Nucleobase derivatives as building blocks to borm Ru(II)-based complexes with high cytotoxicity.

Two new Ru(II)-based complexes containing 2-thiouracil derivatives, known as 2-thiouracil (2TU) and 6-methyl-2-thiouracil (6m2TU), were synthesized using cis,trans-[RuCl2(PPh3)2(bipy)] as a precursor. The obtained compounds with a general formula trans-[Ru(2TU)(PPh3)2(bipy)]PF6 (1) and trans-[Ru(6m2TU)(PPh3)2(bipy)]PF6 (2) were characterized by analytical techniques such as NMR, UV?vis, and IR spectroscopies, elementary analysis, mass spectrometry, and single-crystal X-ray diffraction. Moreover, the investigation of the complexes?DNA interaction were carried out using spectrophotometric titrations and showed that the complexes present a weak interaction with this biomolecule. The compounds were evaluated against HL-60, K-562, HepG2, and B16-F10 cancer cells and against noncancer cells (PBMCs). The results of the biological assay revealed that complex 2 is more promising than complex 1. Finally, the present study suggests that complexes 1 and 2 causes cell death by apoptosis, significantly increasing the percentage of apoptotic HL-60 cells, in which the compounds altered the cell cycle, reducing the cells in G1/G0, G2/M, and S phases

Chemical composition, larvicidal and cytotoxic activity of Annona salzmannii (Annonaceae) seed oil

The seed oil of Annona salzmannii A. DC. was analyzed by GC-MS and 1 H qNMR, revealing a mixture of unsaturated (80.5%) and saturated (18.7%) fatty acids. Linoleic (45.3%) and oleic (33.5%) acid were the major unsaturated fatty acids identified, while palmitic acid (14.3%) was the major saturated fatty acid. The larvicidal effects of A. salzmannii seed oil were evaluated against third-instar larvae of Aedes aegypti (Linn.). The oil exhibited moderate larvicidal activity, with aLC50 of 569.77 ppm (95% CI = 408.11 to 825.88 ppm). However, when the cytotoxic effects of the oil were evaluated, no expressive antiproliferative effects were observed in tumor cell lines B16-F10 (mouse melanoma), HepG2 (human hepatocellular carcinoma), K562 (human chronic myelocytic leukemia), HL-60 (human promyelocytic leukemia), and non-tumor cell line PBMC (peripheral blood mononuclear cells), with IC50 values > 50 μg·mL-1. This is the first study to evaluate the chemical composition, larvicidal and cytotoxic activity of A. salzmannii seed oil

Qualidade fisiológica de sementes de Ocimum selloi benth: sob condições de luz, temperatura e tempo de armazenamento Physiological quality of Ocimum selloi Benth: seeds under conditions of light, temperature and storage time

O atroveran ou elixir-paregórico (Ocimum selloi Benth.) é uma espécie aromática nativa do Brasil, produtora de óleo essencial rico em metil-chavicol. Neste trabalho, objetivou-se avaliar a influência da temperatura, luz e tempo de armazenamento em diferentes ambientes sobre a germinação e o vigor de sementes de O. selloi. Inicialmente, testou-se o efeito da presença e ausência de luz branca sob fotoperíodo de 12 horas para determinar o fotoblastismo das sementes em diferentes temperaturas (20, 25, 30 e 35ºC). Em seguida, testou-se a germinação e emergência no armazenamento sob duas temperaturas (ambiente e câmara fria) aos 0, 2, 4, 6, 8 10 e 12 meses de armazenamento. A espécie foi classificada como fotoblástica neutra, apresentando germinação em ampla faixa de temperatura (20 a 30ºC). A germinação das sementes manteve-se por doze meses de armazenamento em câmara fria e à temperatura ambiente, entretanto, o vigor decresce a partir de seis meses em armazenamento sob temperatura ambiente."Atroveran" or "elixir-paregórico" (Ocimum selloi Benth.) is a Brazilian species that produces an essential oil rich in methyl chavicol. This work aimed to evaluate the influence of light, temperature and time of storage in different environments on the germination and vigor of O. selloi seeds. We initially tested the influence of presence and absence of white light in a 12-hour photoperiod to determine the photoblastism of the seeds under different temperatures (20, 25, 30 and 35ºC). The physiological quality of seeds conserved under two temperatures (room temperature and cold chamber) was tested at 0, 2, 4, 6, 8 10 and 12 months of storage. The species was classified as neutral photoblastic with germination at a wide temperature range (20ºC-30°C). Germination was maintained for twelve months of storage in cold chamber at room temperature, but the vigor was reduced in seeds kept at room temperature after the sixth month of storage

ent-Kaurane diterpenes from the stem bark of Annona vepretorum (Annonaceae) and cytotoxic evaluation.

