Diastereoselective synthesis and biological evaluation of new fluorine-containing α-aminophosphonates as anticancer agents and scaffold to human urokinase plasminogen activator inhibitors.

Phosphonate analogues of α-amino acids are increasingly valued for their significant potential in medicinal chemistry. Fluorine is a "magic" element that plays a huge role in modulating the properties of organic compounds. In this work, we combined the two pharmacophores in the synthesis of three series of new α-aminophosphonates. These compounds were obtained by diastereoselective hydrophosphonylation of imines prepared by an environmentally friendly mechanochemical approach. Results of computational SwissADME analysis suggested favorable drug-like properties of the α-aminophosphonates and indicated their potential for interaction with diverse biological targets including proteases, showing promising pharmacokinetic profiles compared to 5-fluoro-2′-deoxyuridine (FdU) used as a standard anticancer drug. Screening against ten cancer cell lines from seven types of cancer showed that five of the twenty compounds tested (1c , 2a , 2h , 3e , and 3f) exhibited superior activity against the HeLa cell line and lower cytotoxicity against normal MRC-5 cells than FdU. Compound 3e showed notable inhibitory effect on the MDA-MB-231 cell line, while 3a , 3h , and 3g demonstrated significant cytotoxic activity against U-87 MG and U-251 MG lines. Molecular docking highlighted the strong binding of compound 2a to the urokinase-type plasminogen activator (uPA) protein, with a binding affinity of −6.41 kcal/mol, suggesting the anti-metastatic potential of the compound. These findings enable to position the newly synthesized α-aminophosphonates as promising scaffolds for developing targeted anticancer therapies for metastatic cancers characterized by elevated uPA expression. [Display omitted] • New class of fluorinated α-aminophosphonates was synthesized diastereoselectively. • The cytotoxicity of these compounds was tested against seven types of cancer. • The mean values of IC 50 ranged from 8.71 μM for HeLa to 89.54 μM for MDA-MB-231. • Compound 2a strongly binds to the structure of urokinase-type plasminogen activator protein. • The synthesized compounds provide scaffold for development of new anticancer drugs. [ABSTRACT FROM AUTHOR]