Distinction between 2′- and 3′-Phosphate Isomers of a Fluorescent NADPH Analogue Led to Strong Inhibition of Cancer Cells Migration

• Published in: Antioxidants Vol. 10; no. 5; p. 723
• Main Authors: Manuel, Raoul, Lima, Michelle de Souza, Dilly, Sébastien, Daunay, Sylvain, Abbe, Patricia, Pramil, Elodie, Solier, Stéphanie, Guillaumond, Fabienne, Tubiana, Sarah-Simha, Escargueil, Alexandre, Pêgas Henriques, João Antonio, Ferrand, Nathalie, Erdelmeier, Irène, Boucher, Jean-Luc, Bertho, Gildas, Agranat, Israel, Rocchi, Stéphane, Sabbah, Michèle, Slama Schwok, Anny
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01-05-2021; MDPI
• Subjects: Binding sites; Breast cancer; cancer cell migration; Catalysis; Cell adhesion & migration; Cell migration; Enzymes; fluorescence; in vivo imaging; Isomers; Life Sciences; Melanoma; molecular modeling; Multiple myeloma; NAD(P)H oxidase; NADPH oxidases; Nitric-oxide synthase; NO-synthases; Software; Solvents; Spectrum analysis; Tumor cells; France; United States > US; cancer cell migration; in vivo imaging; NADPH oxidases; fluorescence; molecular modeling; NO-synthases
• ISSN: 2076-3921; 2076-3921
• DOI: 10.3390/antiox10050723

Specific inhibition of NADPH oxidases (NOX) and NO-synthases (NOS), two enzymes associated with redox stress in tumor cells, has aroused great pharmacological interest. Here, we show how these enzymes distinguish between isomeric 2′- and 3′-phosphate derivatives, a difference used to improve the specificity of inhibition by isolated 2′- and 3′-phosphate isomers of our NADPH analogue NS1. Both isomers become fluorescent upon binding to their target proteins as observed by in vitro assay and in vivo imaging. The 2′-phosphate isomer of NS1 exerted more pronounced effects on NOS and NOX-dependent physiological responses than the 3′-phosphate isomer did. Docking and molecular dynamics simulations explain this specificity at the level of the NADPH site of NOX and NOS, where conserved arginine residues distinguished between the 2′-phosphate over the 3′-phosphate group, in favor of the 2′-phosphate.