FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico / FundaÃÃo de Amparo à Pesquisa do Estado do Cearà / As quinonas representam uma das mais importantes classes de compostos utilizados na clÃnica oncolÃgica, suas molÃculas sÃo de ocorrÃncia natural e distribuem-se em trÃs grupos (antraquinonas, benzoquinonas e naftoquinonas). Neste trabalho foi estudado a atividade citotÃxica e mecanismos de aÃÃo anticÃncer de um composto pertencente ao grupo benzoquinona, denominado FR42 (benz[g]isoquinolina-5,10-diona) em cÃlulas de glioblastoma humano (SF-295). Primeiramente realizou-se o ensaio de citotoxicidade em um painel de 4 linhagens de cÃlulas cancerÃgenas, sendo que a FR42 apresentou elevada toxicidade para todas as cÃlulas cancerÃgenas testadas, exibiu IC50 entre 1,70-2,45 μM. Com relaÃÃo ao ensaio de citotoxicidade realizado em cÃlulas normais, mostrou IC50 entre 12,18-23,27 μM, houve ligeira seletividade para cÃlulas cancerÃgenas. Estudos em citometria de fluxo realizados em cÃlulas SF-295 sugerem que o composto FR42 na maior concentraÃÃo testada, induz morte celular por apoptose, evidenciado pela fragmentaÃÃo do DNA e despolarizaÃÃo da membrana mitocondrial. O composto FR42 na menor concentraÃÃo testada 2 μM apresentou interferÃncia no ciclo celular, promovendo acÃmulo de cÃlulas na fase G2/M. Os resultados indicam que o composto FR42 possui notÃvel toxicidade para cÃlulas tumorais. / Quinones represent one of the most important classes of compounds used in clinical oncology, and they are natural products easily found in the nature. They have been distributed in three groups (anthraquinones, benzoquinones and naphthoquinones). This study investigated the cytotoxic activity and anticancer mechanism of action of a compound belonging to the benzoquinone group, called FR42 (benz [g] isoquinoline-5 ,10-dione) in human glioblastoma cells (SF-295). First of all, it was performed the cytotoxicity assay on a panel of four cancer cell lines, and the FR42 showed high toxicity to all cancer cells tested, exhibited IC50 between 1.70 to 2.45 mM. In order to the cytotoxicity assay performed on normal cells showed IC50 between 12.18 to 23.27 mM, there was a slight selectivity for tumor cells. Flow cytometry studies performed in SF-295 cells has been suggested that the compound FR42 in the highest concentration tested, induced cell death by apoptosis as evidenced by DNA fragmentation and depolarization of the mitochondrial membrane. FR42 lowest concentration tested (2 mM) presented interference in the cell cycle promoting arresting of cells in G2 / M. The results has been indicated the a notable toxicity from FR42 in cancer cells lines.

