Synthesis of GK-2, a Dimeric Dipeptide Nerve Growth Factor Mimetic and Potential Neuroprotective Agent

A series of dipeptide mimetics of nerve growth factor were synthesized, one of which, bis-(monosuccinyl-Lglutamyl-L-lysine) hexamethylenediamide (GK-2), constructed on the basis of the beta-turn of its fourth loop, was selected for development as a potential neuroprotective drug. This study describes the first phase in the creation of a technology for producing GK-2 - selection of the optimum synthesis scheme. Two nine-stage synthesis schemes were assessed, consisting of lengthening the peptide chain from the N or C terminal. Condensation in both cases was performed using N-hydroxysuccinimide esters. Both schemes yielded product with identical optical and diastereomeric purity, not requiring complex purification and involving similar time input, though the scheme growing the peptide chain from the C terminal was 1.2 times more economical in terms of reagent costs per kg of product and was selected as the main method for developing the laboratory methodology.