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Doctoral Thesis
DOI
10.11606/T.75.2019.tde-14012019-105941
Document
Author
Full name
Ariane Fernandes Bertonha
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Carlos, 2018
Supervisor
Committee
Berlinck, Roberto Gomes de Souza (President)
Guido, Rafael Victório Carvalho
Montanari, Carlos Alberto
Pilli, Ronaldo Aloise
Pupo, Monica Tallarico
Title in Portuguese
Isolamento, síntese de análogos e estudo da relação estrutura atividade de metabólitos secundários
Keywords in Portuguese
agelastatina A
malária
peptaibóis
pseudoceratidina
Abstract in Portuguese

Metabólitos secundários de organismos vivos constituem uma fonte promissora para a descoberta de compostos biologicamente ativos, em particular para o tratamento de doenças como câncer, malária e doenças infecciosas. O capítulo 1 desta tese descreve a síntese e a avaliação da relação estrutura versus atividade de análogos da pseudoceratidina. A pseudoceratidina e sete de seus análogos apresentaram boa atividade contra P. falciparum, cepa 3D7, sensível à cloroquina. Os análogos apresentaram alto índice de seletividade, sugerindo que pequenas modificações estruturais exercem influência na redução da citotoxicidade. A pseudoceratidina também apresentou atividade antiplasmodial contra linhagens resistentes de P. falciparum, cepa K1 (IC50 = 1,1 0,1 μM), com um mecanismo de ação rápido. Outro metabólito secundário de destaque é o alcaloide citotóxico, agelastatina A. No capítulo 2 é descrita a síntese racêmica do esqueleto central ABC da 7-hidroxi agelastatina A. O sistema tricíclico de 5, 6 e 5 membros foi obtido em 4 etapas e com rendimento global de 8% a partir de reagentes comerciais. O capítulo 3 descreve o isolamento de peptaibóis produzidos pelo fungo Hypocrea sp., oriundo da Antártica. Foram isolados seis peptaibóis: a trichogina GA IV, os isômeros AT1M3I-4 e AT1M3I-5, a AT1M3I-3, de esqueleto semelhante à trikoningina KB, a trichokonina VI e a trichokonina VIII. Foram realizados estudos estruturais completos destes peptídeos de massa moecular maior do que 800 Da, inclusive estudos conformacionais por dicroísmo circular. A trichokonina VI e a trichokonina VIII foram ativas contra bactérias Gram-positivas, linhagens de células cancerígenas (MCF-7, MCF-10A, ACP01, HELA e A549) e contra o parasita P. falciparum, cepa 3D7, com IC50 de 0,61 ± 0,17 e 0,53 ± 0,19 μM, respectivamente.

Title in English
Isolation, synthesis of analogues and structure activity relationship studies of bioactive secondary metabolites
Keywords in English
agelastatin A
malária
peptaibol
pseudoceratidine
Abstract in English
Secondary metabolites of living organisms constitute a promising source for the discovery of biologically active compounds, in particular for the treatment of diseases such as cancer, malaria and infectious diseases. Chapter 1 of this thesis describes the synthesis and the evaluation of the structure versus activity relationship of pseudoceratidine analogs. Pseudoceratidine and seven of its analogues showed good activity against P. falciparum, strain 3D7, sensitive to chloroquine. Synthetic analogues showed a high selectivity index, suggesting that small structural modifications influence the reduction of cytotoxicity. Pseudoceratidine also showed antiplasmodial activity against resistant strains of P. falciparum, strain K1 (IC50 = 1.1 ± 0.1 μM), with a fast-acting mechanism. Another important secondary metabolite is the cytotoxic alkaloid, agelastatin A. In Chapter 2 the racemic synthesis of the central ABC core of 7-hydroxy agelastatin A is reported. The tricyclic ring system of 5, 6 and 5 membered was obtained in 4 steps and with an overall yield of 8% from commercial reagents. Chapter 3 describes the isolation of peptaibols produced by the fungus Hypocrea sp., from Antarctica. Six peptaibols have been isolated: trichogin GA IV, isomers AT1M3I-4 and AT1M3I-5, AT1M3I-3, with a similar skeleton to trikoningin KB, trichokonin VI and trichokonin VIII. A complete structural investigation of these peptides has been performed, including conformational analyses by circular dichroism spectroscopy. These peptides have a molecular weight higher than 800 Da. Trichokonin VI and trichokonin VIII were active against Gram-positive bacteria, cancer cells lines (MCF-7, MCF-10A, ACP01, HELA and A549) and against P. falciparum, strain 3D7, with an IC50 of 0.61 ± 0, 17 and 0.53 ± 0.19 μM, respectively.
 
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Publishing Date
2019-01-17
 
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