The synthesis of new phosphonopeptidomimetics and their effect on the functional cardiac output

E. R. Abdurakhmanova, N. O. Dorofeyeva, O. I. Lukashuk, O. V. Holovchenko, V. S. Brovarets


The article presents the synthesis of new phosphorylated peptidomimetics, and the biological activity of the compounds synthesized has been assessed for the fi rst time on the experimental animals – male rats. On the basis of a diethyl ester of 1-benzoylamino-2,2,2-trihloroethylphosphonic acids a novel derivative of 1,3-oxazol-4-phosphonic acid diethyl ester containing the residue of methylaminoethan-1-ol in position 5 of the oxazole ring has been synthesized. The optimal conditions for cleavage of the 1,3-oxazole ring in the acidic medium with formation of phosphorylated peptidomimetics have been found. Thus, when treating it with 85 % aqueous trifl uoroacetic acid a diethyl ester of {benzoylamino[(2-ydroxyethyl)carbamoyl]methyl} phosphonic acid has been obtained, and  the action of hydrogen chloride under anhydrous conditions gives a diethyl ester of {benzoylamino[(2-chloroethyl) carbamoyl]methyl} phosphonic acid. The method developed is very convenient and preparative because reactions proceed in mild conditions without formation of undesirable by-products. Moreover, peptidomimetics are isolated with high yields, and their isolation does not require chromatography. Monitoring of different functional parameters of cardiac hemodynamics was performed in rats in vivo using a microcatheter and the Millar Pressure-Volume System. The study of the effect of the compounds obtained on the cardiac output has shown that their intraperitoneal introduction results in the heart rate decrease and stimulation of the contractile activity of the myocardium.


heart; contractility; 4-phosphorylated 5-amino-1,3-oxazoles; phosphonopeptidomimetics; amino alcohols


Global status report on noncommunicable diseases 2014. Geneva, World Health Organization, 2014.

Hughes A. B. Amino acids, peptides and proteins in organic chemistry, Wiley-VCH, Weinheim, 2009, pp.189.

Umezawa H., Aoyagi T., Suda H., Hamada M. Bestatin, an inhibitor of aminopeptidase b, produced by actinomycetes. The Journal of Antibiotics, 1976, Vol. 29, pp.97-99.

Suda H., Takita T., Aoyagi T., Umezawa H. The structure of bestatin. The Journal of Antibiotics, 1976, Vol. 29, pp.100-101.

Nakamyra H., Suda H., Takita T., Aoyagi T., Umezawa H. X-ray structure determination of (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoic acid, a nev amino acid component of bestatin. The Journal of Antibiotics, 1976, Vol. 29, pp.102-103. doi:10.7164/antibiotics.29.102.

Pearson W. H., Hines J. V. Synthesis of beta-amino-alpha-hydroxy acids via aldol condensation of a chiral glycolate enolate. A synthesis of bestatin. The Journal of Organic Chemistry, 1989, Vol. 54, pp.4235-4237. doi:10.1021/jo00278a050.

Guenard D., Gueritte-Voegelein F., Potier P. Taxol and taxotere: discovery, chemistry, and structure-activity relationships. Accounts of Chemical Research, 1993, Vol. 26, pp.160-167. doi:10.1021/ar00028a005.

Kingston D. G. Taxol, a molecule for all seasons. Chemical Communications, 2001, pp.867-880. doi:10.1039/B100070P.

Lukashuk O. I., Abdurakhmanova E. R., Kondratyuk K. M., Golovchenko O. V., Khokhlov K. V., Brovarets V. S., Kukhar V. P. Introduction of chiral 2-(aminoalkyl) substituents into 5-amino-1,3-oxazol-4-ylphosphonic acid derivatives and their use in phosphonodipeptide synthesis. RSC Advances, 2015, Vol. 5, pp.11198-11206. doi: 10.1039/C4RA13819H.

Kondratyuk K., Lukashuk O., Golovchenko A., Komarov I., Brovarets V., Kukhar V. Synthesis of 5-amino-2-aminoalkyl-1,3-oxazol-4-ylphosphonic acid derivatives and their use in the preparation of phosphorylated eptidomimetics. Tetrahedron, 2013, Vol. 69, pp.6251-6261. doi:10.1016/j.tet.2013.05.017.

Lukashuk O., Kondratyuk K., Golovchenko A., Brovarets V., Kukhar V. A Novel Synthetic Approach to Phosphorylated Peptidomimetics. Heteroatom Chemistry, 2013, Vol. 24. pp.289-297. doi: 10.1002/hc.21093.

Drach B. S., Sviridov E. P. Zhurnal obshchey khimii, 1974, Vol. 2, No.44, pp.348-352.

Kobyakov G. L. Farmateka, 2003, Vol. 14, pp.11-18.

Dorofeieva N. O., Kuzmenko M. O., Sahach V. F. Fiziolohichnyi zhurnal, 2012, No.4, pp.44-51

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