Enantioselective Synthesis and Biological Evaluation of Proline

Mimetic of PLG based on (1R,3S)-2-azabicyclo[2.2.1]heptane

I. E. Sampaio-Dias1,2, D. Neves1, X. Garca-Mera2, J. E. Rodrguez-Borges1
1

CIQ-Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto,

Portugal
2
Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de
Compostela, Spain

Peptides biological importance is linked to its broad range of functions in living organisms acting as hormones, neurotransmitters or neuromodulators, with straight intervention on respiratory, reproductive and immunological systems.[1]
In recent decades, investigators deal with synthesizing structurally modified peptides in
order to improve the stability and biological activity of these compounds to obtain new
potential pharmaceuticals with improved pharmacokinetics and dynamics scores.[2]
This project aims the synthesis of new class of mimetic compounds for neuropeptide
PLG, L-prolyl-L-leucylglycinamide (Fig. 1), which perform important roles in central
nervous system. Therefore, it is proposed the synthesis of new class of tripeptide
structure-related to PLG containing proline mimetic derivative, P* (Fig. 1). This work
might make an enormous contribution to the discovery of new potential therapeutic
agents for the treatment of neurodegenerative diseases such Parkinson.
Summary:
a

Synthesis of enantiopure proline mimetic P* by precursors obtained through azaDiels-Alder reaction using ( )-8-phenylmenthol as chiral auxiliary to form the
desired single cycloadduct in the presence of cyclopentadiene: the methodology in
synthesizing this type of bicyclic compound is well known in our research group.[3]

Synthesis of dipeptide LG-NH2, L-leucylglycinamide (Fig. 1), through coupling reaction between the corresponding amino acids using TBTU as coupling reagent.

P*LG tripeptide synthesis by coupling the dipeptide LG-NH2 in b) with P* by the

same methodology of condensation. Biological evaluation of the tripeptide obtained
will be held at Faculty of Pharmacy, University of Santiago de Compostela, Spain.

Figure 1 From left to right: chemical structures of proline mimetic (P*), the dipeptide LGNH2, the natural PLG tripeptide and the desired PLG analogue (P*LG).

References:
[1] Fletcher, M. D.; Campbell, M. M. Chem. Rev. 1998, 98, 763-795.
[2] Trabochi, A.; Scarpi, D.; Guarna, A. Amino Acids 2008, 34, 1-24.
[3] Garca-Mera, X.; Rodrguez-Borges, J. E.; Vale, M. L. C.; Alves, M. J. Tetrahedron 2011,
67, 7162-7172.