Re-designing environmentally persistent pharmaceutical pollutant through programmed inactivation: The case of methotrexate. (November 2022)

• Record Type: Journal Article
• Authors: Espinosa, Anaïs; Rascol, Estelle; Abellán Flos, Marta; Skarbek, Charles; Lieben, Pascale; Bannerman, Eva; Martinez, Alba Diez; Pethe, Stéphanie; Benoit, Pierre; Nélieu, Sylvie; Labruère, Raphaël
• Is Part Of: Chemosphere. Volume 306(2022)
• Publication Date: 2022-11
• Subjects: Eco-design -- Pharmaceutical pollutants -- Photodegradation -- Retro catabolic drug design -- Structural identification; Pollution -- Periodicals; Pollution -- Physiological effect -- Periodicals; Environmental sciences -- Periodicals; Atmospheric chemistry -- Periodicals; 551.511
• DOI: 10.1016/j.chemosphere.2022.135616
• Languages: English
• ISSNs: 0045-6535

Abstract

Abstract: Environmental emission of pharmaceutical pollutants notably causes the contamination of aquatic ecosystems and drinking water. Typically, reduction of these pollutants in the environment is mostly managed by ameliorated wastewater treatments. Here, we report a method for the eco-design of drugs through the introduction within the molecular structure of a sensitive chemical group responsive to water treatments. The new drugs are thus programmed to fragment more easily and quickly than the original drugs. In this "retro catabolic drug design" strategy, methotrexate was used as drug model and an ether analog displaying a similar pharmacological profile was selected. Using photo-irradiation experiments at 254 nm, a representative drinking water treatment process, the identified transformation products were predominantly obtained from the expected molecular scission. Moreover, a faster kinetics of degradation was measured for the ether analog as compared to methotrexate and its transformation products were far less cytotoxic. Graphical abstract: Image 1 Highlights: The strategy of "retro catabolic drug design" is disclosed for the programmed/improved inactivation of drugs. The drug model is methotrexate and three analogs were synthesized. An ether analog displaying similar antitumor activity was selected and its better human metabolic stability was demonstrated. Using photo-irradiation, the identified transformation products were mostly obtained from the expected molecular scission. A faster kinetics of degradation was measured for the ether analog and its transformation products were less cytotoxic.