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Doctoral Thesis
DOI
10.11606/T.75.2017.tde-29092017-164524
Document
Author
Full name
Éverton Leandro de França Ferreira
Institute/School/College
Knowledge Area
Date of Defense
Published
São Carlos, 2017
Supervisor
Committee
Berlinck, Roberto Gomes de Souza (President)
Marsaioli, Anita Jocelyne
Silva, Dulce Helena Siqueira
Oliveira, Luciana Gonzaga de
Pupo, Monica Tallarico
Title in Portuguese
Estudo químico e de biossíntese de metabólitos secundários produzidos pelas linhagens fúngicas Roussoella sp. DLM33 e Annulohypoxylon moriforme MA9
Keywords in Portuguese
Annulohypoxylon moriforme
Roussoella sp.
Biossíntese
Planejamento experimental
Roussoellatídeo
Abstract in Portuguese
Microorganismos são uma excelente fonte de substâncias bioativas, porém muitas destas substâncias são biossintetizadas em baixas quantidades. A utilização de técnicas de planejamento experimental e de análise multivariada permite melhorar as condições de cultivo e incrementar a produção de metabolitos secundários. A linhagem fúngica Roussoella sp. DLM-33 produziu o composto roussoellatídeo (33) inédito na literatura com esqueleto de carbono novo. A utilização do planejamento fatorial fracionado e da metodologia multicritério permitiu incrementar a produção do composto roussoellatídeo (33), para investigar sua biossíntese utilizando precursores marcados com 13C. Experimentos de incorporação com precursores [1-13C]acetato de sódio, [1,2-13C]acetato de sódio e [metil-13C]metionina permitiu verificar que a biossíntese do composto (33) envolve dois rearranjos de Favorskii e uma ciclização de Diels-Alder intermolecular entre duas cadeias policetídicas independentes. Também, o estudo químico do meio de cultivo da linhagem Annulohypoxylon moriforme MA9, levou ao isolamento e identificação de dois compostos inéditos denominados por: (E)-3-benzilidenohexahidro-2-metilpirrolo[1,2-a]-pirazina-1,4-diona (36) e 4,7,9-trihidroxi-3-metoxi-2,3,6b,7-tetrahidro-1H-benzo[j]fluoranten-8-ona (53), e 10 compostos conhecidos: TCM-95A (43), TMC-95B (44), daidzeína (45), 5-hidroxi-3,4-dihidro-2H-naftalen-1-ona (46), 4,8-dihidroxi-3,4-dihidro-2H-naftalen-1-ona (47), 4-metoxi-1-naftalenol (48) e 3-benzil-hexahidro-pirrolo[1,2-a]-pirazina-1,4-diona (49), hypoxylonol C (50), hypoxylonol B (51) e hypoxylonol E (52). Os compostos 43 e 44 foram descobertos ainda quando presentes no extrato bruto de Annulohypoxylon moriforme MA9 por meio da co-cristalização do extrato com a enzima responsável pela atividade do proteassomo. Os dados obtidos por cristalografia de raio-X juntamente com os dados da literatura permitiram determinar suas estruturas químicas.
Title in English
Chemical study and study of the biosynthesis of secondary metabolites produced by fungal line Roussoela sp. DLM33 e Annulohypoxylon moriforme MA9
Keywords in English
Annulohypoxylon moriforme
Roussoella sp.
Biosynthesis
Experimental planning
Roussoellatide
Abstract in English
.Microorganisms are an excellent source of bioactive substances. However, most metabolites are biosynthesized in small amounts. The use of experimental design and multivariate analysis allows to improve the culture conditions and increase the production of secondary metabolites. The fungal strain Roussoella sp. DLM33 produced the roussoellatide (33), which is unprecedented and present a with novel carbon backbone chemical structure. Utilizing fractional factorial design and multicriteria analyses allowed us to increase the production of the roussoellatide (33) in order to investigate its biosynthesis using precursors labeled with 13C. Feeding experiments utilizing [1-13C]acetate, [1,2-13C]acetate, and [methyl-13C]methionine enabled us to verify that the biosynthesis 33 we postulate the involvement of two Favorskii rearrangements and one intermolecular Diels-Alder cyclization between two independent polyketide chains. Also, the chemical investigation of the culture medium of the strain Annulohypoxylon moriform MA9 led to the isolation and identification of two new compounds: (E)-3-benzylidenehexahydro-2-methylpyrrolo[1,2-a]pyrazine-4-dione (36) and 4,7,9-trihydroxy-3-methoxy-2,3,6b,7-tetrahydro-1H-benzo[j]fluoranenen-8-one (53), along with 10 compounds already known in the literature: TCM-95B (43), TMC-95A (44), daidzein (45), 5-hydroxy-3,4-dihydro-2H-naphthalen-1-one (46), 4,8-dihydroxy-3,4-dihydro-2H-naphthalen-1-one (47), 4-methoxy-1-naphthalenol (48) and 3-benzylhexahydro-pyrrolo [1,2-a]pyrazine-1,4-dione (49), hypoxylonol C (50), hypoxylonol B (51) and hypoxylonol E (52). Compounds 43 and 44 were discovered by the co-crystallization of the extract medium with the enzyme responsible for the proteasome activity. Data obtained by X-ray crystallography, NMR and MS analyses combined or data available in the literature allowed to determine their chemical structures.
 
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Publishing Date
2017-10-04
 
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