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Studies were made to elucidate the pathways involved in the synthesis of phenazine pigments produced by Pseudomanas species. Iodinin, phenazine-1-carboxylic acid, oxychlororaphine and pyocyanine, though structurally related, have different biosynthetic pathways. The following observations related to these studies constitute a contribution to knowledge. [...]

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Pseudomonas chlororaphis (aureofaciens) 30-84 is a biocontrol bacterium effective against take-all disease of wheat. Phenazine (PZ) production by strain 30-84 is the primary mechanism responsible for pathogen inhibition and the rhizosphere persistence of 30-84. The PhzR/PhzI system of strain 30-84 directly regulates PZ production and mutations in this QS system are defective in biofilm formation. Genetic complementation or direct addition of AHL signal restored biofilm formation to a phzI mutant. Mutations in PZ biosynthesis were equally defective in biofilm formation. Addition of PZ or genetic complementation of the PZ biosynthetic mutation restored biofilm formation. QS and PZ production also were involved in the establishment of populations on wheat seeds and plant roots. Presence of 10% wild type strain 30-84 in mixtures with QS or PZ mutants restored root colonization. These data demonstrate that QS and specifically PZ production are essential for biofilm formation by strain 30-84. This is a new role for PZs in the rhizosphere community.Strain 30-84 produces primarily phenazine-1-carboxylic acid (PCA) and 2-hydroxy-PCA (2-OH-PCA). We generated derivatives of strain 30-84 that produced the same total amount of PZs as the wild type but produced only PCA, or more efficiently converted PCA to 2-OH-PCA. These derivatives with altered PZ ratios differed from the wild type in initial attachment, biofilm architecture, and dispersal. Increased 2-OH-PCA production increased initial attachment, although both alterations resulted in thicker biofilms and reduced dispersal rates. Loss of 2-OH-PCA production resulted in a significant reduction in pathogen inhibition. My findings indicate that alterations in the endogenous ratios of PZs have wide-ranging effects on the biology of strain 30-84. I initiated studies to understand the mechanisms by which PZs affect surface attachment and biofilm development. Addition of PZs to metabolically inactivated cells improved adhesion compared to the inactive cells alone, suggesting that PZs may improve initial binding to surfaces. Results from whole genome transcription profiles of wild type strain 30-84 to a PZ mutant indicate that genes potentially involved in biofilm formation were up-regulated in the presence of PZs. These results provide initial evidence that PZs may modulate cell adhesion and biofilm formation via multiple mechanisms.

Phenazines and heterocyclic N-oxides have proven to be interesting classes of antitumoral as well as antibiotic agents . The natural product myxin (1-hydroxy-6-methoxyphenazine- N5, N10-dioxide) which belongs to both of these unique classes of molecules, has been found to cause bio-reductively activated, radical-mediated DNA strand cleavage via a de-oxygenative mechanism, making it a potential anti-tumoral as well as anti-bactierial candidate. In order to investigate as well as improve the bioactive properties of myxin, the following study was designed to synthesize glycosylated myxin analogs. A small catalog of these compounds were synthesized, some of them exhibiting comparable biological activity to that of myxin.

