Síntese de peptídeos lineares precursores dos alcalóides Condalina-A, Scutianina-M, Scutianina-L e Adouetina-Y: estudos estruturais e suas atividades biológicas

Abstract

This thesis describes the synthesis of a series of peptides precursors of cyclopeptide alkaloids Condaline-A, Scutianine-M, Scutianine-L e Adouetine-Y. Their antimicrobial activity was evaluated to conduct a study of their structure-activity relationships (SAR). In addition, we can evaluate their action against some enzymes involved in degenerative diseases of the central nervous system (CNS), as well as the antioxidant activity of these precursors. For the synthesis of these peptides, the non-proteinogenic amino acid b-Phenylserine was obtained in its diastereoisomeric forms (D, L-threo and D, L-erythro) and separated by recrystallization. The general strategy of synthesis employed the classical techniques of protection and deprotection of the amino acids with the usual coupling reagents to the peptide synthesis in solution, what enabled the construction of di-, tri-and tetrapeptides in pure forms. This strategy enabled the achievement of the tripeptides with the N-terminal, protected, free, N, N-dimethyl and N-methylated, with their structures confirmed by NMR experiments, and also for the dipeptide Z-L-Phe-L-threo-Pheser-OMe, and the tripeptide and N, N-(Me)2-LPhe- D-threo-Pheser-L-Ile-OMe, it was possible to obtain crystals that were analyzed by X-ray diffraction, in order to achieve structural confirmation and support in determining the stereochemistry. To study the SAR, the natural peptides and metabolites were subjected to analysis of their antimicrobial activity through the micro-dilution method using different microorganisms: two Gram-positive bacteria [Staphylococcus aureus, Staphylococcus epidermidis], three Gram-negative bacteria [Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae] and two fungi [Saccharomyces cerevisiae, Candida albicans]. Additionally, a screening was conducted with these compounds to identify some possible inhibitors of acetylcholinesterase (AChE), prolyl-oligopeptidase (POP) and dipeptidilpeptidase-IV (DPP-IV), as well as some compound capable of capture free radicals (antioxidant activity).