Este trabalho apresenta as estruturas determinadas por difração de raio X de dois compostos naftoquinônicos, 3,4-diidro-[2,2-dimetil]-2H-nafto[1,2-b]pirano-5,6-diona (β-lapachona) e dimetil-1,4-naftoquinona. A estrutura cristalina destes compostos mostrou que estes são estabilizados por ligações de hidrogênio do tipo C-H...O, formando estruturas supramoleculares. Dos compostos derivados da β-lapachona, os naftoimidazóis têm-se mostrado muito ativos contra o T. cruzi, agente causador da doença de Chagas. Partindo das estruturas modeladas de 29 compostos naftoimidazólicos, propriedades eletrônicas, geométricas e topológicas foram calculadas para análise estatística por mínimos quadrados parciais (PLS). Após a análise e redução das variáveis foram selecionados os descritores Morp17p, X4a, piPC09, RDF065v, BELp6, RDF060p, R4u, RDF035m e RCI que foram utilizados para a construção um modelo de regressão com o método de PLS. Para o modelo, o menor erro de validação foi obtido com 3 fatores e os coeficientes de correlação R= 0,71 e Q= 0,82. O estudo de docking de alguns compostos naftoquinônicos e naftoimidazólicos mostrou que, do ponto de vista energético e de complementaridade química, estes compostos possuem pouca probabilidade de se ligarem no sítio ativo da tripanotiona redutase (TR), uma enzima essencial para o metabolismo do T. cruzi, bem como no sítio ativo da enzima humana glutationa redutase (GR), homóloga a TR. Há, no entanto, uma tendência geral destes compostos se ligarem no sítio da interface, sobretudo, de se ligarem neste sítio da enzima humana. / This work presents the structure determined by X-ray analyses for two naphthoquinone compounds 3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6- dione and dimethyl-1,4-naphthoquinone. The crystal packing of these compounds showed the existence of intermolecular hydrogen bonds of the type CH...0. These intermolecular forces are responsible for the self-assembly in three-dimensional supramolecular structure. A set of 29 naphthoimidazoles, derived from β-lapachone, that has shown activity against T. cruzi, the agent of Chagas disease, were modeled. From these structures electronic, geometric, topological, etc, properties were calculated to be used in the investigation by statistic analysis, using the partial least squares method (PLS). After reduction of the number of variables, the best PLS model found was the one obtained with the following variables: Morp17p, X4a, piPC09, RDF065v, BELp6, RDF060p, R4u, RDF035m and RCI. For the PLS model, the lower error of validation was obtained using 3 factors with the coefficients R=0.71 and Q=0.82. Two sets of compounds, naphtoquinones and naphthoimidazoles, were studied by docking method. The results showed that, for both, naphtoquinones and naphthoimidazoles and both trypanothione and glutathione reductase, the compounds have low probability to bind in the active site, and are more likely to bind in the interface site, especially in the interface site of the human protein.

This project forms part of a collaborative effort between the marine natural products chemists at Rhodes University and the medical biochemists at the University of Cape Town’s School of Medicine. Our UCT collaborators tested the cytotoxicity of a group of toluhydroquinones and toluquinones (9-15) against the oesophageal cancer cell line WHCO1 and revealed that the triprenylated toluhydroquinone 11 and it’s oxidised analogue 12 were the most active. This thesis presents an investigation into the role of the polyprenyl side-chain in the cytotoxicity of compound 11 and it’s oxidised analogue 12 by synthesizing and testing the cytotoxicity of simplified analogues of this compound. The synthesis of the two ortho-prenylated toluhydroquinone analogues 5-methyl-2-[(2'E,6'E)-3',7' -dimethyl-2',6'-octadienyl]-1,4-benzenediol (19) and 5-methyl-2-[(2'E,6'E)-3',7',11'-trimethyl-2',6',10'-dodecatrienyl]-1,4-benzenediol (21) and their two ortho-prenylated toluquinone analogues, 5-methyl-2-[(2'E,6'E)-3',7'-dimethyl-2',6'-octadienyl]-2,5-cyclohexadiene-1,4-dione (20) and 5-methyl-2-[(2'E,6'E)-3',7',11'-trimethyl-2',6',10'-dodecatrienyl]-2,5-cyclohexadiene-1,4-dione (22) is described. Our initial attempts to couple geranyl bromide, farnesyl bromide and farnesal to the aromatic precursors m-cresol and 1,4-dimethoxy-2-methylbenzene using directed ortho-prenylation and phenoxide carbon-alkylation were unsuccessful. The four target analogues were eventually synthesized via the initial metal halogen exchange reaction between 1-bromo-2,5-dimethoxy-4-methylbenzene and geranyl bromide/farnesyl bromide using n-BuLi and TMEDA in ditheyl ether at 0 °C to yield 92 and 104 respectively in moderate yield. The demethylation of both compounds preceded smoothly using AgO giving the target analogues 20 and 22 in good yield (approx. 90 %). The reduction of quinones 20 and 22 with sodium dithionite gave 19 and 21 in quantitative yield. The synthesis reported here is the first regioselective synthesis of these compounds. The anti-oesophageal cancer activity of 19-22 and two commercially available non-prenylated analogues 17 and 18 were tested against WHCO1. The conclusion drawn from the anti-oesophageal cancer study was that the polyprenyl side-chain plays a negligable role in the cytotoxicity of compounds such as 11 and 9 against the oesophageal cancer cell line WHCO1.