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This work aims the structural determination of phenazines compounds, and derivatives that present bioactivity for the treatment of malaria, using the X-ray diffraction method. Chapter 1 shows an introduction to pharmacologicol products and the importance of this structural resolution. Chapter 2 prejent the general characteristics of malaria in Brazil. Chapter 3 theoretical fundaments on the of X-ray diffraction technique, followed in chapter 4, by a description of the methods of crystallization and the steps of structural resolution. Finally, chapter 5, brings the discussion and results obtained in the structural resolution of four studed compounds. The studied phenazines composites were: 5,5-Dimetil-5,6-dihydro-7H- 4b,13-diazadibenzo[a,de]antracen-8-ona (FENA), 4-(3'-metil-but-2'-enil)-benzo[a]- fenazin-3-ona (FLA), cloro(dibenzo[a, c]fenazin-1-il-K2,C1, N14) piridinopaládio(II) (FENA-Pd), 8-bromine-7,7-dimethyl-5,10-dioxo-7,8,9,10- tetrahydro-5H-benzo[3,4 ] oxecino[5,6-b]quinoxaline-16-N-oxidates (FENA-Br). All the data collection had been obtained in on automatic KappaCCD diffractometer using MoKα monocromatic radiation, of wave length of 0.71073 Å (molybdenum). The compound called FENA crystallize in the monoclinic system and belongs to space group P21/a, with net parameters a = 7.1442(2) Å, b = 12.5463(3) Å, c = 17.1835(4) Å, β = 95.520(1) Å, with a volume, V = 1533.07(7) Å3. The calculation of the density, assuming Z = 4 molecules for unit cell, resulted in a value of 1.242 g.cm -3. The compound called FLA, crystallize in the monoclinic system and belongs to the space group C 2/c, with cell parameters of a = 21.0180(1)Å, b = 9.1359(3) Å, c = 17.7772(9) Å, β = 109.402(2), with a volume, V = 3219.70(24) Å 3. The calculation of the density, assuming Z = 8 molecules for unit cell, resulted in a value of 1.297 g.cm -3. The compound called FENA-Pd crystallize in the Monoclinic system, belongs to the space group P21/a, with parameters of a = 12.0413(4), b = 13.4986(6), c = 12.3869(5) Å, β = 106.074(2), V = 1934.6(1) Å3. The calculation of the density, assuming Z = 4 molecules for unit cell, resulted in a value of 1.72/g.cm-3 for the density of the crystal. The compound called FENA-Br, crystallize in the orthorombic system and belongs to the space group P 21 21 21, with cell parameters of a = 6.2552(1) Å, b = 14.6703(3) Å, c = 20.5061(5) Å, calculated density 1.558 g.cm -3, assuming Z = 4. / Fundação de Amparo a Pesquisa do Estado de Alagoas / O presente trabalho objetiva a determinação estrutural de compostos fenazínicos e derivados, que apresentam bioatividade para o tratamento da malária, empregando o método de difração de Raios X. No capítulo 1 tem-se uma introdução aos produtos de interesse farmacológicos e a importância da resolução estrutural. O capítulo 2 apresenta as características gerais sobre a malária no mundo e no Brasil. O capitulo 3 baseia-se em uma fundamentação teórica sobre a técnica de difração de Raios X, seguido, no capítulo 4, da descrição sobre os métodos de recristalização e as etapas de resolução estrutural por difração de Raios X. Por último, o capítulo 5, traz os resultados e discussões obtidos na resolução dos quatro compostos em estudo. Os compostos fenazínicos estudados neste trabalho foram: 5,5-Dimetil- 5,6-dihydro-7H-4b,13-diazadibenzo[a,de]antracen-8-ona (FENA), 4-(3 -metil-but-2 - enil)-benzo[a]-fenazin-3-ona (FLA), cloro(dibenzo[a,c]fenazin-1-il-K2,C1,N14) piridinopaládio(II) (FENA-Pd), 8-bromo-7,7-dimetil-5,10-dioxo-7,8,9,10- tetrahidro-5H-benzo[3,4]oxecino[5,6-b]quinoxalino-16-N-oxido (FENA-Br). Todos os dados das intensidades difratadas foram obtidos num difratômetro automático KappaCCD, utilizando radiação monocromatizada por um cristal de grafite, de comprimento de onda igual a 0,71073 Å (molibdênio). O composto denominado como FENA, cristaliza no sistema monoclínico e pertence ao grupo espacial P21/a, com parâmetros de rede, a = 7,1442(2) Å, b = 12,5463(3) Å, c = 17,1835(4) Å, β = 95,5200(10) Å, com um volume, V= 1533,07(7) Å 3. O cálculo da densidade supondo Z = 4 moléculas por cela unitária resultou num valor de 1,242 g.cm-3. O composto denominado como FLA, cristaliza no sistema monoclínico e o grupo espacial C2/c, com parâmetros de rede, a = 21,0180(1) Å, b = 9,1359(3) Å, c = 17,7772(9) Å, β = 109,402(2)°, com um volume, V= 3219,70(24) Å 3. O cálculo da densidade supondo Z = 8 moléculas por cela unitária resultou num valor de 1,297 g.cm-3. O composto denominado como FENA-Pd cristaliza no sistema cristalino Monoclínico, pertencente ao grupo espacial P21/a, com parâmetros de rede a = 12,0413(4), b =13,4986(6), c =12,3869(5) Å, β = 90°, V = 1934,66(12) Å3. O cálculo da densidade supondo Z = 4 moléculas por cela unitária resultou num valor de 1,72g.cm-3 para a densidade do cristal. O composto denominado como FENA-Br, cristaliza no sistema ortorrômbico sendo seu grupo espacial P 212121, com parâmetros de rede a = 6,25520(10) Å, b = 14,6703(3) Å , c = 20,506(5) Å , e densidade calculada de 1,558 g.cm-3, supondo Z = 4.

