corrêa; Barbosa, Éverton de Almeida Alves; Loterio, Robson Kriiger; Paiva, Janine Cerqueira de; Gonçalves, Victor Hugo Sousa; Viol, Lívia Cristina de Souza; Marques-da-Silva, Eduardo de Almeida; Silva Júnior, Abelardo; Almeida, Márcia Rogéria; Fietto, Juliana Lopes Rangel; Machado-Neves, Mariana; Ferreira, Rafaela Salgado; et al.The Serine/arginine-rich protein kinases (SRPK) are involved in pre-mRNA splicing control through the phosphorylation of the SR protein family of splicing factors. Over the last years, several studies have shown the relevance of SRPK for human cancers and their potential as promising drug targets. In this context, we have previously selected three trifluoromethyl arylamides (named here as SRVIC24, SRVIC30 and SRVIC36) with improved in vitro antileukemia effect and ability of impairing the cellular activity of SRPK. Given the increasing amount of reports on the implication of these kinases in metastatic cancers, in this study, we have evaluated the antimetastatic effect of these compounds and the known SRPK inhibitor (SRPIN340) on a murine model of metastatic melanoma. The compounds were able to impact the melanoma cell metastatic behavior by decreasing migration, invasion, adhesion, and colony formation in in vitro assays. Also, they presented antimetastatic in vivo activity, without apparent signs of systemic toxicity after treatments, as revealed by the histology of organs and analysis of key serum biochemical markers. Moreover, the effect of the treatments on SRPK1 nuclear translocation and SR protein phosphorylation was observed. Finally, molecular docking studies were carried out to gain structural information on the SRPK-compound complexes. Together, these data suggest that SRPK pharmacological inhibition should be considered as an interesting therapeutic strategy against metastatic cancers.Item Chemical constituents and an alternative medicinal veterinary herbal soap made from Senna macranthera(Hindawi, 2015-02-14) Andrade, Flávia Inoue; Purgato, Gislaine Aparecida; Maia, Thalita de Faria; Siqueira, Raoni Pais; Lima, Sâmia; Diaz, Gaspar; Diaz, Marisa Alves NogueiraUpon undergoing biomonitoring, the most active dichloromethane extract retrieved from Senna macranthera roots led to the isolation of three main compounds: emodine, physione, and chrysophanol. In this sequence, these compounds revealed a potential antibacterial activity against Staphylococcus aureus strains isolated from animals with mastitis infections with minimum inhibitory concentration (MIC) values of 20, 90, and 90 μg mL−1, respectively. Therefore, an herbal soap was also produced from this same active extract. This soap was tested in vitro using gloves contaminated by animals with bovine mastitis that had been discarded after use by milkers and showed similar results to previously tested compounds. These results indicate the potential of this plant as an alternative veterinary medicine for the production of antibacterial soaps that aimed at controlling bovine mastitis infections in small Brazilian farms.Item Potential antileukemia effect and structural analyses of SRPK inhibition by N-(2- (Piperidin-1-yl)-5-(Trifluoromethyl)Phenyl) isonicotinamide (SRPIN340)(Plos One, 2014-04-08) Siqueira, Raoni Pais; Barbosa, Éverton de Almeida Alves; Polêto, Marcelo Depólo; Righetto, Germanna Lima; Seraphim, Thiago Vargas; Salgado, Rafael Locatelli; Ferreira, Joana Gasperazzo; Oliveira, Leandro Licursi de; Laranjeira, Angelo Brunelli Albertoni; Almeida, Márcia Rogéria; Fietto, Juliana Lopes Rangel; Kobarg, Jörg; Oliveira, Eduardo Basílio de; Teixeira, Robson Ricardo; Borges, Júlio César; Silva Júnior, Abelardo; Bressan, Gustavo Costa; et al.Dysregulation of pre-mRNA splicing machinery activity has been related to the biogenesis of several diseases. The serine/arginine-rich protein kinase family (SRPKs) plays a critical role in regulating pre-mRNA splicing events through the extensive phosphorylation of splicing factors from the family of serine/arginine-rich proteins (SR proteins). Previous investigations have described the overexpression of SRPK1 and SRPK2 in leukemia and other cancer types, suggesting that they would be useful targets for developing novel antitumor strategies. Herein, we evaluated the effect of selective pharmacological SRPK inhibition by N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340) on the viability of lymphoid and myeloid leukemia cell lines. Along with significant cytotoxic activity, the effect of treatments in regulating the phosphorylation of the SR protein family and in altering the expression of MAP2K1, MAP2K2, VEGF and FAS genes were also assessed. Furthermore, we found that pharmacological inhibition of SRPKs can trigger early and late events of apoptosis. Finally, intrinsic