RESUMO
Liraglutide is a new generation lipopeptide drug used for the treatment of type II diabetes. In this work, we describe new approaches for its preparation fully by chemical methods. The key step of these strategies is the synthesis in solution of the Lys/γ-Glu building block, Fmoc-Lys-(Pal-γ-Glu-OtBu)-OH, in which Lys and Glu residues are linked through their side chains and γ-Glu is N(α) -palmitoylated. This dipeptide derivative is then inserted into the peptide sequence on solid phase. As liraglutide is obtained with great purity and high yield, our approach can be particularly attractive for an industrial production. We also report here the results of a circular dichroism conformational analysis in a membrane mimetic environment that offers new insights into the mechanism of action of liraglutide. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.
Assuntos
Hipoglicemiantes/síntese química , Lipopeptídeos/síntese química , Liraglutida/síntese química , Técnicas de Síntese em Fase Sólida/métodos , Sequência de Aminoácidos , Fluorenos/química , Ácido Glutâmico/química , Humanos , Lisina/química , Membranas Artificiais , Fosfatidilcolinas/química , Conformação Proteica , Dodecilsulfato de Sódio/química , Trifluoretanol/químicaRESUMO
INTRODUCTION: New low-cost strategies and enhancement of the already described methods to manufacture peptide molecules on an industrial scale are highly requested, particularly for peptides such as octreotide, which, along with goserelin and leuprolide, dominate the global peptide market. A number of patents related to the production of octreotide can be found, concerning both solution and solid-phase synthesis. Thus, there is a need to revise the existing synthetic approaches in order to organize them in a more comprehensible way. AREA COVERED: The octreotide patent landscape could help improvement of the methods for manufacturing of octreotide in industrial scale, leading to the appearance of innovative approaches. EXPERT OPINION: The pharmaceutical value of octreotide can be seen from its high market percentage among other peptide drugs. The complex chemical structure of octreotide represents the main challenge for its industrial production. Two synthetic steps are crucial in the preparation of octreotide: (i) threoninol attachment or on resin formation working in solid-phase and (ii) disulphide bond formation to achieve cyclic structure. Analysis of various patents filed to date allows us to see the trend in simplification of the synthetic approaches from the labor intensive syntheses in solution to the more versatile and rapid solid-phase methods.
Assuntos
Medicamentos Genéricos/síntese química , Octreotida/síntese química , Peptídeos/síntese química , Química Farmacêutica/métodos , Indústria Farmacêutica/métodos , Medicamentos Genéricos/química , Humanos , Octreotida/química , Patentes como Assunto , Peptídeos/químicaRESUMO
An efficient copper-catalyzed domino halogen exchange-cyanation procedure for aryl bromides was developed utilizing 10 mol % CuI, 20 mol % KI, 1.0 equiv of the inexpensive N,N'-dimethylethylenediamine as ligand, and 1.2 equiv of NaCN in toluene at 110 degrees C. The new method represents a significant improvement over the traditional Rosenmund-von Braun reaction: the reaction conditions are much milder, and the use of stoichiometric amounts of copper(I) cyanide and polar solvents is avoided; therefore the isolation and purification of the aromatic nitrile products is greatly simplified. In addition, the new method exhibits excellent functional group compatibility comparable to that of the analogous Pd-catalyzed cyanation methodology.