In general, natural and synthetic phenazines have attracted much attention because of their biological activities, like antitumour agents antimalarials, antibiotics, among others. The natural phenazines are isolated as secondary metabolites of terrestrial and marine microorganisms, mainly of Pseudomonas spp. and Streptomyces spp. This work aiming the structural determination of phenazinics compounds, derivatives that present bioactivity for the treatment of malaria and tuberculosis, using the X-ray diffraction method. The phenazinics compounds had been: (Fena-3244): 14b-Chloro-4amethoxy- 3,3-dimethyl-2,3,4a,14b-tetrahydro-1H-benzo[a]-pyrano[2,3-c]phenazine, (Fena-3243): 1,5-Dioxa-3-dimethyl-benzo[g ]oxanane[e -b]quinoxaline (Fena- 3279): 2,5,5-Trimethyl-benzo[c]-cyclohexan[c ]pyran[e ,a]phenazine (Fena- 3245): 1-allyl2-oxa-10-hydro-2H, 10H-benzo[c]phenazine. All the data collection had been obtained in one automatic KappaCCD, diffractometer using monocromatizada radiation for a graphite crystal, of wave length of 0.71073 Å (molybdenum). The compound Fena-3244 crystallize in the Monoclinic system and belongs to space group P121/n1, with cell parameters a =15.5498 (6) Å, b = 6.97000 (10) Å, c = 17.4872 (7) Å, β = 92.488 (2) Å, with a volume, V = 1893.51 (11) Å3. The compound Fena-3243, crystallize in the Monoclinic system and belongs to the space group P121/C1, with cell parameters of a = 8.3700 (5) Å, b = 11.5120 (9) Å, c = 18.5370 (10) Å, β = 110.223 (4)°, with a volume, V= 1676.03 (19) Å 3. The compound Fena-3279, crystallize in the crystalline system Triclinic, belongs to the space group P - 1, with parameters of a = 10.9810 (4), b = 12.6080 (7), c =16.0080 (6) Å, α = 88.449 (3)°, β = 71.118 (2)°, γ = 87.203 (2)°, V = 1047.18 (8) Å3 . The compound Fena-3245, crystallize in the Triclinic system and belongs to the space group P - 1, with cell parameters of a = 9.4880 (5) Å, b= 17.7650 (13) Å , c= 18.0760 (12) Å , V= 2818.4 (3) Å3 . The results for the compound Fena-3244 and Fena-3243 confirmed their proposed structures for different spectroscopic techniques (NMR, Utraviolet). The results for Fena-3279 show the existing doubts about the aromaticity of ring C. For Fena-3245 revealed the discrepancy structural model of the proposed model as compared to the functional binder group in C5. There were also certain all possible interactions of hydrogen in the bundling of crystalline molecules, allowing them to be established their respective arrangements. / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Em geral, fenazinas naturais e sintéticas têm atraído muita atenção devido às suas atividades biológicas interessantes, como agentes antitumorais antimaláricos, antibióticos entre outros. As fenazinas naturais são isoladas como metabólitos secundários de microorganismos terrestres e marinhos, principalmente de Pseudomonas spp. e Streptomyces spp. O presente trabalho tem por objetivo a determinação das estruturas cristalinas e moleculares de 4 compostos fenazínicos derivados do Lapachol, que apresentam bioatividade para o tratamento da tuberculose e da malária, empregando o método de difração de raios X. Os compostos fenazínicos estudados neste trabalho foram: (Fena-3244): 14b-Cloro-4a-metoxi-3,3-dimetil-2,3,4a,14b-tetrahidro-1H-benzo[a]-pirano [2,3- c]fenazina (Fena-3243): 1,5-Dioxa-3-dimetil-benzo[g ]oxanana[e -b]quinoxalina (Fena-3279): 2,5,5-Trimetil-benzo[c]-ciclohexano[c ]piran[e ,a]fenazina (Fena- 3245): 1-allil-2-oxa-10-hidro-2H, 10H-benzo[c]fenazina.Todos os dados das intensidades difratadas foram obtidos num difratômetro automático KappaCCD, utilizando radiação monocromatizada por um cristal de grafite, de comprimento de onda igual a 0,71073 Å (molibdênio). O composto (Fena-3244) cristaliza no sistema monoclínico e grupo espacial P121/n1, tendo como parâmetros de rede: a = 15,5498(6) Å, b = 6,9700(10) Å, c = 17,4872(7) Å, β = 92,488(2)° e um volume, V= 1893,51(11) Å 3. O composto (Fena-3243) cristaliza no sistema monoclínico e grupo espacial P121/c1, tendo como parâmetros de rede: a = 8,3700(5) Å, b = 11,5120(9) Å, c = 18,5370(10) Å, β = 110,223(4)°, com um volume, V= 1676,03(19) Å 3. O composto (Fena-3279) cristaliza no sistema triclínico e grupo espacial P-1, tendo como parâmetros de rede: a = 10,9810(4) Å, b = 12,6080(7) Å, c = 16,0080(6) Å, α= 88,45(3)°, β = 71,118(2)°, γ = 87,203(2)° com um volume, V= 1047,18(8) Å 3. O composto (Fena-3245) cristaliza no sistema triclínico e grupo espacial P-1, tendo como parâmetros de rede: a = 9,4880(5) Å, b = 17,7650(13) Å, c = 18,0760(12) Å, α= 112,321(3)°, β = 90,267(4)°, γ = 90,077(4)° com um volume, V= 2818,4(3) Å 3. Os resultados obtidos para os compostos Fena-3244, Fena-3243 confirmaram as respectivas estruturas propostas por diferentes técnicas espectroscópicas (RMN, Utravioleta). Os resultados para Fena-3279 elucidaram a duvida existente quanto à aromaticidade do anel C. Para Fena-3245 evidenciaram a discordância do modelo estrutural comparado ao modelo proposto quanto ao grupo funcional ligante em C5. Foram determinadas também todas as possíveis interações de hidrogênio nos empacotamentos cristalinos das moléculas, permitindo que fossem estabelecidos os seus respectivos arranjos.

Please read the abstract in the section 00front of this document / Thesis (PhD)--University of Pretoria, 2010. / Immunology / unrestricted