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2015-05-19T19:20:02Z No. of bitstreams: 1 Dutra LM ant-kaurane diterpenes.pdf: 499055 bytes, checksum: 997b925a2d8b2fbcc92a1bb4c34cbb80 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2015-05-19T19:36:45Z (GMT) No. of bitstreams: 1 Dutra LM ant-kaurane diterpenes.pdf: 499055 bytes, checksum: 997b925a2d8b2fbcc92a1bb4c34cbb80 (MD5)Made available in DSpace on 2015-05-19T19:36:45Z (GMT). No. of bitstreams: 1 Dutra LM ant-kaurane diterpenes.pdf: 499055 bytes, checksum: 997b925a2d8b2fbcc92a1bb4c34cbb80 (MD5) Previous issue date: 2014Federal University of Sergipe. Department of Chemistry. São Cristóvão, SE, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilHospital São Rafael. Center of Biotechnology and Cell Therapy. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Hospital São Rafael. Center of Biotechnology and Cell Therapy. Salvador, BA, BrasilHospital São Rafael. Center of Biotechnology and Cell Therapy. Salvador, BA, BrasilFederal University of Sergipe. Department of Chemistry. Itabaiana, SE, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilThis work describes a novel ent-kaurane diterpene, ent-3ß-hydroxy-kaur-16-en-19-al along with five known ent-kaurane diterpenes, ent-3ß,19-dihydroxy-kaur-16-eno, ent-3ß-hydroxy-kaur-16-eno, ent-3ß-acetoxy-kaur-16-eno, ent-3ß-hydroxy-kaurenoic acid and kaurenoic acid, as well as caryophyllene oxide, humulene epoxide II, ß-sitosterol, stigmasterol and campesterol from the stem bark of Annona vepretorum Mart. (Annonaceae). Cytotoxic activities towards tumor B16-F10, HepG2, K562 and HL60 and non-tumor PBMC cell lines were evaluated for ent-kaurane diterpenes. Among them, ent-3ß-hydroxy-kaur-16-en-19-al was the most active compound with higher cytotoxic effect over K562 cell line (IC50 of 2.49 µg/mL) and lower over B16-F10 cell line (IC50 of 21.02 µg/mL)

Ru(II) complexes containing uracil nucleobase analogs with cytotoxicity against tumor cells.

We report on chemistry and cytotoxic studies of four new ruthenium (II) complexes containing uracil derivatives. All compounds are neutral, presenting the formula [Ru(PPh3)2(2TU)2] (1), [Ru(PPh3)2(6m2TU)2] (2), [Ru(dppb)(2TU)2] (3) and [Ru(dppb)(6m2TU)2] (4), where PPh3?=?triphenylphosphine; dppb?=?1,4-bis(diphenylphosphino)butane, 2TU?=?2-thiouracil and 6m2TU?=?6-methyl-2-thiouracil. They were characterized using NMR, UV?vis and IR spectroscopies, microanalytical analysis and mass spectrometry. Furthermore, the crystal structures of 1?4 were determined by single-crystal X-ray diffraction. The coordination of 2-thiouracil derivatives with ruthenium increases regions able to carry out hydrogen bonds with the biological targets, such as DNA. We evaluated the interaction of the complexes with DNA by UV/Vis spectrophotometric titration, and as a result, the values of DNA-binding constants are in the range of 0.8?1.8???104?M?1. Moreover, the interaction of the complexes with BSA was investigated. In vitro, activities against B16-F10 (mouse melanoma), HepG2 (human hepatocellular carcinoma), HL-60 (human promyelocytic leukemia) and K562 (human chronic myelocytic leukemia) and non-tumor cells: PBMC (human peripheral blood mononuclear cells activated with concanavalin A ? human lymphoblast) were carried out. Cytotoxicity assays revealed that complexes (2) and (4) present biological activity against tumor cells comparable with oxaliplatin, the reference platinum drug, revealing that they are promising molecules for developing new antitumor compounds

Ruthenium(II) complexes with 6-methyl-2-thiouracil selectively reduce cell proliferation, cause DNA double-strand break and trigger caspase-mediated apoptosis through JNK/p38 pathways in human acute promyelocytic leukemia cells

