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Nor-β-lapachone has shown several biological properties. Regarding cytotoxic activity against cancer cell lines, it has been recognized as an important prototype. However, quinonoid drugs present a major challenge because of their toxicity. In this study, we evaluated the cytotoxicity and genetic toxicity of nor-β-lapachone in human lymphocytes and HL-60 leukemia cells and murine V79 fibroblasts, to shed some light on its selectivity toward cancer cells. As measured by MTT test, exposure of V79 cells to nor-β-lapachone resulted in a weak cytotoxicity (IC(50) = 13.41 μM), and at a concentration up to 21.9 μM, no cytotoxic effect was observed in lymphocytes, while in HL-60 cells, nor-β-lapachone elicited significantly greater cytotoxicity (IC(50) = 1.89 μM). Cultures coexposed to GSH-OEt showed an increased viability, which may indicate a neutralization of ROS generated by quinonoid treatment. In fact, only the highest concentrations of nor-β-lapachone (10 or 20 μM) caused an increase in oxidative stress in nontumor levels cells as measured by TBARS and nitrite/nitrate detection. This was accompanied by an alteration in intracellular thiol content. However, NAC pre-exposure restored the redox equilibrium of the cells and the concentration of thiol levels to control values. Nor-β-lapachone at 2.5 and 5 μM failed to induce DNA damage in nontumor cells, but at the highest concentrations tested, it induced single and double DNA strand breaks and increased the frequency of chromosomal aberrations. Interestingly, these damages were prevented by NAC pretreatment or exacerbated by prior exposure to the GSH-depleting agent 1-bromoheptane. In electrochemical experiments, nor-β-lapachone at the same concentrations as those used in genotoxic tests did not damage DNA directly, but at the highest concentration tested (200 μM), it caused a very weak DNA interaction. Corroborating electrochemical data, oxidative modifications of DNA bases were observed, as checked by DNA repair enzymes EndoIII and FPG, which reinforced the indirect actions caused by nor-β-lapachone through ROS generation and not via DNA intercalation. The DNA repair capacities were higher for nontumor cells than for leukemia cells, which may be related to the selective cytoxicity of nor-β-lapachone toward cancer cells. Our data suggest that ROS play an important role in nor-β-lapachone toxicity and that its DNA-damaging effect occurs only at concentrations several times higher than that needed for its antiproliferative effect on cancer cells.

In the first comprehensive biological assessment of the tambjamine class of marine alkaloids, synthetically derived samples of compounds 1-9 have been subjected to evaluation as antimicrobial agents and screened for their cytotoxic effects on various human cancer cell lines. Most were strongly active against the fungus Malassezia furfur (>amphotericin B) and showed considerable, but non-selective, antiproliferative activity against both human cancer and normal cell lines. Tambjamines I and J (6 and 7, resp.) displayed significant apoptosis-inducing effects.

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.

Although their exact role in controlling tumour growth and apoptosis in humans remains undefined, acridine and thiazolidine compounds have been shown to act as tumour suppressors in most cancers. Based on this finding, a series of novel hybrid 5-acridin-9-ylmethylene-3-benzyl-thiazolidine-2,4-diones were synthesised via N-alkylation and Michael reaction. The cell viability was analysed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and DNA interaction assays were performed using electrochemical techniques.

