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

Abstract

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.

Keywords: Anticancer activity; Diastereoselective hydrophosphonylation; Fluorine; Molecular docking; Urokinase-type plasminogen activator; α-Aminophosphonates.