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.).
Shevchenko et al. (2026) studied this question.