Synthesis of BDNF-mimetic dimeric dipeptide GSB-106, a potential neuroprotector drug

Abstract

The BDNF-mimetic dimeric dipeptide bis-(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide (GSB-106) based on the structure of beta-turn loop 4 (BDNF-Asp93-Ser94-Lys95-Lys96-) was synthesized. GSB-106 showed neuroprotective activity in vitro at concentrations 10–6-10–8 M and antidepressant activity in vivo in rats at i.p. injected doses of 0.1-1 mg/kg. The target peptide GSB-106 was obtained using three schemes in order to select the optimum synthetic pathway. The first scheme was based on the strategy of Boc/Z protecting groups using the method of pentafluorophenyl esters. The second scheme also used the Boc/Z strategy and the N-hydroxysuccinimide ester method. The third scheme used the Z/Boc strategy and the azide method. These three methods for synthesizing GSB-106 were compared with respect to yield and optical purity. The optimum result was obtained by using the third scheme that involved Z/Boc protecting groups and the azide method of peptide bond formation.