A series of analogous reactions employing as a nucleus I-phenylazimidoquinone has been investigated.

No description available.

No description available.

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第21137号 / 農博第2263号 / 新制||農||1057(附属図書館) / 学位論文||H30||N5111(農学部図書室) / 京都大学大学院農学研究科応用生命科学専攻 / (主査)教授 三芳 秀人, 教授 宮川 恒, 教授 加納 健司 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

The research presented in this study demonstrates the critical role that organic synthesis plays in natural product chemistry. The biological activity demonstrated by 2-methyl-6-(3-methyl-2- butenyl)benzo-1,4-quinone prompted an investigation into the synthesis of this compound. This natural product showed significant activity against Staphylococcus epidermidis. Therefore the aim of this study was to synthesise 2-methyl-6-(3-methyl-2-butenyl)benzo-1,4- quinone and structural analogues. The regioselective synthetic route formulated for the synthesis of 2-methyl-6-(3-methyl-2- butenyl)benzo-1,4-quinone involved five steps. Different strategies towards the synthesis of this compound were investigated. The regioselective C-alkylation step was proving to be the most challenging. The synthetic strategies investigated included carbon alkylation of a phenoxide, directed-o-metallation, metal-halogen exchange and copper(II) Grignard-type metal halogen exchange. Problems were encountered with regioselectivity when carbon alkylation of a phenoxide was employed for the o-prenylation of o-cresol. The C-prenylated isomer was formed along with the O-prenylated isomer. When the reaction temperature was lowered, the yield of the desired C-prenylated isomer improved, whereas the yield of O-prenylated isomer declined. Although the reaction was performed under different conditions, the formation of the O-prenylated isomer could not be prevented. Therefore, another synthetic strategy was considered. The directed-o-metallation reaction was subsequently employed because of the associated regioselectivity. Unfortunately the desired product was not obtained when this method was employed. The reaction was attempted using different conditions, but the product could not be isolated. Since the directed-o-metallation protocol did not yield the desired results, another method was considered. Therefore, a metal-halogen exchange reaction was employed. The metal-halogen exchange transformation was preceded by the preparation of the o-brominated precursor. Regioselectivity-related problems were initially encountered during the synthesis of the obrominated precursor. The o-brominated isomer was formed in a 1:1 ratio with the pbrominated isomer. Further investigation led to a synthetic protocol that afforded the desired o-brominated isomer in a better yield. The metal-halogen exchange transformation was subsequently attempted, but the product was obtained in an unsatisfactory yield. Therefore, another method was employed in an effort to achieve regioselective C-alkylation with a better yield. Copper(II) Grignard-type metal-halogen exchange was successfully employed to achieve regioselective C-alkylation in good yield. The subsequent step was the deprotection, although problems were encountered, it was eventually achieved. The final step was the oxidation to obtain the desired compound, 2-methyl-6-(3-methyl-2-butenyl)benzo-1,4- quinone. The same procedure was successfully applied in the synthesis of structural analogues 2-isopentyl-6-methylbenzo-1,4-quinone, 2-(3,7-dimethylocta-2,6-dienyl)-6-methyl-1,4- benzoquinone and 2-(3,7-dimethyl-octyl)-6-methyl-1,4-benzoquinone. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2010.

by Chi-Ching Mak. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1993. / Includes bibliographical references (leaves 65-70). / Acknowledgement --- p.i / Abbreviation --- p.ii / List of spectra --- p.iii / Contents --- p.iv / Abstract --- p.v / Chapter Part One: --- "Synthesis of Poly substituted-1,4-Quinones" / Chapter 1.1 --- Introduction / Chapter 1.2 --- Results and discussion --- p.9-16 / Chapter 1.3 --- Conclusion --- p.17 / Chapter Part Two: --- Synthesis of Allylsilanes / Chapter 2.1 --- Introduction --- p.18-25 / Chapter 2.2 --- Results and discussion --- p.26-34 / Chapter 2.3 --- Conclusion --- p.35 / Experimental Section --- p.36-64 / References --- p.65-70 / Spectra --- p.71-86

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1981. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND SCIENCE. / Includes bibliographical references. / by John Wesley Frost. / Ph.D.