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2019-10-08T14:08:30Z No. of bitstreams: 1 Bomfim M, l. Ruthenium (II).pdf: 5950873 bytes, checksum: 69b76d29b685a484dd9c71691535be5e (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2019-10-08T14:32:30Z (GMT) No. of bitstreams: 1 Bomfim M, l. Ruthenium (II).pdf: 5950873 bytes, checksum: 69b76d29b685a484dd9c71691535be5e (MD5)Made available in DSpace on 2019-10-08T14:32:30Z (GMT). No. of bitstreams: 1 Bomfim M, l. Ruthenium (II).pdf: 5950873 bytes, checksum: 69b76d29b685a484dd9c71691535be5e (MD5) Previous issue date: 2019-01-07Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Federal University of Bahia. Institute of Health Sciences. Department of Biomorphology. Salvador, BA, Brazil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Federal University of Ouro Preto. Department of Chemistry. Ouro Preto, MG, Brazil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Federal University of São Carlos. Department of Chemistry. São Carlos, SP, Brazil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Ruthenium(II) complexes with 6-methyl-2-thiouracil cis-[Ru(6m2tu)2(PPh3)2] (1) and [Ru(6m2tu)2(dppb)] (2) (where PPh3 = triphenylphosphine; dppb = 1,4-bis(diphenylphosphino)butane; and 6m2tu = 6-methyl-2-thiouracil) are potent cytotoxic agents and able to bind DNA. The aim of this study was to evaluate in vitro cellular underlying mechanism and in vivo effectiveness of these ruthenium(II) complexes in human acute promyelocytic leukemia HL-60 cells. Both complexes displayed potent and selective cytotoxicity in myeloid leukemia cell lines, and were detected into HL-60 cells. Reduction of the cell proliferation and augmented phosphatidylserine externalization, caspase-3, -8 and -9 activation and loss of mitochondrial transmembrane potential were observed in HL-60 cells treated with both complexes. Cotreatment with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, reduced Ru(II) complexes-induced apoptosis. In addition, both metal complexes induced phosphorylation of histone H2AX (S139), JNK2 (T183/Y185) and p38α (T180/Y182), and cotreatment with JNK/SAPK and p38 MAPK inhibitors reduced complexes-induced apoptosis, indicating DNA double-strand break and activation of caspase-mediated apoptosis through JNK/p38 pathways. Complex 1 also reduced HL-60 cell growth in xenograft model. Overall, the outcome indicated the ruthenium(II) complexes with 6-methyl-2-thiouracil as a novel promising antileukemic drug candidates

Ru(II)?thyminate complexes : new metallodrug candidates against tumor cells.

Herein, we used thymine (HThy) as a ligand to form two new ruthenium(II) complexes with formula [Ru(PPh3)2(Thy)(bipy)]PF6 (1) and [Ru(Thy)(bipy)(dppb)]PF6 (2). The complexes were characterized by spectroscopic, spectrometric and X-ray crystallography analyses. Complexes 1 and 2 can interact with ctDNA presenting binding constants, Kb, of 0.4 and 1.2 ? 103 M?1, respectively. Their cytotoxic activities towards tumor cell lines (B16-F10, HepG2, K562 and HL-60) and non-tumor cells (PBMCs) were evaluated using the Alamar blue assay. Complex 1 exhibits high cytotoxicity against tumor cells, showing IC50 values of 0.01 and 1.81 ?M against the HL-60 and HepG2 cell lines, respectively. Therefore, compound 1 can be considered as a promising antitumor metallodrug

Antitumor Properties of the Essential Oil From the Leaves of Duguetia gardneriana.