tryptophan fluorescence emission, molecular docking and molecular dynamics were analyzed to gain structural information on the SRPK/SRPIN340 complex. These data suggest that SRPK pharmacological inhibition should be considered as an alternative therapeutic strategy for fighting leukemias. Moreover, the obtained SRPK-ligand interaction data provide useful structural information to guide further medicinal chemistry efforts towards the development of novel drug candidates.Item Serine/arginine protein kinase (SRPK) inhibition as a potential therapeutic strategy against leukemia cells(Universidade Federal de Viçosa, 2018-02-28) Siqueira, Raoni Pais; Bressan, Gustavo Costa; http://lattes.cnpq.br/8235055163837420Serine/Arginine protein kinase (SRPK) are key components of the splicing machinery trough the phosphoregulation of SR Proteins, which are crucial for exon selection in the alternative splicing. However, SRPK have frequently been found overexpressed or/and with altered activity in a number of cancers, including leukemias. Thus, the discovery of small molecule inhibitors against these kinases is of potential interest to identify novel therapeutic opportunities. Here, it is described the pharmacological inhibition of SRPK by N(2(piperidin1yl)5 (trifluoromethyl)phenyl)isonicotinamide (SRPIN340) on the viability of lymphoid and myeloid leukemia cell lines. Along with significant cytotoxic activity, the effect of treatments in regulating the phosphorylation of the SR protein family and in altering the expression of MAP2K1, MAP2K2, VEGF and FAS genes were also assessed. Furthermore, it was found that pharmacological inhibition of SRPKs can trigger early and late events of apoptosis. Finally, intrinsic tryptophan fluorescence emission, molecular docking and molecular dynamics were analyzed to gain structural information on the SRPK/SRPIN340 complex. In a second study, it is described the synthesis of a series of twentytwo trifluoromethyl arylamides based on the SRPIN340 scaffold and the evaluation of their antileukemia effects. Some derivatives presented superior cytotoxic effects against myeloid and lymphoid leukemia cell lines compared to SRPIN340. In particular, compounds N(2(4bromophenylamino)5(trifluoromethyl)phenyl)2chloronicotinamide (24), N(2(4bromophenylamino)5(trifluoromethyl)phenyl)nicotinamide (30), and N(2(4 bromophenylamino)5(trifluoromethyl)phenyl)benzamide (36) presented IC 50 values within the 6.0 – 35.7 μM (μmol L 1 ) range. In addition, these three compounds were able to trigger apoptosis and autophagy, and they exhibited synergistic effects in combination with the chemotherapeutic agent vincristine. Moreover, compound 30 was more efficient than SRPIN340 in impairing the intracellular phosphorylation status of SR proteins as well as the expression of MAP2K1, MAP2K2, VEGF, and RON oncogenic isoforms in leukemia cells. Taken together, these results suggest that SRPK pharmacological inhibitors may be considered for the development of novel therapeutic strategies against leukemias and other types of cancers.Item Síntese e avaliação da atividade citotóxica de derivados do eugenol contendo núcleos 1,2,3-triazólicos(Química Nova, 2018-05) Gazolla, Poliana Aparecida Rodrigues; Teixeira, Róbson Ricardo; Silva, Adalberto Manoel da; Vaz, Boniek Gontijo; Vasconcelos, Géssica Adriana; Siqueira, Raoni Pais; Gonçalves, Victor Hugo Sousa; Pereira, Higor Sette; Bressan, Gustavo CostaEugenol is an aromatic compound found in several plant species. It presents important biological activities including cytotoxicity. In this paper, it is described the synthesis and the evaluation of the cytotoxic activity of eugenol derivatives bearing 1,2,3-triazole functionalities. Eugenol, extracted via hydrodistillation from dried flower buds of Eugenia caryophyllata (=Syzygium aromaticum), was submitted to alkylation reactions to afford two terminal alkynes in good yields. The key reaction involved in the preparation of eugenol derivatives corresponded to the Copper(I)-catalyzed Azide-Alkyne Cycloaddition (CuAAC), between alkynylated eugenol derivatives and different benzyl azides. The evaluation of the cytotoxicity of twenty seven synthesized derivatives against HL60 leukemia cell line revealed that at 100 µmol L-1, five of them, namely 4-((4-allyl-2-methoxyphenoxy)methyl)-1-(3-bromobenzyl)-1H-1,2,3-triazole (6n), 4-(3-(4-allyl-2-methoxyphenoxy)propyl)-1-benzyl-1H-1,2,3-triazole (7a), 4-(3-(4-allyl-2-methoxyphenoxy)propyl)-1-(4-chlorobenzyl)-1H-1,2,3-triazole (7c), 4-(3-(4-allyl-2-methoxyphenoxy)propyl)-1-(4-iodobenzyl)-1H-1,2,3-triazole (7e) and 4-(3-(4-allyl-2-methoxyphenoxy)propyl)-1-(3-bromobenzyl)-1H-1,2,3-triazole (7m), were capable of significantly decreasing cell viability. These most active triazolic