Phosphonic Acid Analogs of Fluorophenylalanines as Inhibitors of Human and Porcine Aminopeptidases N: Validation of the Importance of the Substitution of the Aromatic Ring

Weronika Wanat (1) , Michał Talma (1) , Błażej Dziuk (1) , Jean-Luc Pirat (2) , Paweł Kafarski (1)

1 Department of bioorganic chemistry
2 ICGM - Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier

A library of phosphonic acid analogs of phenylalanine substituted with fluorine, chlorine and trifluoromethyl moieties on the aromatic ring was synthesized and evaluated for inhibitory activity against human (hAPN) and porcine (pAPN) aminopeptidases. Fluorogenic screening indicated that these analogs are micromolar or submicromolar inhibitors, both enzymes being more active against hAPN. In order to better understand the mode of the action of the most active compounds, molecular modeling was used. It confirmed that aminophosphonic portion of the enzyme is bound nearly identically in the case of all the studied compounds, whereas the difference in activity results from the placement of aromatic side chain of an inhibitor. Interestingly, both enantiomers of the individual compounds are usually bound quite similarly.

Mots clés: fluorine; phosphonic acid analogs; human and porcine aminopeptidase; molecular modeling; inhibitors

Domaines: Chimie thérapeutique; Chimie organique

Weronika Wanat, Michał Talma, Błażej Dziuk, Jean-Luc Pirat, Paweł Kafarski. Phosphonic Acid Analogs of Fluorophenylalanines as Inhibitors of Human and Porcine Aminopeptidases N: Validation of the Importance of the Substitution of the Aromatic Ring. Biomolecules, 2020, 10 (4), pp.579. ⟨10.3390/biom10040579⟩. ⟨hal-02864301⟩