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. / 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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La chimie de clic est devenue indispensable dans les nombreux domaines de chimie associée à la conception de médicament. Dans ce contexte, comme nous savons(connaissons) l'étude concernant l'impact d'insertion triazole sur la conformation de peptaibol est limitée, nous avons conduit l'étude pour examiner l'impact et l'adaptabilité de 1, 1 4-disubstituted, 2, l'insertion 3-triazole dans peptaibols différent. Selon le résultat de cette expérience touchant à l'activité réduite et la conformation perturbée de l'analogue peptaibol, le substitut dipeptide décoré du fragment triazole portant substituents hydrophobe divers a été inséré à très N-ter la partie du peptaibol. L'amélioration du bioactivity et de la restauration de la conformation pour les analogues peptaibol a été observée et le fait a été aussi soutenu par les résultats obtenus de l'étude biophysique des analogues choisis d'ALM F50/5. Nous avons plus loin prolongé notre étude pour employer notre stratégie à être appliqué sur le peptide P42 thérapeutique qui souffre de la limitation de manque de perméabilité et de stabilité. Le peptide P42 est impliqué dans le pathophysiology de la maladie d'Huntington neurodégénératif. Un total de 12 analogues de peptide de P42-camelote a été synthétisé par SPPS par notre protocole optimize. Dans la deuxième partie, nous avons développé une stratégie pour synthétiser lipopeptide cyclique produit de l'espèce cynaobacterial marine. Notre objectif principal était de synthétiser Hormothamnin A, undecapeptide cyclique consistant de plusieurs acides aminés artificiels incluant dehydroamino acide (Dhaa) qui fait la synthèse de ce peptide compliqué. En raison de cette raison, premièrement, nous avons voulu appliquer notre stratégie de synthétiser Trichormamide A, une sorte relativement plus simple de cylic lipopeptide. Après l'accomplissement de cette tâche, une première tentative a été faite pour synthétiser Hormothamnin A. Le résultat préliminaire de ceci est présenté dans cette section. Enfin, nous avons essayé de développer une méthodologie robuste pour synthétiser Fmoc-Dhaa dans la phase de solution et son insertion dans l'ordre peptaibol par une norme(un standard) SPPS le protocole. Les résultats préliminaires que nous avons concernant la synthèse Dhaa et son insertion dans peptaibol sont aussi discutés ici de plus avec la synthèse de phase solide de Bergofungin naturel D. / The click chemistry has become indispensible in the many areas of chemistry associated with drug design. In this context, as we know the study concerning the impact of triazole insertion on the conformation of peptaibol is limited, we have conducted the study to investigate the impact and adaptability of the 1, 4-disubstituted 1, 2, 3-triazole insertion into different peptaibols. Depending on the outcome of this experiment relating to reduced activity and perturbed conformation of the peptaibol analogue, the dipeptide surrogate decorated with the triazole moiety bearing various hydrophobic substituents was inserted at the very N-ter part of the peptaibol. The improvement of the bioactivity and restoration of the conformation for the peptaibol analogues was observed and the fact was also supported by the results obtained from the biophysical study of the selected analogues of ALM F50/5. We have further extended our study to employ our strategy to be applied on the therapeutic P42 peptide which suffers from the limitation of lack of permeability and stability. P42 peptide is involved in the pathophysiology of neurodegenerative Huntington’s disease. A total of 12 analogues of P42-TAT peptide were synthesized through SPPS by our optimized protocol. In the second part, we have developed a strategy for synthesizing the cyclic lipopeptide originated from marine cynaobacterial species. Our main objective was to synthesize Hormothamnin A, a cyclic undecapeptide consisting of several unnatural amino acids including dehydroamino acid (Dhaa) which makes the synthesis of this peptide complicated. Due to this reason, firstly, we have chosen to apply our strategy to synthesize Trichormamide A, a relatively simpler kind of cylic lipopeptide. After accomplishing this task, a first attempt was made to synthesize Hormothamnin A. The preliminary result of this is presented in this section. At last, we have tried to develop a robust methodology to synthesize Fmoc-Dhaa in solution phase and its insertion into the peptaibol sequence through a standard SPPS protocol. The preliminary results we have got concerning the Dhaa synthesis and its insertion into peptaibol are also discussed here in addition with the solid phase synthesis of natural Bergofungin D

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