derivatives were also evaluated against B16F10 melanoma and Nalm6 leukemia cell lines. While only compound 7a was active against the former, compounds 6n, 7a, and 7m displayed activity against the latter. Derivative 7a was active against all cell lines. It is believed that eugenol derivatives bearing triazole functionalities may represent a scaffold to be explored toward the development of new agents against cancer.Item Splicing regulators and their roles in cancer biology and therapy(BioMed Research International, 2015-04-01) Silva, Maria Roméria da; Moreira, Gabriela Alves; Silva, Ronni Anderson Gonçalves da; Barbosa, Éverton de Almeida Alves; Siqueira, Raoni Pais; Teixera, Róbson Ricardo; Almeida, Márcia Rogéria; Silva Júnior, Abelardo; Fietto, Juliana Lopes Rangel; Bressan, Gustavo CostaAlternative splicing allows cells to expand the encoding potential of their genomes. In this elegant mechanism, a single gene can yield protein isoforms with even antagonistic functions depending on the cellular physiological context. Alterations in splicing regulatory factors activity in cancer cells, however, can generate an abnormal protein expression pattern that promotes growth, survival, and other processes, which are relevant to tumor biology. In this review, we discuss dysregulated alternative splicing events and regulatory factors that impact pathways related to cancer. The SR proteins and their regulatory kinases SRPKs and CLKs have been frequently found altered in tumors and are examined in more detail. Finally, perspectives that support splicing machinery as target for the development of novel anticancer therapies are discussed.Item Synthesis and antimetastatic activity evaluation of cinnamic acid derivatives containing 1,2,3-triazolic portions(Toxicology in Vitro, 2018-12) Lima, Graziela Domingues de Almeida; Rodrigues, Michelle Peixoto; Moreira, Gabriela Alves; Mendes, Tiago Antônio de Oliveira; Siqueira, Raoni Pais; Silva, Adalberto Manoel da; Vaz, Boniek Gontijo; Fietto, Juliana Lopes Rangel; Bressan, Gustavo Costa; Teixeira, Róbson Ricardo; Machado-Neves, MarianaIt is herein described the preparation and evaluation of antimetastatic activity of twenty-six cinnamic acid derivatives containing 1,2,3-triazolic portions. The compounds were prepared using as the key step the Copper(I)-catalyzed azide (A)-alkyne (A) cycloaddition (C) (CuAAC reaction), also known as click reaction, between alkynylated cinnamic acid derivatives and different benzyl azides. The reactions were carried in CH2Cl2/H2O (1:1 v/v) at room temperature, and the triazole derivatives were obtained in yields ranging from 73%99%. Reaction times varied from 5 to 40 min. The identity of the synthesized compounds was confirmed by IR and NMR (1H and 13C) spectroscopic techniques. They were then submitted to in vitro bioassays to investigate how they act over metastatic behavior of murine melanoma. The most potent compound, namely 3-(1-benzyl-1H-1,2,3-triazol-4-yl)propyl cinnamate (9a), showed significant antimetastatic and antiproliferative activities against B16-F10 cells. In addition, gelatin zymography and molecular docking analyses pointed to the fact that this compound has potential to interact with matrix metalloproteinase 9 (MMP-9) and MMP-2, which are directly involved in melanoma progression. Therefore, these findings suggest that cinnamic acid derivatives containing 1,2,3-triazolic portions may have potential for development of novel candidates for controlling malignant metastatic melanoma.Item Synthesis, molecular properties prediction and cytotoxic screening of 3-(2-aryl-2-oxoethyl)isobenzofuran-1(3H)-ones(Elsevier Bioorganic & Medicinal Chemistry Letters, 2016-04-25) Maia, Angélica Faleiros da Silva; Siqueira, Raoni Pais; Oliveira, Fabrício Marques de; Ferreira, Joana Gasperazzo; Silva, Silma Francielle da; Caiuby, Clarice Alves Dale; Oliveira, Leandro Licursi de; Paula, Sérgio Oliveira de; Souza, Rafael Aparecido Carvalho; Guilardi, Silvana; Bressan, Gustavo Costa; Teixeira, Róbson RicardoIn the present investigation, a collection of nineteen 3-(2-aryl-2-oxoethyl)isobenzofuran-1(3H)-ones was synthesized and screened for their cytotoxic activity against a panel of three leukemia cancer cell lines. The compounds were prepared via ZrOCl2·8H2O catalyzed condensation reactions between phthalaldehydic acid and different acetophenones. The reactions were carried out free of solvent and the isobenzofuran-1(3H)-ones were obtained in good yields (80–92%). The identities of the synthesized compounds were confirmed upon IR and NMR (1H and 13C) spectroscopy as well as high resolution mass spectrometry analyses. Structures of compounds 1, 4 and 16 were also investigated by X-ray analysis. The synthesized compounds were submitted to