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2015-07-10T12:11:59Z No. of bitstreams: 1 Rodrigues ACBC Antitumor....pdf: 142853 bytes, checksum: db7ecf9b40d453b0b76d913201aa845d (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2015-07-10T13:39:36Z (GMT) No. of bitstreams: 1 Rodrigues ACBC Antitumor....pdf: 142853 bytes, checksum: db7ecf9b40d453b0b76d913201aa845d (MD5)Made available in DSpace on 2015-07-10T13:39:36Z (GMT). No. of bitstreams: 1 Rodrigues ACBC Antitumor....pdf: 142853 bytes, checksum: db7ecf9b40d453b0b76d913201aa845d (MD5) Previous issue date: 2015Fundação 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, BrasilFederal University of Sergipe. Department of Chemistry. São Cristovão, SE, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, BrasilFederal University of Sergipe. Department of Biology. São Cristovão, SE, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Departamento de Propedêutica. Salvador, BA, BrasilFederal University of Amazonas. Department of Chemistry. Manaus, AM, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilDuguetia gardneriana, popularly known in the Brazilian northeast as “jaquinha”, is a species belonging to the family Annonaceae. The aim of this work was to assess the chemical composition and antitumor properties of the essential oil from the leaves of D. gardneriana in experimental models. The chemical composition of the essential oil was analyzed via gas chromatography-flame ionization detector and gas chromatography-mass spectrometry. In vitro cytotoxic activity was determined in cultured tumor cells, and in vivo antitumor activity was assessed in B16-F10-bearing mice. The identified compounds were β-bisabolene (80.99%), elemicin (8.04%), germacrene D (4.15%), and cyperene (2.82%). The essential oil exhibited a cytotoxic effect, with IC50 values of 16.89, 19.16, 13.08, and 19.33 μg/mL being obtained for B16-F10, HepG2, HL-60, and K562 cell lines, respectively. On the other hand, β-bisabolene was inactive in all of the tested tumor cell lines (showing IC50 values greater than 25 μg/ mL). The in vivo analysis revealed tumor growth inhibition rates of 5.37–37.52% at doses of 40 and 80mg/kg/day, respectively. Herein, the essential oil from the leaves of D. gardneriana presented β-bisabolene as the major constituent and showed cytotoxic and antitumor potential

Ruthenium Complexes Containing Heterocyclic Thioamidates Trigger Caspase-Mediated Apoptosis Through MAPK Signaling in Human Hepatocellular Carcinoma Cells

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2019-08-12T11:56:33Z No. of bitstreams: 1 Neves, P. S. Ruthenium.pdf: 14036538 bytes, checksum: 79f785f779926c39ce5fc9242f9ee9a8 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2019-08-12T12:18:54Z (GMT) No. of bitstreams: 1 Neves, P. S. Ruthenium.pdf: 14036538 bytes, checksum: 79f785f779926c39ce5fc9242f9ee9a8 (MD5)Made available in DSpace on 2019-08-12T12:18:54Z (GMT). No. of bitstreams: 1 Neves, P. S. Ruthenium.pdf: 14036538 bytes, checksum: 79f785f779926c39ce5fc9242f9ee9a8 (MD5) Previous issue date: 2019Brazilian agencies Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB), and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP).Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Federal University of São Carlos. Department of Chemistry. São Carlos, SP, Brazil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Federal University of Bahia. Institute of Health Sciences. Department of Biomorphology. Salvador, BA, Brazil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Federal University of São Carlos. Department of Chemistry. São Carlos, SP, Brazil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Herein, ruthenium complexes containing heterocyclic thioamidates [Ru(mmi)(bipy)(dppb)]PF6 (1), [Ru(tzdt)(bipy)(dppb)]PF6 (2), [Ru(dmp)(bipy)(dppb)]PF6 (3) and [Ru(mpca)(bipy)(dppb)]PF6 (4) were investigated for their cellular and molecular effects in cancer cell lines. Complexes 1 and 2 were the most potent of the four compounds against a panel of different cancer cell lines in monolayer cultures and showed potent cytotoxicity in a 3D model of multicellular spheroids that formed from human hepatocellular carcinoma HepG2 cells. In addition, both complexes were able to bind to DNA in a calf thymus DNA model. Compared to the controls, a reduction in cell proliferation, phosphatidylserine externalization, internucleosomal DNA fragmentation, and the loss of the mitochondrial transmembrane potential were observed in HepG2 cells that were treated with these complexes. Additionally, coincubation with a pan-caspase inhibitor (Z-VAD(OMe)-FMK) reduced the levels of apoptosis that were induced by these compounds compared to those in the negative controls, indicating that cell death through apoptosis occurred via a caspase-dependent pathway. Moreover, these complexes also induced the phosphorylation of ERK1/2, and coincubation with an MEK inhibitor (U0126), which is known to inhibit the activation of ERK1/2, but not JNK/SAPK and p38 MAPK inhibitors, reduced the complexes-induced apoptosis compared to that in the negative controls, indicating that the induction of apoptotic cell death occurred through ERK1/2 signaling in HepG2 cells. On the other hand, no increase in oxidative stress was observed in HepG2 cells treated with the complexes, and the complexes-induced apoptosis was not reduced with coincubation with the antioxidant N-acetylcysteine or a p53 inhibitor compared to that in the negative controls, indicating that apoptosis occurred via oxidative stress- and p53-independent pathways. Finally, these complexes also reduced the growth of HepG2 cells that were engrafted in C.B-17 SCID mice compared to that in the negative controls. These results indicated that these complexes are novel anticancer drug candidates for liver cancer treatment