Synthesis of H-Lys-Lys-Gly-OH Tripeptide and Study of Its Acute Toxicity
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Pharmaceutical Chemistry Journal, Vol. 54, No. 9, December, 2020 (Russian Original Vol. 54, No. 9, September, 2020)
SYNTHESIS OF H-LYS-LYS-GLY-OH TRIPEPTIDE AND STUDY OF ITS ACUTE TOXICITY O. A. Popova,1 N. D. Bunyatyan,1,2 G. M. Bobizoda,3 M. Samiev,3 A. B. Prokof’ev,1,2 V. A. Evteev,1 and L. N. Sernov4 Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 54, No. 9, pp. 32 – 36, September, 2020.
Original article submitted August 5, 2020. Tripeptide H-Lys-Lys-Gly-OH was synthesized. Its toxic properties and biological activity were studied. The tripeptide was synthesized by extending the peptide chain from the C-terminus by synthesizing N2, N6-dicarbobenzoxylysine [N2,N6-(Cbz)2Lys] and N6-carbobenzoxylysine (N6-CbzLys) methyl ester hydrochloride and condensing them by the mixed anhydride method to produce the methyl ester of N2,N6-(Cbz)2Lys-N6-CbzLys. The next step in the tripeptide synthesis consisted of obtaining glycine benzyl ester (Gly-OBzl) hydrochloride and condensing it with N2,N6-(Cbz)2Lys-N6-CbzLys hydrazide to produce the protected target tripeptide Z-Lys(Z)-Lys-Gly-OBzl. The last step consisted of removing the protection using hydrogenolysis over Ni-Re catalyst. Test results showed that the synthesized tripeptide had low toxicity. Keywords: tripeptide, carbobenzoxy protection, glycine, mixed anhydride, catalytic hydrogenolysis, chromatography, synthesis.
of N6-Cbz-L-Lys via the azide and mixed anhydride methods. Various peptides of lysyllysine up to tetra-L-lysyl-Llysine were synthesized using these methods.
The present work focused on the development of a synthesis for a tripeptide containing the amino acids lysine (Lys) and glycine that could be used to improve protein metabolism in mammals. A synthesis of N6-Cbz-L-Lys via direct Cbz protection of the Cu complex of L-Lys was reported [1].
EXPERIMENTAL CHEMICAL PART The tripeptide was synthesized using L-amino acids. Chromatography used Silufol plates (75 × 25 mm) and solvent systems CHCl3–MeOH–HOAc (9:1:0.5, A), BuOH– Py–HOAc–H2O (5:5:1:4, B), and n-BuOH–H2O–HOAc (4:1:1, C).. Chromatograms were detected using ninhydrin solution (0.5%) in Me2CO and I2 vapor. Amines of bifunctional amino acids were protected temporarily using carbobenzoxy chloride (CbzCl) and methyl and benzyl esters. Peptide bonds were formed using mixed anhydride and azide methods. The free tripeptide was obtained via hydrogenolysis over a Ni catalyst. Lysine amines were protected by CbzCl by synthesizing (Cbz)2Lys from L-Lys hydrochloride dissolved in NaOH solution (2 N) and CbzCl (Schotten—Baumann method). N2,N6-(Cbz)2Lys. A solution of Lys·2HCl (10 g) was treated with NaOH solution (2 N, 68.4 mL) to produce the sodium salt of lysine, which was treated with a mixture of CbzCl (24 g) and a solution of NaOH (4 N, 56.8 mL) accord-
The Cu was removed from the Cbz-L-Lys complex via precipitation by H2S. A convenient method for preparing the methyl ester via direct esterification (25ºC, 12 h, 94% yield) was developed [2]. Peptides were obtained by us from esters 1
2 3 4
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