in vitro bioassays against HL-60, K562 and NALM6 cancer cell lines using MTT cytotoxicity assay. After 48 h of treatment, twelve derivatives were able to reduce cell viability and presented IC50 values equal to or below 20 μmol L−1 against at least one of the evaluated lineages. The most active compound corresponded to 3-(3-methylphenyl-2-oxoethyl)isobenzofuran-1(3H)-one (18) (IC50 values obtained for HL-60, K562 and NALM6 were, respectively, 13.5 μmol L−1, 8.83 μmol L−1, and 5.24 μmol L−1). In addition, compound 18 was capable of triggering apoptosis on NALM6 cells. All isobenzofuranones herein evaluated did not present cytotoxicity on peripheral blood mononuclear cells (PBMC), suggesting selective cytotoxic effect on leukemic cells. A computational study allowed prediction of pharmacokinetics and drug-likeness properties of the synthesized compounds. DFT calculations were performed to obtain the energy values of HOMO, LUMO, and dipole moments of isobenzofuranones.Item Synthesis, theoretical studies, and effect on the photosynthetic electron transport of trifluoromethyl arylamides(Pest Management Science, 2017-05-25) Teixeira, Róbson Ricardo; Barros, Marcus Vinícius de Andrade; Bressan, Gustavo Costa; Siqueira, Raoni Pais; Santos, Fabíola Suelen dos; Bertazzini, Michele; Kiralj, Rudolf; Ferreira, Márcia Miguel Castro; Forlani, GiuseppeThe photosynthetic apparatus is targeted by various herbicides, including several amides such as diuron and linuron. Considering the need for the discovery of new active ingredients to cope with weed resistance, the synthesis of a series of trifluoromethyl aryl amides is herein described whose inhibitory properties were assessed in vitro on the photosynthetic electron transport chain, and in vivo on the growth of a model cyanobacterial strain. Theoretical studies were also carried out. Starting with 1‐fluoro‐2‐nitro‐4‐(trifluoromethyl) benzene, the preparation of the amides was achieved via a three‐step sequence, namely nucleophilic aromatic substitution, reduction with SnCl2/HCl, and acylation reactions. The measurement of ferricyanide reduction by functionally intact spinach chloroplasts showed that several derivatives are capable of inhibiting the photosynthetic apparatus. The most active amides presented IC50 values close to 1 μmol L−1, and showed the presence of a 4‐bromophenyl group as a common structural feature. The addition of these brominated amides to the culture medium of a model cyanobacterial strain, Synechococcus elongatus PCC 6301, caused various degrees of growth inhibition. Theoretical studies (molecular modeling and quantitative structure–activity relationship) of all amides and their comparison with some known herbicides confirmed these experimental findings and provided more in‐depth information about the possible molecular target of these compounds. Trifluoromethyl amides herein described, which were shown to act at the PSII level, may represent a novel scaffold to be exploited aiming at the development of new active ingredients for weed control.Item Trifluoromethyl arylamides with antileukemia effect and intracellular inhibitory activity over serine/arginine-rich protein kinases (SRPKs)(European Journal of Medicinal Chemistry, 2017-03-31) Siqueira, Raoni Pais; Barros, Marcus Vinícius de Andrade; Barbosa, Éverton de Almeida Alves; Onofre, Thiago Souza; Gonçalves, Victor Hugo Sousa; Pereira, Higor Sette; Silva Júnior, Abelardo; Oliveira, Leandro Licursi de; Almeida, Márcia Rogéria; Fietto, Juliana Lopes Rangel; Teixeira, Róbson Ricardo; Bressan, Gustavo CostaThe serine/arginine-rich protein kinases (SRPKs) have frequently been found with altered activity in a number of cancers, suggesting they could serve as potential therapeutic targets in oncology. Here we describe the synthesis of a series of twenty-two trifluoromethyl arylamides based on the known SRPKs inhibitor N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340) and the evaluation of their antileukemia effects. Some derivatives presented superior cytotoxic effects against myeloid and lymphoid leukemia cell lines compared to SRPIN340. In particular, compounds 24, 30, and 36 presented IC50 values ranging between 6.0 and 35.7 μM. In addition, these three compounds were able to trigger apoptosis and autophagy, and to exhibit synergistic effects with the chemotherapeutic agent vincristine. Furthermore, compound 30 was more efficient than SRPIN340 in impairing the intracellular phosphorylation status of SR proteins as well as the expression of MAP2K1, MAP2K2, VEGF, and RON oncogenic isoforms. Therefore, novel compounds with increased intracellular effects against SRPK activity were obtained, contributing to medicinal chemistry efforts towards the development of new anticancer agents.