Синтез димерного дипептидного миметика фактора роста нервов гк-2, потенциального нейропротективного препарата
Abstract
A series of dimeric dipeptide mimetics of nerve growth factor (NGF) was obtained. One of these, bis-(N-monosuccinyl-L-glutamyl-L-lysine) hexamethylenediamine (GK-2), designed on the basis of loop 4 beta-turn structure, was selected for development of a new potential neuroprotective drug. The paper describes the first stage of the GK-2 synthesis technology development – selection of the optimum synthetic scheme. Two nine-step schemes of synthesis, consisting in extension of the peptide chain from N- or C-terminal were considered. Condensation in both cases was carried out using N-hydroxysuccinimide esters. In the first case, Z (Bzl) groups were used for the protection of side functions. For the C-terminal carboxyl protection, salification was used. In the second scheme, Z/Boc strategy of protecting groups was used. For the first scheme, hexamethylenediamine was attached at the final stage, and in the second scheme – at the first stage. Both schemes have resulted in a product with the same optical and diastereomeric purity, did not require complex purification methods, and took approximately equal times. The method with peptide chain building from C-terminal proved to ensure 1.2 times lower cost of basic reagents per kilogram product and was selected as the basis for the development of laboratory regulations.
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