Submitted by Guilherme Lemeszenski (guilherme@nead.unesp.br) on 2013-08-22T18:52:39Z No. of bitstreams: 1 S0001-37652011000400024.pdf: 741344 bytes, checksum: 4a5a75ea1516a9d47a8cb41102df0a79 (MD5) Made available in DSpace on 2013-08-22T18:52:39Z (GMT). No. of bitstreams: 1 S0001-37652011000400024.pdf: 741344 bytes, checksum: 4a5a75ea1516a9d47a8cb41102df0a79 (MD5) Previous issue date: 2011-12-01 Made available in DSpace on 2013-09-30T18:08:00Z (GMT). No. of bitstreams: 2 S0001-37652011000400024.pdf: 741344 bytes, checksum: 4a5a75ea1516a9d47a8cb41102df0a79 (MD5) S0001-37652011000400024.pdf.txt: 48909 bytes, checksum: fc39ce4d8979b0cb1ba426b53ebc7658 (MD5) Previous issue date: 2011-12-01 Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-20T14:20:39Z No. of bitstreams: 2 S0001-37652011000400024.pdf: 741344 bytes, checksum: 4a5a75ea1516a9d47a8cb41102df0a79 (MD5) S0001-37652011000400024.pdf.txt: 48909 bytes, checksum: fc39ce4d8979b0cb1ba426b53ebc7658 (MD5) Made available in DSpace on 2014-05-20T14:20:40Z (GMT). No. of bitstreams: 2 S0001-37652011000400024.pdf: 741344 bytes, checksum: 4a5a75ea1516a9d47a8cb41102df0a79 (MD5) S0001-37652011000400024.pdf.txt: 48909 bytes, checksum: fc39ce4d8979b0cb1ba426b53ebc7658 (MD5) Previous issue date: 2011-12-01 Financiadora de Estudos e Projetos (FINEP) Banco do Nordeste do Brasil (BNB) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Usos populares e pesquisas científicas têm destacado a importância dos extratos da planta Casearia sylvestris e seu grande potencial bioativo. Neste trabalho, objetiva-se revisar as propriedades farmacológicas de C. sylvestris, enfatizando sua potencialidade antiulcerogênica, antiinflamatória, antiofídica e antitumoral. O extrato etanólico e o óleo essencial das folhas possuem atividade antiulcerogênica promissora, diminuindo o volume gástrico sem alterar o pH estomacal, corroborando sua aplicação contra dores gastrointestinais. Já os extratos aquosos das folhas têm atividade inibitória contra fosfolipase A2 presente em venenos de cobras, atenuando os efeitos lesivos sobre a musculatura esquelética resultantes da inoculação das toxinas. Essa ação antifosfolipásica provavelmente está relacionada ao seu uso como antiinflamatório, sugerindo um bloqueio análogo ao dos fármacos antiinflamatórios não-esteroidais na formação de mediadores oriundos do ácido araquidônico e na ativação da ciclooxigenase. Ensaios de fracionamento bioguiado dos extratos culminaram no isolamento e identificação de inúmeros metabólitos secundários, especialmente os diterpenos clerodânicos casearinas (A-X) e casearvestrinas (AC), compostos que têm surpreendido por sua ação citotóxica e antitumoral. Assim, a planta C. sylvestris apresenta um enorme arsenal farmacológico já mundialmente comprovado por seu vasto uso popular, estimulando pesquisas por novas moléculas e a busca pela compreensão de suas propriedades biológicas. Folk uses and scientific investigations have highlighted the importance of Casearia sylvestris extracts and their relevant bioactive potential. The aim of this work was to review the pharmacological properties of C. sylvestris, emphasizing its anti-ulcer, anti-inflammatory, anti-ophidian and antitumor potentialities. Ethanolic extracts and essential oil of their leaves have antiulcerogenic activity and reduce gastric volume without altering the stomach pH, which corroborates their consumption on gastrointestinal disorders. Leaf water extracts show phospholipase A2 inhibitory activity that prevents damage effects on the muscular tissue after toxin inoculation. This antiphospholipasic action is probably related to the use as an anti-inflammatory, proposing a pharmacological blockage similar to that obtained with non-steroidal anti-inflammatory drugs on arachidonic acid and cyclooxygenase pathways. Bioguided-assay fractionations lead to the identification of secondary metabolites, especially the clerodane diterpenes casearins (A-X) and casearvestrins (A-C), compounds with a remarkable cytotoxic and antitumor action. Therefore, the C. sylvestris shrub holds a known worldwide pharmacological arsenal by its extensive folk utilization, exciting searches for new molecules and a better comprehension about biological properties. Universidade Federal do Piauí (FUFPI) Campus Senador Helvídio Nunes de Barros Departamento de Ciências Biológicas Universidade Federal do Ceará (UFC) Faculdade de Medicina Departamento de Fisiologia e Farmacologia Universidade Estadual Paulista Instituto de Química Núcleo de Bioensaios, Biossíntese e Ecofisiologia de Produtos Naturais Universidade Estadual Paulista Faculdade de Ciências Farmacêuticas Departamento de Princípios Ativos Naturais e Toxicologia Universidade Estadual Paulista Instituto de Química Núcleo de Bioensaios, Biossíntese e Ecofisiologia de Produtos Naturais Universidade Estadual Paulista Faculdade de Ciências Farmacêuticas Departamento de Princípios Ativos Naturais e Toxicologia

Essential oil (EO) of Alpinia zerumbet leaves, at non-toxic concentrations (50-300 μg/mL), did not induce genotoxicity in human leukocytes. However, at the highest concentration (500 μg/mL) tested caused a reduction in cell proliferation and viability, and an increase in DNA damage. Moreover, in vivo experiments showed that EO (400 mg/kg) did not exert mutagenicity on peripheral blood cells and bone marrow in mice. In DPPH test, EO showed scavenging effects against DPPH radicals, and other free radicals (determination of intracellular GSH and lipid peroxidation assays). Furthermore, EO was able to reduce the intracellular levels of ROS, and prevented leukocytes DNA against oxidative damage. The ability of EO to reduce H(2)O(2) toxicity was observed only when cells were treated with EO during and after exposure to H(2)O(2). With the co- and post-treatment procedures, EO decreased the frequency of apoptotic and micronucleated leukocytes as well DNA strand breaks. However, a synergistic effect was observed in cultures exposed to 500 μg/mL EO. In conclusion, EO at concentrations up to 300 μg/mL or doses up to 400mg/kg are not mutagenic in leukocytes and in mice, but do have antioxidative and protective effects against the cytotoxicity and clastogenesis induced by H(2)O(2).

Several arylamino derivatives of nor-beta-lapachone were synthesized in moderate to high yields and found to show very potent cytotoxicity against six neoplastic cancer cells: SF-295 (central nervous system), HCT-8 (colon), MDAMB-435 (breast), HL-60 (leukaemia), PC-3 (prostate), and B-16 (murine melanoma), with IC(50) below 1 microg/mL. Their cytotoxicities were compared to doxorubicin and with their synthetic precursors, beta-lapachone and nor-beta-lapachone. The activity against a normal murine fibroblast L-929 showed that some of the compounds were selective against cancer cells. The absence of hemolytic activity (EC(50)>200 microg/mL), performed with erythrocyte suspensions, suggests that the cytotoxicity of the compounds was not related to membrane damage of mouse erythrocytes. For comparison purposes, one isomeric compound based on nor-alpha-lapachone was also synthesized and showed lower activity than the related ortho-derivative. The modified arylamino quinones appear as interesting new lead compounds in anti-cancer drug development.