Synthesis and Study of Enzymatic Stability of Phosphinic Pseudo-Pro-Gly-Tripeptide Derivatives of Dopamine and Serotonin

Objective: Expanding the range of biologically active compounds is a necessary direction in determining drug candidates. Methods: Condensation of the phosphinic acid structural isomer Pro-(POOH)-Gly and biogenic amines dopamine and serotonin into one molecule was carried out by forming a classical peptide bond. Phosphine tripeptide compounds Pro-(POOH)-Gly-DA and Pro-(POOH)-Gly-5-HT in a free water-soluble form were synthesized. A modification of the previously published procedure made it possible to obtain the N,P-protected building block Z-Pro-(POOAd)-Gly-OH, which was then converted into Z-Pro-(POOAd)-Gly-Su with an activated carboxyl moiety. The latter was condensed with dopamine and serotonin. The free compounds Pro-(POOH)-Gly-DA and Pro-(POOH)-Gly-5-HT were obtained by removal of the N-Cbz group by catalytic hydrogenation and removal of the adamantyl ether group with trifluoroacetic acid. Results and Discussion: The synthesis was carried out and it was found that the free compounds Pro-(POOH)-Gly-DA and Pro-(POOH)-Gly-5-HT are enzymatically stable in the presence of proline endopeptidase, leucine aminopeptidase, carboxypeptidase Y and B, therefore, can be considered as hybrid compounds that increase the stability of biogenic amines. In addition, during the hydrolysis of Pro-(POOH)-Gly-DA and Pro-(POOH)-Gly-5-HT compounds in vivo, the formed phosphinic acid analogue of Pro-Gly may be useful in the treatment of a number of pathologies. Conclusions: Hybrid compounds consisting of a phosphine dipeptide and DA or 5-HT have been obtained for the first time. The stability of these compounds in the presence of amino- and carboxypeptidases has been determined. Therefore, they can be considered as candidates for medicines to prevent or slow down the development of various pathologies (Parkinson’s disease, depression, etc.).