Designing and synthesis of a new dimeric dipeptide mimetic of the 4th loop of neurotrophin-3 bis-(N-monoglutaryl-L-asparaginyl-Lasparagine) hexamethidenediamide and its D,D-stereoisomer

Introduction. Neurotrophin-3 (NT-3), like other proteins of the neurotrophin family, plays an important role in maintaining the homeostasis of the nervous system, and disorders of its signaling are associated with a wide range of neurological and psychiatric diseases. It is possible to overcome the limitations of the clinical use of NT-3 (low bioavailability, risk of side effects) by creating pharmacologically suitable low molecular weight mimetics.

Purpose. To design and synthesize a new potential dipeptide mimetic of the 4th loop of NT-3 hexamethylenediamide <i>bis-(N</i>-monoglutaryl-L-asparaginyl-L-asparagine), and to synthesize its enantiomer, in order to study their biological activity and identify its specificity.

Materials and methods. The compounds were obtained by classical peptide synthesis methods in solution using the Boc strategy of protective groups and the method of activated pentafluorophenyl esters. The structure and diastereomeric purity of the target peptides and intermediates were established using one-dimensional ¹Н, ¹³С and two-dimensional NMR spectroscopy. Chromatographic homogeneity was determined using TLC and RP HPLC. The target dipeptides were characterized by the specific optical rotation angle ([α]_D).

Results. A seven-step synthesis scheme for the L,L- and D,D-enantiomers of hexamethylenediamide bis-(N-monoglutaryl-asparaginyl-asparagine) (GTS-304LL, GTS-304DD) was proposed. The target dipeptides were obtained using this scheme with an overall yield of 37–38 % and a chromatographic purity of 97–99 %.

Conclusions. New substituted asparagine-containing dipeptides, potential neurotrophin-3 mimetics, were obtained. The compounds were characterized for further study of their biological activity.

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