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Synthesis of diketopiperazines in view of biological interest

Grant number: 05/01482-2
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): October 01, 2005
Effective date (End): May 31, 2007
Field of knowledge:Health Sciences - Pharmacy
Principal researcher:Ivone Carvalho
Grantee:Maristela Braga Martins Teixeira
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

2,5-diketopiperazines are cyclic dipeptides, found in various natural products. Diverse biological activities of these compounds have been described, amongst which there are: inhibition of PAI-1 (plasminogen activator inhibitor-1); antitumor and antimicrobial activity; inhibition of alpha-glucosidase and glycogen phosphorylase enzymes; action on GABA and 5HT receptors. Although the majority of the biologically active diketopiperazines has been isolated from natural products, synthetic routes make it possible to obtain great diversity of analogs. Solid phase synthesis is the most employed one, even though intramolecular reaction of dipeptides is also observed in solution, sometimes as a parallel product of reactions involving aminoacids. In this work, it is proposed the synthesis of 2,5-diketopiperazines in solution through cyclization of dipeptides, which will be prepared by the combination of various natural aminoacids. Peptide bonds and cyclizations will be controlled by protecting the aminoacids’ reactive groups, and desprotecting them in a regiosselective fashion. The coupling and cyclization reactions will be carried through in sequence, since the selective desprotection of N-Fmoc of the coupled product should lead to spontaneous cyclization. The obtained products will be analyzed by NMR, IR and HPLC, and submitted to assays in order to verify possible biological activities: inhibition of glucosidases; antimicrobial, antiinflamatory and trypanocidal activities; influence in signal transduction by measuring PKA and PKC enzymes activities.

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